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Manjunatha BS, Handge KT, Shah VS, Al-Thobaiti YE, Pateel DGS. Immunohistochemical expression of matrix metalloproteinase-9 and 13 in oral squamous cell carcinoma and their role in predicting lymph node metastasis. World J Methodol 2025; 15:94514. [DOI: 10.5662/wjm.v15.i2.94514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/23/2024] [Accepted: 10/20/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND One of the main characteristics of oral squamous cell carcinoma (OSCC) is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness. A primary feature of malignant tumors is their penetration of neighboring tissues, such as lymphatic and blood arteries, due to the tumor cells' capacity to break down the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM. MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions. MMP-13, a collagenase family member, is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens, whereas MMP-9 is thought to accelerate the growth of tumors. Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.
AIM To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.
METHODS A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study. The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control. All the observations were recorded and Pearson’s χ² test with Fisher exact test was used for statistical analysis.
RESULTS Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size. The majority of the patients were in advanced TNM stages (III and IV), and showed intense expression of MMP-9 and MMP-13.
CONCLUSION The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness. Intense expression of MMP-9 and MMP-13, irrespective of histological grade of OSCC, correlates well with TNM stage. Consequently, it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors. The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques, hence enhancing the prognosis of patients diagnosed with OSCC.
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Affiliation(s)
- Bhari Sharanesha Manjunatha
- Department of Basic Oral Medicine and Allied Dental Sciences, Taif University, At`Taif 26571, Makkah, Saudi Arabia
| | - Keshav T Handge
- Department of Oral and Maxillofacial Pathology, Dr. Vasantrao Pawar Medical College, Hospital and Research Centre, Nashik 423101, Maharashtra, India
| | - Vandana Sandeep Shah
- Department of Oral Pathology and Microbiology, KM Shah Dental College and Hospital, Sumandeep Vidyapeeth, Vadodara 391760, Gujarat, India
| | - Yasser Eid Al-Thobaiti
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, Al-Haweiah 26571 Makkah, Saudi Arabia
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Mohammad SI, Vasudevan A, Nadhim Mohammed S, Uthirapathy S, M M R, Kundlas M, Siva Prasad GV, Kumari M, Mustafa YF, Ali Hussein Z. Anti-metastatic potential of flavonoids for the treatment of cancers: focus on epithelial-mesenchymal transition (EMT) process. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04235-3. [PMID: 40434422 DOI: 10.1007/s00210-025-04235-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/26/2025] [Indexed: 05/29/2025]
Abstract
The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors.
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Affiliation(s)
- Suleiman Ibrahim Mohammad
- Electronic Marketing and Social Media, Economic and Administrative Sciences Zarqa University, Zarqa, Jordan
- INTI International University, 71800, Negeri Sembilan, Malaysia
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
- Shinawatra University, 99 Moo 10, Bangtoey, Samkhok, Pathum Thani, 12160, Thailand
| | - Sumaya Nadhim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Mayank Kundlas
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Zainab Ali Hussein
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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Mubarak MM, Baba IA, Wani ZA, Kantroo HA, Ahmad Z. Matrix metalloproteinase-9 (MMP-9): A macromolecular mediator in CNS infections: A review. Int J Biol Macromol 2025; 311:143902. [PMID: 40328391 DOI: 10.1016/j.ijbiomac.2025.143902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/21/2025] [Accepted: 05/01/2025] [Indexed: 05/08/2025]
Abstract
Matrix metalloproteinase-9 (MMP-9) is a macromolecular zinc-dependent endopeptidase that plays a critical role in the pathogenesis of Central Nervous System (CNS) infections by modulating extracellular matrix remodelling and blood-brain barrier (BBB) dynamics. This review elucidates the structural and functional properties of MMP-9, highlighting its distinct domain architecture that enables substrate specificity and regulatory mechanisms. MMP-9-mediated BBB disruption is a hallmark of bacterial, viral, fungal, and parasitic CNS infections, facilitating immune cell infiltration and pathogen entry while exacerbating neuroinflammation and tissue damage. Elevated MMP-9 levels in cerebrospinal fluid (CSF) correlate with disease severity, suggesting its potential as a diagnostic biomarker. Advances in therapeutic strategies targeting MMP-9, including small molecule inhibitors, monoclonal antibodies, and peptide-based therapies, demonstrate promising results in mitigating BBB disruption and neuroinflammation. This comprehensive review underscores the dual role of MMP-9 as both a biomarker and therapeutic target, advocating for its inclusion in adjunctive treatment regimens to improve outcomes in CNS infections. Future research should focus on refining MMP-9 inhibitors for clinical use, ensuring specificity, and minimizing off-target effects to harness its full therapeutic potential.
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Affiliation(s)
- Mohamad Mosa Mubarak
- Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar Srinagar, J&K 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ishfaq Ahmad Baba
- Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar Srinagar, J&K 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Zubair Ahmad Wani
- Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar Srinagar, J&K 190005, India
| | - Hadiya Amin Kantroo
- Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar Srinagar, J&K 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Zahoor Ahmad
- Clinical Microbiology and PK-PD Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar Srinagar, J&K 190005, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Ng D, Cyr D, Khan S, Dossa F, Swallow C, Kazazian K. Molecular mechanisms of metastatic peritoneal dissemination in gastric adenocarcinoma. Cancer Metastasis Rev 2025; 44:50. [PMID: 40317360 PMCID: PMC12049340 DOI: 10.1007/s10555-025-10265-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
Peritoneal dissemination portends a dismal prognosis in patients with gastric adenocarcinoma in the context of limited effective treatments. The underlying cellular processes that drive gastric peritoneal carcinomatosis remain unclear, limiting the application of novel targeted therapies. In this comprehensive review, we aimed to identify and summarize all existing context-dependent molecular mechanisms that have been implicated in peritoneal dissemination and peritoneal carcinomatosis establishment from primary gastric adenocarcinoma. We applied a multilevel examination including data from in vivo murine models using human gastric cancer cell lines, in vitro technique-based studies, ex vivo models, and genomic/proteomic and molecular profiling analyses to report on various aspects of gastric cancer peritoneal metastasis biology. Mechanisms promoting peritoneal dissemination were grouped into three main functional categories: (1) intrinsic cancer cell biology, (2) cancer cell-peritoneal surface adhesion, and (3) peritoneal tumor microenvironment. We identified significant overlap among the three categories, indicating a complex interplay between multiple molecular mechanisms. By interrupting these pathways, peritoneal-directed therapies have the potential to improve quality and length of life in patients with high-risk primary gastric cancer.
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Affiliation(s)
- Deanna Ng
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - David Cyr
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Shawn Khan
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Fahima Dossa
- Complex General Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carol Swallow
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Karineh Kazazian
- Department of Surgery, University of Toronto, Toronto, Canada.
- Department of Surgical Oncology, Toronto General Hospital, University Health Network, 200 Elizabeth Street, 10 Eaton North, Room 219, Toronto, M5G 2 C4, Canada.
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Gupta V, Rastogi P, Ajay S, Lal N, Verma UP, Singhal R, Pathak AK, Nigam N, Rastogi P. To evaluate the effect of oral zinc supplementation on salivary MMP-8 levels in periodontitis: A randomized, double-blind, placebo-controlled study. J Oral Biol Craniofac Res 2025; 15:493-499. [PMID: 40144642 PMCID: PMC11932852 DOI: 10.1016/j.jobcr.2025.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/21/2025] [Accepted: 02/23/2025] [Indexed: 03/28/2025] Open
Abstract
Background and objective Zinc is an essential micronutrient that plays a crucial role in maintaining oral health. Periodontitis is a widespread oral disease characterized by inflammation and destruction of the gums and surrounding tissues. The objective of this study was to evaluate the effect of oral zinc supplementation as an adjunct to scaling and root planing in the treatment of periodontitis by evaluating its effects on clinical parameters and salivary MMP-8 level. Methods 42 patients were enrolled in the study from the periodontology OPD of a tertiary care hospital in India. The subjects were divided into two groups: group 1 and group 2 consisting of 21 patients each of moderate to severe periodontitis. Group 1 was given oral zinc supplementation along with scaling and root planing (SRP) and group 2 was given placebo tablet along with SRP for 1 month. Several periodontal parameters were assessed, including Papillary bleeding Index (BI), Gingival index (GI), Probing pocket depth (PPD) and Clinical attachment level (CAL) at baseline as well as at 1 month post treatment. Around 3 ml of whole unstimulated saliva was collected for MMP-8 estimation by ELISA method at baseline as well as at 1 month. Results The data was analyzed using SPSS version 26. All clinical parameters and MMP-8 level in saliva were comparable at baseline. 1 month after respective treatment modalities were performed in each group, it was found that all clinical parameters and salivary MMP-8 level showed significant differences with group 1 (zinc + SRP) showing highly significant decrease in GI, PPD and CAL (p < 0.01) and significant decrease in BI and salivary MMP-8 level when compared to group 2 (placebo + SRP) (p < 0.05). Conclusion When compared with scaling and root planing alone, the administration of oral zinc supplementation along with scaling and root planing showed greater reduction in clinical parameters and salivary MMP-8 levels in patients with moderate to severe periodontitis. Zinc has a positive effect in management of periodontitis and can serve as an easy, cost effective, harmless and beneficial adjunct in treatment of periodontitis.
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Affiliation(s)
- Vishakha Gupta
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Pavitra Rastogi
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Sadhna Ajay
- Department of Biochemistry, Autonomous State Medical College, 2nd Floor, Academic block, Jaunpur, U.P, 222001, India
| | - Nand Lal
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Umesh Pratap Verma
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Rameshwari Singhal
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Anjani Kumar Pathak
- Department of Periodontology, Faculty of Dental Science, King George Medical University, 5th Floor, New Dental Building, Lucknow, U.P, 226003, India
| | - Nitu Nigam
- Cytogenetics Lab, Center for Advanced Research, King George Medical University, Lucknow, U.P, 226003, India
| | - Paridhi Rastogi
- Babu Banarasi Das College of Dental Sciences, BBD City, Faizabad Road, Lucknow, U.P, 226028, India
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Li M, Deng T, Chen Q, Jiang S, Li H, Li J, You S, Xie HQ, Shen B. A versatile platform based on matrix metalloproteinase-sensitive peptides for novel diagnostic and therapeutic strategies in arthritis. Bioact Mater 2025; 47:100-120. [PMID: 39897588 PMCID: PMC11787566 DOI: 10.1016/j.bioactmat.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/11/2025] [Accepted: 01/12/2025] [Indexed: 02/04/2025] Open
Abstract
Matrix metalloproteinases (MMPs), coupled with other proteinases and glycanases, can degrade proteoglycans, collagens, and other extracellular matrix (ECM) components in inflammatory and non-inflammatory arthritis, making them important pathogenic molecules and ideal disease indicators and pharmaceutical intervention triggers. For MMP responsiveness, MMP-sensitive peptides (MSPs) are among the most easily synthesized and cost-effective substrates, with free terminal amine and/or carboxyl groups extensively employed in multiple designs. We hereby provide a comprehensive review over the mechanisms and advances in MSP applications for the management of arthritis. These applications include early and precise diagnosis of MMP activity via fluorescence probe technologies; acting as nanodrug carriers to enable on-demand drug release triggered by pathological microenvironments; and facilitating cartilage engineering through MMP-mediated degradation, which promotes cell migration, matrix synthesis, and tissue integration. Specifically, the ultra-sensitive MSP diagnostic probes could significantly advance the early diagnosis and detection of osteoarthritis (OA), while MSP-based drug carriers for rheumatoid arthritis (RA) can intelligently release anti-inflammatory drugs effectively during flare-ups, or even before symptoms manifest. The continuous progress in MSP development may acceleratedly lead to novel management regimens for arthropathy in the future.
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Affiliation(s)
- Mingyang Li
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tao Deng
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Quan Chen
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Shenghu Jiang
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hang Li
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiayi Li
- Department of Nephrology, The People's Hospital of Yubei District of Chongqing, Chongqing, China
| | - Shenglan You
- Animal Imaging Core Facilities, West China Hospital, Sichuan University, China
| | - Hui-qi Xie
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Stem Cell and Tissue Engineering Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Shen
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Alarcón‐Sánchez MA, Rodríguez‐Montaño R, Mosaddad SA, Heboyan A. Levels of IL-1β, MMP-8, and MMP-9 in the Saliva of Subjects With Periodontitis: A Systematic Review and Meta-Analysis. J Clin Lab Anal 2025; 39:e70040. [PMID: 40289477 PMCID: PMC12089797 DOI: 10.1002/jcla.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/23/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Proinflammatory cytokines and enzymes responsible for tissue destruction are important in the development of periodontitis. This study compared salivary concentrations of interleukin-1 beta (IL-1β), matrix metalloproteinases (MMP-8), and (MMP-9) in individuals with and without periodontitis to evaluate their diagnostic utility as potential biomarkers. MATERIALS AND METHODS A comprehensive search was performed across PubMed, Scopus, ScienceDirect, and Google Scholar, supplemented by manual searches in relevant journals up to January 2024. Eligibility criteria focused on human studies with defined diagnostic criteria for periodontitis and saliva samples analyzed for IL-1β, MMP-8, and MMP-9. Data were extracted to compare salivary levels of these markers between periodontitis patients and healthy controls. The Joanna Briggs Institute tool was used to evaluate the risk of bias and quality of the included studies. Statistical analysis employed a random effects model to calculate standardized mean differences and assess heterogeneity and publication bias. RESULTS The search yielded 122 articles, with 27 meeting the inclusion criteria. Fifteen percent of these studies presented a moderate risk of bias, while the remaining 85% exhibited a low risk of bias. The meta-analyses indicated significantly higher levels of IL-1β, MMP-8, and MMP-9 in the saliva of subjects with periodontitis compared to healthy individuals: IL-1β: Standardized Mean Difference (SMD) = 163.29 (95% CI = 104.64-221.95), p < 0.001; MMP-8: SMD = 282.22 (95% CI = 209.68-354.77), p < 0.001; MMP-9: SMD = 311.85 (95% CI = 179.64-444.05), p < 0.001. CONCLUSION Elevated salivary levels of IL-1β, MMP-8, and MMP-9 are linked to periodontitis.
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Affiliation(s)
- Mario Alberto Alarcón‐Sánchez
- Doctor of Science in Molecular Biology in Medicine Program, University Center of Health SciencesUniversity of Guadalajara (CUCS‐UdeG)GuadalajaraJaliscoMexico
- Institute of Research in Dentistry, Department of Integral Dental Clinics, University Center of Health SciencesUniversity of Guadalajara (CUCS‐UdeG)GuadalajaraJaliscoMexico
| | - Ruth Rodríguez‐Montaño
- Institute of Research in Dentistry, Department of Integral Dental Clinics, University Center of Health SciencesUniversity of Guadalajara (CUCS‐UdeG)GuadalajaraJaliscoMexico
- Department of Health and Illness as an Individual and Collective Process, University Center of TlajomulcoUniversity of Guadalajara (CUTLAJO‐UdeG)Tlajomulco de ZuñigaJaliscoMexico
| | - Seyed Ali Mosaddad
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical SciencesSaveetha UniversityChennaiIndia
- Department of Conservative Dentistry and Bucofacial Prosthesis, Faculty of OdontologyComplutense University of MadridMadridSpain
- Department of Prosthodontics, School of DentistryShiraz University of Medical SciencesShirazIran
| | - Artak Heboyan
- Department of Prosthodontics, Faculty of StomatologyYerevan State Medical University after Mkhitar HeratsiYerevanArmenia
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Navarro P, Castillo J, Jones J, García A, Caturla N. Skin Photoprotection and Anti-Aging Benefits of a Combination of Rosemary and Grapefruit Extracts: Evidence from In Vitro Models and Human Study. Int J Mol Sci 2025; 26:4001. [PMID: 40362239 PMCID: PMC12071866 DOI: 10.3390/ijms26094001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/14/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Skin exposure to ultraviolet radiation (UVR) causes oxidative stress, inflammation, and collagen degradation and can trigger erythema. While topical formulas protect the skin from UV damage, there is growing evidence that certain botanical ingredients taken orally may have an added benefit. This study evaluated the photoprotective, anti-photoaging, and anti-erythema efficacy of a combination of rosemary and grapefruit extract (Nutroxsun®). Radical oxygen species (ROS) generation and interleukin production were determined in UV-irradiated keratinocytes (HaCaT). Also, collagen and elastin secretion and metalloproteinase (MMP-1 and MMP-3) content were assessed in UV-irradiated fibroblasts (NHDFs). Furthermore, a placebo-controlled, randomized, crossover study was conducted in 20 subjects (phototypes I to III) receiving two doses, 100 and 200 mg, of the ingredient. Skin redness (a* value, CIELab) after exposure to one minimal erythemal dose of UVR was assessed. As a result, the botanical blend significantly attenuated the UVR-induced reductions of procollagen I and elastin and lowered MMP-1 and MMP-3 protein secretion. Also, a reduction in ROS and proinflammatory interleukins (IL-1, IL-8, and IL-6) was observed. Finally, the botanical blend, at both doses, significantly reduced UV-induced erythema reaction from the first day of intake and accelerated recovery. These findings reinforce the potential of this ingredient as an effective dietary solution to protect the skin against UV-induced damage.
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Affiliation(s)
- Pau Navarro
- Research and Development Department, Monteloeder SL, Miguel Servet 16, 03203 Elche, Spain; (P.N.); (J.J.); (A.G.)
| | - Julián Castillo
- Food Technology & Nutritional Department, Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jerónimos, Carretera Guadalupe, 30107 Murcia, Spain;
| | - Jonathan Jones
- Research and Development Department, Monteloeder SL, Miguel Servet 16, 03203 Elche, Spain; (P.N.); (J.J.); (A.G.)
| | - Adrián García
- Research and Development Department, Monteloeder SL, Miguel Servet 16, 03203 Elche, Spain; (P.N.); (J.J.); (A.G.)
| | - Nuria Caturla
- Research and Development Department, Monteloeder SL, Miguel Servet 16, 03203 Elche, Spain; (P.N.); (J.J.); (A.G.)
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Yang Q, Kaw HY, Yu J, Ma X, Yang K, Zhu L, Wang W. Basic Nitrogenous Heterocyclic Rings at the 7-Position of Fluoroquinolones Foster Their Induction of Antibiotic Resistance in Escherichia coli. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:6787-6798. [PMID: 40116633 DOI: 10.1021/acs.est.4c11346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
The extensive prescription of fluoroquinolone antibiotics has resulted in their ubiquitous presence in the environment, fueling the ongoing development of antibiotic resistance. Besides antibiotics, fluoroquinolone production intermediates, an overlooked category of pollutants that oftentimes possess the intact fluoroquinolone core structure, may also contribute to this public health crisis. To assess their relative potency and collectively examine the structural effects of fluoroquinolones on resistance development, wild-type Escherichia coli K12 was exposed to ten fluoroquinolone antibiotics and five intermediates at their environmentally relevant concentrations for 30 days. Phenotypic resistance alterations revealed that the absence of the C7 ring system in fluoroquinolones significantly impaired their capacity to induce resistance in E. coli, potentially due to diminished oxidative DNA damage and gyrase-mediated dsDNA breaks. Genetic and transcriptional analyses indicated that a uniform resistance mechanism emerged under both antibiotic and intermediate stress. Quantitative structure-activity relationship (QSAR) analysis further emphasized the positive impact of both basic nitrogenous heterocyclic rings at C7 (particularly the hydrogen-bond-donor pharmacophores) and aromatic rings at N1 in promoting resistance development, while highlighting the adverse effects of hydrophobic and hydrogen-bond-donor groups at N1. A robust QSAR model was developed and applied to assess the relative risks of other 105 fluoroquinolones. This study underscored the direct role of fluoroquinolone production intermediates in promoting environmental antibiotic resistance and illustrated how different structural features of fluoroquinolone pollutants will influence this process, offering theoretical insights for future antibiotic design and environmental regulation efforts.
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Affiliation(s)
- Qi Yang
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Han Yeong Kaw
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Jing Yu
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Xuejing Ma
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Kun Yang
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Lizhong Zhu
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
| | - Wei Wang
- State Key Laboratory of Soil Pollution Control and Safety, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
- Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang Province 310058, China
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10
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Li X, Xu Z. Applications of Matrix Metalloproteinase-9-Related Nanomedicines in Tumors and Vascular Diseases. Pharmaceutics 2025; 17:479. [PMID: 40284474 PMCID: PMC12030376 DOI: 10.3390/pharmaceutics17040479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/25/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is implicated in tumor progression and vascular diseases, contributing to angiogenesis, metastasis, and extracellular matrix degradation. This review comprehensively examines the relationship between MMP-9 and these pathologies, exploring the underlying molecular mechanisms and signaling pathways involved. Specifically, we discuss the contribution of MMP-9 to tumor epithelial-mesenchymal transition, angiogenesis, and metastasis, as well as its involvement in a spectrum of vascular diseases, including macrovascular, cerebrovascular, and ocular vascular diseases. This review focuses on recent advances in MMP-9-targeted nanomedicine strategies, highlighting the design and application of responsive nanoparticles for enhanced drug delivery. These nanotherapeutic strategies leverage MMP-9 overexpression to achieve targeted drug release, improved tumor penetration, and reduced systemic toxicity. We explore various nanoparticle platforms, such as liposomes and polymer nanoparticles, and discuss their mechanisms of action, including degradation, drug release, and targeting specificity. Finally, we address the challenges posed by the heterogeneity of MMP-9 expression and their implications for personalized therapies. Ultimately, this review underscores the diagnostic and therapeutic potential of MMP-9-targeted nanomedicines against tumors and vascular diseases.
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Affiliation(s)
| | - Zhuping Xu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China;
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11
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Rostom MM, Rashwan AA, Sotiropoulou CD, Hozayen SZ, Abdelhamid AM, Abdelhalim MM, Eltahtawy O, Emara HM, Elemam NM, Kontos CK, Youness RA. MIAT: A pivotal oncogenic long noncoding RNA tunning the hallmarks of solid malignancies. Transl Oncol 2025; 54:102329. [PMID: 40014977 PMCID: PMC11910686 DOI: 10.1016/j.tranon.2025.102329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/06/2025] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Long non-coding RNAs (LncRNAs) have emerged as intriguing players in cellular regulation, challenging the traditional view of non-coding RNAs as mere "dark genome". Non-coding DNA makes up most of the human genome and plays a pivotal role in cancer development. These RNA molecules, which do not code for proteins, have captivated researchers with their diverse and crucial roles in gene regulation, chromatin dynamics, and other cellular processes. In several physiological and pathological circumstances, lncRNAs serve critical functions. This review will tackle the complex function of the lncRNA myocardial infarction-associated transcript (MIAT) in various solid malignancies. A special emphasis would be directed on the correlation between cancer patients' clinicopathological features and the expression profile of MIAT. MIAT is a oncogenic regulator in many malignant tumors, where it can control the growth, invasion, metastasis, and resistance to death of cells. As a result, MIAT is thought to be a possible biomarker and therapeutic target for cancer patients. The biological functions, mechanisms and potential clinical implications of MIAT during carcinogenesis and finally the current possible therapeutic approaches targeting MIAT are also outlined in this review.
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Affiliation(s)
- Monica M Rostom
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt
| | - Alaa A Rashwan
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo (AUC), 11835, Cairo, Egypt
| | - Christina D Sotiropoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701, Athens, Greece
| | - Sama Z Hozayen
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | | | - Miriam Mokhtar Abdelhalim
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | - Omar Eltahtawy
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | - Hadir M Emara
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt; Department of Nanotechnology, School of Sciences and Engineering, The American University in Cairo (AUC), 11835, Cairo, Egypt
| | - Noha M Elemam
- Clinical Sciences Department, College of Medicine, University of Sharjah, 27272, Sharjah, UAE; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, UAE
| | - Christos K Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701, Athens, Greece
| | - Rana A Youness
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt.
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12
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Lee CI, Lee YJ, Lee TH, Lee CY, Tsao HM, Cheng EH, Huang CC, Yang SF, Lee MS. TIMP2 rs2277698 polymorphism associated with adverse IVF outcomes in Han Chinese women. Front Endocrinol (Lausanne) 2025; 16:1542534. [PMID: 40151207 PMCID: PMC11948279 DOI: 10.3389/fendo.2025.1542534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/19/2025] [Indexed: 03/29/2025] Open
Abstract
Background Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are critical regulators of extracellular matrix (ECM) proteolysis and play a pivotal role in trophoblast invasion during embryo implantation. This study aimed to investigate the effects of single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes on clinical outcomes in women undergoing in vitro fertilization (IVF). Methods This retroprospective study included 1014 women undergoing their first fresh IVF cycle without donor eggs at Lee Women's Hospital between January 2014 and December 2015. Peripheral blood samples were collected from all participants for DNA extraction and SNP genotyping using real-time polymerase chain reaction. The study focused on three SNPs: TIMP1 (rs4898 C/T), TIMP2 (rs2277698 C/T), and MMP2 (rs243865 C/T). Associations between these SNPs and IVF outcomes, including clinical pregnancy, embryo implantation, abortion, and live birth rates, were analyzed. Results Among 560 patients analyzed, no significant differences were observed in baseline characteristics between the live birth and non-live birth groups. However, the minor alleles (CT+TT) of MMP2 (rs243865) and TIMP2 (rs2277698) were significantly more frequent in the non-live birth group (MMP2: 24.4% vs. 17.7%, p = 0.044; TIMP2: 48.1% vs. 34.4%, p = 0.001). In contrast, no significant differences in the genotype distribution of TIMP1 (rs4898) were noted between the groups. Logistic regression analysis identified the minor T allele of TIMP2 as a significant predictor of non-live birth (adjusted odds ratio: 1.725; 95% CI: 1.217-2.445; p = 0.002). Combined genotypes of MMP2/TIMP2, such as CC/CT+TT and CT+TT/CT+TT, were associated with an increased risk of non-live birth, even after adjusting for covariates. Conclusions The study demonstrates that the minor T allele of TIMP2 (rs2277698 C/T) is associated with poor IVF outcomes, particularly non-live birth. This finding highlights the potential role of genetic variations in TIMP2 in influencing clinical outcomes of IVF. Further research is warranted to elucidate the underlying mechanisms in larger and more diverse populations.
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Affiliation(s)
- Chun-I. Lee
- Division of Infertility, Lee Women’s Hospital, Taichung, Taiwan
- Department of Obstetrics and Gynecology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Jen Lee
- Genetic Diagnosis Laboratory, Lee Women’s Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Tsung-Hsien Lee
- Division of Infertility, Lee Women’s Hospital, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan
| | - Chi-Ying Lee
- Genetic Diagnosis Laboratory, Lee Women’s Hospital, Taichung, Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Hui-Mei Tsao
- Genetic Diagnosis Laboratory, Lee Women’s Hospital, Taichung, Taiwan
| | - En-Hui Cheng
- Genetic Diagnosis Laboratory, Lee Women’s Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Chia Huang
- Division of Infertility, Lee Women’s Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan
| | - Maw-Sheng Lee
- Division of Infertility, Lee Women’s Hospital, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan
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13
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Li G, Wang M, Luo L, Tang D, Xu N, Huang R, Yang Y, Chen G, Liu Z, Wang H, Huang X. Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance. Eur J Med Chem 2025; 285:117249. [PMID: 39823807 DOI: 10.1016/j.ejmech.2025.117249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/27/2024] [Accepted: 01/05/2025] [Indexed: 01/20/2025]
Abstract
Nowadays, hybrid molecule with dual targets activity or effect is regarded as an effective strategy for combating the drug resistance development in cancer therapy. Herein, novel of bifunctional conjugates targeting tubulin and MMPs inhibitors were synthesized. Among them, 15j exhibited robust anticancer activity in vitro and in vivo, with IC50 values of 0.154-0.296 μM against four human cancer cells and a 74.7 % (@20 mg/kg) tumor growth inhibition in vivo without obvious systemic toxicity. Mechanistic studies indicated that 15j exerted inhibitory effects on both tubulin polymerization, MMP-2 and MMP-9 activity. Moreover, 15j remarkably inhibited cell proliferation, migration and invasion, and accordingly disrupted the NF-κB signaling transduction. Furthermore, 15j effectively initiated mitochondria-dependent apoptotic pathway by causing mitochondrial dysfunction, promoting the accumulation of reactive oxygen species, and inducing DNA damage. Collectively, these results demonstrated that 15j, as a tubulin/MMPs dual-targeting inhibitor, has exhibited significant potential for the lung cancer therapy.
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Affiliation(s)
- Guimei Li
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China
| | - Meng Wang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China; National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China
| | - Li Luo
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China
| | - Demin Tang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China
| | - Nan Xu
- National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China
| | - Rizhen Huang
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China
| | - Yong Yang
- National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China
| | - Guiping Chen
- National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China
| | - Zhikun Liu
- National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China.
| | - Hengshan Wang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China.
| | - Xiaochao Huang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China; National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China.
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14
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Wang W, Lu Y, Qin GM, Ni LF, Xu BX, Liu CF, Yu BF, Wang HL, Pang M. LncRNA RP11-297P16.4 Promotes the Invasion and Metastasis of Non-Small-Cell Lung Carcinoma by Targeting the miR-145-5p/MMP-2/9 Axis. Biomedicines 2025; 13:617. [PMID: 40149594 PMCID: PMC11940468 DOI: 10.3390/biomedicines13030617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/25/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Long noncoding RNAs (lncRNAs) participate in the occurrence and development of non-small-cell lung carcinoma (NSCLC). But for certain lncRNAs, their effects on NSCLC remain unclear. This work discovered that lncRNA RP11-297P16.4 is elevated in NSCLC. Methods: LncRNA RP11-297P16.4 expression within LUAD tissues and cells was measured through RT-qPCR and Western blot. To assess the role of the lncRNA RP11-297P16.4 in NSCLC, gain- or loss-of-function experiments were conducted using an NSCLC mouse tumor model. Results: Silencing of the lncRNA RP11-297P16.4 inhibited the NSCLC cell line invasion and migration potential, but re-expression of the lncRNA RP11-297P16.4 had the opposite effect. A luciferase reporter confirmed that the lncRNA RP11-297P16.4 functions as a competitive endogenous RNA (ceRNA) through the sponge of miR-145-5p. The expression of lncRNA RP11-297P16.4 was negatively correlated to the level of miR-145-5p in NSCLC cells, which sponged miR-145-5p and suppressed tumor cell migration and invasion by targeting matrix metalloproteinase 2 (MMP-2) and MMP-9. Conclusions: Our findings suggested that the lncRNA RP11-297P16.4/miR-145-5p/MMP-2/9 regulatory axis is the key pathway for mediating the migration and invasion of NSCLC.
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Affiliation(s)
- Wei Wang
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Yu Lu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Guang-Mei Qin
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Lin-Feng Ni
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Bai-Xue Xu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Chao-Feng Liu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Bao-Feng Yu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Hai-Long Wang
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Min Pang
- NHC Key Laboratory of Pneumoconiosis, Shanxi Province Key Laboratory of Respiratory Disease, Department of Pulmonary and Critical Care Medicine, The First Hospital, Shanxi Medical University, Taiyuan 030001, China
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15
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Welhaven HD, Welfley AH, Brahmachary PP, Smith DF, Bothner B, June RK. Tissue-specific and spatially dependent metabolic signatures perturbed by injury in skeletally mature male and female mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.09.30.615873. [PMID: 39975211 PMCID: PMC11838485 DOI: 10.1101/2024.09.30.615873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Joint injury is a risk factor for post-traumatic osteoarthritis. However, metabolic and microarchitectural changes within the joint post-injury in both sexes remain unexplored. This study identified tissue-specific and spatially-dependent metabolic signatures in male and female mice using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and LC-MS metabolomics. Male and female C57Bl/6J mice were subjected to non-invasive joint injury. Eight days post-injury, serum, synovial fluid, and whole joints were collected for metabolomics. Analyses compared between injured, contralateral, and naïve mice, revealing local and systemic responses. Data indicate sex influences metabolic profiles across all tissues, particularly amino acid, purine, and pyrimidine metabolism. MALDI-MSI generated 2D ion images of bone, the joint interface, and bone marrow, highlighting increased lipid species in injured limbs, suggesting physiological changes across injured joints at metabolic and spatial levels. Together, these findings reveal significant metabolic changes after injury, with notable sex differences.
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Affiliation(s)
- Hope D. Welhaven
- Department of Chemistry & Biochemistry, Montana State University, Bozeman MT
| | - Avery H. Welfley
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman MT
| | | | - Donald F. Smith
- Department of Chemistry & Biochemistry, Montana State University, Bozeman MT
| | - Brian Bothner
- Department of Chemistry & Biochemistry, Montana State University, Bozeman MT
| | - Ronald K. June
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman MT
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Dorjay Tamang JS, Banerjee S, Baidya SK, Das S, Ghosh B, Jha T, Adhikari N. An overview of matrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies. Eur J Med Chem 2025; 283:117154. [PMID: 39709794 DOI: 10.1016/j.ejmech.2024.117154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/08/2024] [Accepted: 12/06/2024] [Indexed: 12/24/2024]
Abstract
Matrix metalloproteases (MMPs) are the proteolytic enzymes accountable for extracellular matrix (ECM) modification through their Zn2+-dependent catalytic activity. Among these, MMP-12 is one of the crucial MMPs that contributes to various disease states including different types of cancers and other major pathophysiological conditions including COPD, asthma, emphysema, skin diseases, arthritis, vascular diseases, and neurological disorders. The majority of the MMP-12 inhibitors should have three constitutional pharmacophoric features (i.e., a hydrophobic group to occupy the S1' pocket, a zinc-binding motif for chelating to the catalytic Zn2+ ion present at the catalytic site, and a flexible and hydrogen bond forming linker region between the S1' pocket substituent and the zinc chelating group for interacting with the catalytic and Ω-loop amino acid residues). This review mainly focuses on the various roles of MMP-12 in different diseases along with the structural comparison with other MMPs as well as promising and MMP-12-selective inhibitors and molecular modeling studies performed on MMP-12 inhibitors. Therefore, this review will provide comprehensive information to the researchers for designing effective and MMP-12-selective inhibitors for therapeutic advancement in the future.
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Affiliation(s)
- Jigme Sangay Dorjay Tamang
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Sandip Kumar Baidya
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Sanjib Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
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17
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Wang L, Nakamura A. Where are we in targeting hypoxia-induced pathways in inflammatory arthritis? Current understanding, insights, and future directions. Int Immunopharmacol 2025; 146:113883. [PMID: 39718060 DOI: 10.1016/j.intimp.2024.113883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/30/2024] [Accepted: 12/15/2024] [Indexed: 12/25/2024]
Abstract
INTRODUCTION Joint tissues affected by inflammatory arthritis (IA) create hypoxic microenvironments that sustain the inflammatory response. Although targeting molecules in hypoxia-induced pathways has provided valuable insights into potential novel therapies for various types of IA, progress remains preclinical, and no clinical trials have been conducted for IA. METHODS A literature search was conducted to create a narrative review exploring the role of hypoxia and its signaling pathways in IA pathogenesis, as well as the potential and future directions for IA therapies that target hypoxia-induced molecules before moving forward to clinical applications. RESULTS Hypoxia is a prevalent feature of the IA synovial microenvironment and contributes to disease progression. Various studies and preclinical models demonstrate how hypoxia-inducible factors, vascular endothelial growth factors, and matrix metalloproteinases, among other molecules, influence rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Despite these findings, drug development targeting these molecules in IA has been limited due to challenges in delineating the mechanistic pathways of hypoxia, the distinct roles of hypoxia-induced molecules depending on anatomical sites, and concerns regarding pharmacokinetics and patient safety. However, given that hypoxia-induced molecule-targeting therapies have been successfully approved for treating cancers and cardiovascular diseases, further research is needed to advance the application of similar medications in IA. CONCLUSIONS Given the pathogenic effects of hypoxic microenvironments in IA, it is imperative to continue gathering compelling evidence to advance hypoxia-induced therapies. Furthermore, elucidating the safety and efficacy of such drugs in various preclinical models, in collaboration with chemists and the pharmaceutical industry, is crucial for accelerating the development of novel, optimized treatment methods.
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Affiliation(s)
- Lisa Wang
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Faculty of Health Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada.
| | - Akihiro Nakamura
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Faculty of Health Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada; Translational Institute of Medicine, Department of Medicine, Queen's University, Ontario, Canada; Rheumatology Clinic, Kingston Health Science Centre, Kingston, Ontario, Canada.
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18
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Nie H, Huang ZS, Liu G, Li TS. Diabetes-induced alteration of metal ion levels declines the activity of MMPs to decrease aortic aneurysm risk. Life Sci 2025; 360:123243. [PMID: 39549935 DOI: 10.1016/j.lfs.2024.123243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/03/2024] [Accepted: 11/11/2024] [Indexed: 11/18/2024]
Abstract
AIMS Diabetes mellitus (DM) links the risk of cardiovascular diseases. Inverse to the enhanced expression of matrix metalloproteinases (MMPs), the development of aortic aneurysm is lower in diabetic population. We examined the hypothesis that DM-induced alteration of metal ion levels declines the activity of MMPs to decrease aortic aneurysm risk. METHODS & RESULTS By culturing vascular smooth muscle cells (VSMCs) or macrophages with different concentrations of glucose in the medium, we confirmed that high glucose significantly increased the expression of fibronectin and CTGF in VSMCs, and induced MMP2 expression and MMP9 secretion in macrophages. We also established an abdominal aortic aneurysm model in streptozotocin-induced diabetic mice and evaluated aneurysm development six weeks later. Compared to the healthy controls, diabetic mice had significantly lower levels of Zn2+ and Mg2+ in serum and developed significantly smaller sizes of aneurysms with higher expression of fibronectin and CTGF; but dietary zinc supplementation to diabetic mice effectively neutralized these differences. Gelatin zymography assay indicated that the enzymatic digestion activity of MMP2 was changed under different concentrations of ZnSO4 and MgSO4. Clinical data analysis also confirmed that DM, serum Zn2+ level, and aortic aneurysm risk closely correlated with each other. CONCLUSION It seems that DM-induced alteration of metal ion levels declines the activity of MMPs to negate aortic aneurysm development. Our data provide novel mechanistical insight and therapeutic strategy for aortic aneurysms.
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Affiliation(s)
- Han Nie
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; Department of Stem Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Zi-Sheng Huang
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Geng Liu
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; Department of Stem Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; Department of Stem Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
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19
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Reddy RA, Varshini MS, Kumar RS. Matrix Metalloproteinase-2 (MMP-2): As an Essential Factor in Cancer Progression. Recent Pat Anticancer Drug Discov 2025; 20:26-44. [PMID: 37861020 PMCID: PMC11826896 DOI: 10.2174/0115748928251754230922095544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/21/2023] [Accepted: 08/24/2023] [Indexed: 10/21/2023]
Abstract
The development of cancer has been a multistep process involving mutation, proliferation, survival, invasion, and metastasis. Of all the characteristics of cancer, metastasis is believed to be the hallmark as it is responsible for the highest number of cancer-related deaths. In connection with this, Matrix metalloproteinases (MMPs), that has a role in metastasis, are one of the novel therapeutic targets. MMPs belong to the family of zinc-dependent endopeptidases and are capable of degrading the components of the extracellular matrix (ECM). The role of MMPs in ECM remodeling includes tissue morphogenesis, uterine cycling, growth, tissue repair, and angiogenesis. During pathological conditions, MMPs play a critical role in the excessive degradation of ECM which includes arthritis, tumour invasion, tumour metastasis, and several other autoimmune disorders. Moreover, they are believed to be involved in many physiological aspects of the cell, such as proliferation, migration, differentiation, angiogenesis, and apoptosis. It is reported that dysregulation of MMP in a variety of cancer subtypes have a dual role in tumour growth and metastasis processes. Further, multiple studies suggest the therapeutic potential of targeting MMP in invading cancer. The expression of MMP-2 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-2 may be a potential treatment strategy for different diseases, including cancers. Hence, the present review discusses the therapeutic potential of targeting MMP in various types of cancers and their recent patents.
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20
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Hulahan TS, Angel PM. From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment. J Exp Clin Cancer Res 2024; 43:329. [PMID: 39716322 DOI: 10.1186/s13046-024-03236-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/19/2024] [Indexed: 12/25/2024] Open
Abstract
Ductal carcinoma in situ (DCIS) is a noninvasive breast disease that variably progresses to invasive breast cancer (IBC). Given the unpredictability of this progression, most DCIS patients are aggressively managed similar to IBC patients. Undoubtedly, this treatment paradigm places many DCIS patients at risk of overtreatment and its significant consequences. Historically, prognostic modeling has included the assessment of clinicopathological features and genomic markers. Although these provide valuable insights into tumor biology, they remain insufficient to predict which DCIS patients will progress to IBC. Contemporary work has begun to focus on the microenvironment surrounding the ductal cells for molecular patterns that might predict progression. In this review, extracellular microenvironment alterations occurring with the malignant transformation from DCIS to IBC are detailed. Not only do changes in collagen abundance, organization, and localization mediate the transition to IBC, but also the discrete post-translational regulation of collagen fibers is understood to promote invasion. Other extracellular matrix proteins, such as matrix metalloproteases, decorin, and tenascin C, have been characterized for their role in invasive transformation and further demonstrate the prognostic value of the extracellular matrix. Importantly, these extracellular matrix proteins influence immune cells and fibroblasts toward pro-tumorigenic phenotypes. Thus, the progressive changes in the extracellular microenvironment play a key role in invasion and provide promise for prognostic development.
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Affiliation(s)
- Taylor S Hulahan
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Peggi M Angel
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
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21
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Wang L, Yang H, Zhang C, Zhang Y, He Y, Liu Y, Ma P, Li J, Fan Z. A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes. Int J Oral Sci 2024; 16:65. [PMID: 39616150 PMCID: PMC11608271 DOI: 10.1038/s41368-024-00328-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 10/05/2024] [Accepted: 10/17/2024] [Indexed: 04/12/2025] Open
Abstract
Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
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Affiliation(s)
- Lingxiao Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory for Tooth Regeneration and Function Reconstruction of Oral Tissues, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Haoqing Yang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory for Tooth Regeneration and Function Reconstruction of Oral Tissues, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Chen Zhang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory for Tooth Regeneration and Function Reconstruction of Oral Tissues, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Yue Zhang
- Department of Periodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Yilin He
- Department of Dental Implant Center, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Yang Liu
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory for Tooth Regeneration and Function Reconstruction of Oral Tissues, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Pan Ma
- Department of Dental Implant Center, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Jun Li
- Department of Dental Implant Center, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory for Tooth Regeneration and Function Reconstruction of Oral Tissues, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
- Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
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22
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Wang L, Yang H, Zhang C, Zhang Y, He Y, Liu Y, Ma P, Li J, Fan Z. A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes. Int J Oral Sci 2024; 16:65. [DOI: 3.doi: 10.1038/s41368-024-00328-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 10/05/2024] [Accepted: 10/17/2024] [Indexed: 05/19/2025] Open
Abstract
AbstractBlood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
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23
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Stepanenko OV, Sulatsky MI, Mikhailova EV, Stepanenko OV, Sulatskaya AI. Degradation of pathogenic amyloids induced by matrix metalloproteinase-9. Int J Biol Macromol 2024; 281:136362. [PMID: 39395518 DOI: 10.1016/j.ijbiomac.2024.136362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/27/2024] [Accepted: 10/04/2024] [Indexed: 10/14/2024]
Abstract
Over the past decade, the greatest promise for treating severe and currently incurable systemic and neurodegenerative diseases has turned to agents capable of effectively degrading pathological amyloid deposits without causing side effects. Specifically, amyloid destruction observed in immunotherapy is hypothesized to occur through activation of proteolytic enzymes. This study examines poorly understood effects of an immune enzyme, extracellular matrix metalloproteinase-9 (MMP9), on amyloids associated with Alzheimer's and Parkinson's diseases, lysozyme, insulin, and dialysis-related amyloidoses. The study establishes the universality of MMP9's effect on various amyloids, with its efficacy largely depending on the fibrillar cluster size. Irreversible amyloid degradation by MMP9 is attributed to the destruction of intramolecular interactions rather than intermolecular hydrogen bonds in the fibril backbone. This process results in the loss of ordered fiber structure without reducing aggregate size or increasing cytotoxicity. Thus, MMP9 can mitigate side effects of anti-amyloid therapy associated with the formation of low-molecular-weight degradation products that may accelerate fibrillogenesis and amyloid propagation between tissues and organs. MMP9 shows promise as a component of safe anti-amyloid drugs by enhancing the accessibility of binding sites through "loosening" amyloid clusters, which facilitates subsequent fragmentation and monomerization by other enzymes.
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Affiliation(s)
- Olga V Stepanenko
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
| | - Maksim I Sulatsky
- Laboratory of Cell Morphology, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
| | - Ekaterina V Mikhailova
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
| | - Olesya V Stepanenko
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
| | - Anna I Sulatskaya
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
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24
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Pandey R, Gupta N, Jha T, Manzoor TBE. Association of matrix metalloproteinases (MMPs) gene polymorphisms with periodontitis: a systematic review. GMS HYGIENE AND INFECTION CONTROL 2024; 19:Doc53. [PMID: 39553301 PMCID: PMC11565592 DOI: 10.3205/dgkh000508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Matrix metalloproteinases (MMPs) are proteinases released by gingival cells, macrophages and neutrophils, induced by potentially pathogenic periodontal bacteria of the subgingival plaque, which play a critical role in the pathogenesis of periodontal disease. The expression of MMPs is controlled by chromosome 11. Single nucleotide polymorphisms (SNPs) are linked with variations in the secretion of MMPs, resulting in periodontal disease progression. Genetic studies aim to find the markers for early diagnosis and prevention of the related diseases. This systematic review focuses on finding the association between the MMPs and periodontitis among Indians. A literature review was performed, including studies published between January 1st 2012 and May 2024 were incorporated. This systematic review included 1,046 participants in seven Indian studies, and substantial evidence was found for an association between MMP-9 (-1562C/T) and periodontitis in Indian population.
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Affiliation(s)
- Ruchi Pandey
- Department of Periodontology, Manav Rachna Dental College, School of Dental Sciences, MRIIRS, Faridabad, Haryana, India
| | - Nandini Gupta
- Undergraduate student Manav Rachna Dental College, School of Dental Sciences, MRIIRS, Faridabad, Haryana, India
| | - Tripti Jha
- Undergraduate student Manav Rachna Dental College, School of Dental Sciences, MRIIRS, Faridabad, Haryana, India
| | - Tooba Bint E Manzoor
- Undergraduate student Manav Rachna Dental College, School of Dental Sciences, MRIIRS, Faridabad, Haryana, India
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25
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Hartley B, Bassiouni W, Roczkowsky A, Fahlman R, Schulz R, Julien O. N-Terminomic Identification of Intracellular MMP-2 Substrates in Cardiac Tissue. J Proteome Res 2024; 23:4188-4202. [PMID: 38647137 PMCID: PMC11460328 DOI: 10.1021/acs.jproteome.3c00755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 04/25/2024]
Abstract
Proteases are enzymes that induce irreversible post-translational modifications by hydrolyzing amide bonds in proteins. One of these proteases is matrix metalloproteinase-2 (MMP-2), which has been shown to modulate extracellular matrix remodeling and intracellular proteolysis during myocardial injury. However, the substrates of MMP-2 in heart tissue are limited, and lesser known are the cleavage sites. Here, we used degradomics to investigate the substrates of intracellular MMP-2 in rat ventricular extracts. First, we designed a novel, constitutively active MMP-2 fusion protein (MMP-2-Fc) that we expressed and purified from mammalian cells. Using this protease, we proteolyzed ventricular extracts and used subtiligase-mediated N-terminomic labeling which identified 95 putative MMP-2-Fc proteolytic cleavage sites using mass spectrometry. The intracellular MMP-2 cleavage sites identified in heart tissue extracts were enriched for proteins primarily involved in metabolism, as well as the breakdown of fatty acids and amino acids. We further characterized the cleavage of three of these MMP-2-Fc substrates based on the gene ontology analysis. We first characterized the cleavage of sarco/endoplasmic reticulum calcium ATPase (SERCA2a), a known MMP-2 substrate in myocardial injury. We then characterized the cleavage of malate dehydrogenase (MDHM) and phosphoglycerate kinase 1 (PGK1), representing new cardiac tissue substrates. Our findings provide insights into the intracellular substrates of MMP-2 in cardiac cells, suggesting that MMP-2 activation plays a role in cardiac metabolism.
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Affiliation(s)
- Bridgette Hartley
- Department
of Biochemistry, University of Alberta, Edmonton T6G 2H7, Canada
| | - Wesam Bassiouni
- Department
of Pharmacology, University of Alberta, Edmonton T6G 2S2, Canada
| | - Andrej Roczkowsky
- Department
of Pharmacology, University of Alberta, Edmonton T6G 2S2, Canada
| | - Richard Fahlman
- Department
of Biochemistry, University of Alberta, Edmonton T6G 2H7, Canada
| | - Richard Schulz
- Department
of Pharmacology, University of Alberta, Edmonton T6G 2S2, Canada
- Department
of Pediatrics, University of Alberta, Edmonton T6G 2S2, Canada
| | - Olivier Julien
- Department
of Biochemistry, University of Alberta, Edmonton T6G 2H7, Canada
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26
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Ma B, Shi J, Zhang Y, Li Z, Yong H, Zhou YN, Liu S, A S, Zhou D. Enzymatically Activatable Polymers for Disease Diagnosis and Treatment. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2306358. [PMID: 37992728 DOI: 10.1002/adma.202306358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/03/2023] [Indexed: 11/24/2023]
Abstract
The irregular expression or activity of enzymes in the human body leads to various pathological disorders and can therefore be used as an intrinsic trigger for more precise identification of disease foci and controlled release of diagnostics and therapeutics, leading to improved diagnostic accuracy, sensitivity, and therapeutic efficacy while reducing systemic toxicity. Advanced synthesis strategies enable the preparation of polymers with enzymatically activatable skeletons or side chains, while understanding enzymatically responsive mechanisms promotes rational incorporation of activatable units and predictions of the release profile of diagnostics and therapeutics, ultimately leading to promising applications in disease diagnosis and treatment with superior biocompatibility and efficiency. By overcoming the challenges, new opportunities will emerge to inspire researchers to develop more efficient, safer, and clinically reliable enzymatically activatable polymeric carriers as well as prodrugs.
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Affiliation(s)
- Bin Ma
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Jiahao Shi
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yuhe Zhang
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Zhili Li
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Haiyang Yong
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Ya-Nan Zhou
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Shuai Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Sigen A
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
- School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China
| | - Dezhong Zhou
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
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27
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Fotopoulos I, Hadjipavlou-Litina D. Approaches for the discovery of cinnamic acid derivatives with anticancer potential. Expert Opin Drug Discov 2024; 19:1281-1291. [PMID: 39105559 DOI: 10.1080/17460441.2024.2387122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
INTRODUCTION Cinnamic acid is a privileged scaffold for the design of biologically active compounds with putative anticancer potential, following different synthetic methodologies and procedures. Since there is a need for the production of potent anticancer, cinnamate moiety can significantly contribute in the design of new and more active anticancer agents. AREAS COVERED In this review, the authors provide a review on the synthetic approaches for the discovery of cinnamic acid derivatives with anticancer potential. Results from molecular simulations, hybridization, and chemical derivatization along with biological experiments in vitro and structural activity relationships are given, described, and discussed by the authors. Information for the mechanism of action is taken from original literature sources. EXPERT OPINION The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity and drug-likeness, the mechanism of action in animals and humans, development of more efficient assays for various cancer types; (ii) hybridization techniques outbalance in the discovery and production of compounds with higher activity and greater selectivity; (iii) repositioning offers new anticancer cinnamic agents.
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Affiliation(s)
- Ioannis Fotopoulos
- Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
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28
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Zhang Y, Liu L, Yue L, Huang Y, Wang B, Liu P. Uncovering key mechanisms and intervention therapies in aging skin. Cytokine Growth Factor Rev 2024; 79:66-80. [PMID: 39198086 DOI: 10.1016/j.cytogfr.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
Advancements in understanding skin aging mechanisms, which encompass both external and internal aging processes, have spurred the development of innovative treatments primarily aimed at improving cosmetic appearance. These findings offer the potential for the development of novel therapeutic strategies aimed at achieving long-term, non-therapy-dependent clinical benefits, including the reversal of aging and the mitigation of associated health conditions. Realizing this goal requires further research to establish the safety and efficacy of targeting aging-related skin changes, such as pigmentation, wrinkling, and collagen loss. Systematic investigation is needed to identify the most effective interventions and determine optimal anti-aging treatment strategies. These reviews highlight the features and possible mechanisms of skin aging, as well as the latest progress and future direction of skin aging research, to provide a theoretical basis for new practical anti-skin aging strategies.
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Affiliation(s)
- Yuqin Zhang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China
| | - Lin Liu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China
| | - Lixia Yue
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Yongzhuo Huang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
| | - Bing Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China.
| | - Peifeng Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China.
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Cortes Ballen AI, Amosu M, Ravinder S, Chan J, Derin E, Slika H, Tyler B. Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets. Cells 2024; 13:1574. [PMID: 39329757 PMCID: PMC11430559 DOI: 10.3390/cells13181574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/05/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.
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Affiliation(s)
| | | | | | | | | | | | - Betty Tyler
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (A.I.C.B.); (M.A.); (S.R.); (J.C.); (E.D.); (H.S.)
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30
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Wang BF, Wang YY, Lin H, Yi YL. Oncostatin M promotes epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps. Tissue Barriers 2024:2399235. [PMID: 39225375 DOI: 10.1080/21688370.2024.2399235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/22/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Oncostatin M (OSM) may be involved in the promotion of mucosal epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) by inducing matrix metalloproteinase (MMP) -1 and -7. The aim was to evaluate the roles and mechanisms of action of OSM on MMP-1 and -7 synthesis from nasal epithelial cells (NECs). METHODS OSM, OSM receptor (OSMR), MMP-1 and -7 expression was evaluated in nasal mucosa or primary NECs from scrapings by quantitative polymerase chain reaction (qPCR), immunofluorescence and immunohistochemistry. OSM and other cytokines were used to stimulate air-liquid interface (ALI) cultured NECs. qPCR, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence were used to evaluate the expression of OSMR, MMP-1, -7 and occludin in NECs. RESULTS Elevated levels of OSMRβ, MMP-1 and -7 were found in the tissues and scraped NECs of Eos CRSwNP in comparison to them obtained from the inferior turbinate (IT) and control subjects. The levels of OSM and OSMRβ mRNA in tissues were positively correlated with the levels of MMP-1 and -7. OSM stimulation of NECs increased the expression of MMP-1 and -7, and the responses were suppressed by a STAT3 inhibitor, and a PI3K inhibitor respectively. In parallel studies, we found that stimulation with OSM disrupted the localization of occludin, a tight junction protein in NECs. The response was suppressed by a pan-MMP inhibitor. CONCLUSION OSM induces the synthesis and release of MMP-1 and -7 in NECs. Furthermore, MMP-1 and -7 promote mucosal epithelial barrier dysfunction in patients with Eos CRSwNP.
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Affiliation(s)
- Bao-Feng Wang
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, P.R. China
| | - Ying-Ying Wang
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, P.R. China
| | - Hai Lin
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun-Lan Yi
- Department of Otolaryngology-Head and Neck Surgery, Jinzhou medical College, Jinzhou, China
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Aleksandrova A, Mekhtiev A, Timoshenko O, Kugaevskaya E, Gureeva T, Gisina A, Zavialova M, Scherbakov K, Rudovich A, Zhabinskii V, Khripach V. Effects of Isoxazolyl Steroids on Key Genes of Sonic Hedgehog Cascade Expression in Tumor Cells. Molecules 2024; 29:4026. [PMID: 39274874 PMCID: PMC11396458 DOI: 10.3390/molecules29174026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/06/2024] [Accepted: 08/13/2024] [Indexed: 09/16/2024] Open
Abstract
Activation of the Hedgehog (Hh) signaling pathway is often associated with the progression of various types of cancer. The purpose of study was to search for inhibitors of the Hh signaling pathway among eight compounds belonging to the group of isoxazolyl steroids. The evaluation of the effectiveness of the compounds was based on the analysis of their cytotoxicity, effect on the cell cycle, on the expression of key Hh-signaling-pathway genes (Ptch1, Smo, and Gli1) and putative target genes MMP-2 and MMP-9. Four compounds with the most pronounced cytotoxic effect were identified: compounds 1, 2 (HeLa cells) and 3, 4 (A549 cells). Compounds 1 and 2 significantly reduced the expression of the Ptch1, Smo, Gli1 genes, but had the opposite effect on MMP-2 gene expression: Compound 1 increased it, and compound 2 decreased it. Compounds 3 and 4 did not have a noticeable inhibitory effect on the expression of the Shh pathway receptors, but significantly inhibited MMP-2 and MMP-9 expression. Thus, it was shown that inhibition of the Shh signaling pathway by isoxazolyl steroids can have the opposite effect on MMPs gene expression, which is what should be taken into account in further studies of these compounds as therapeutic agents.
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Affiliation(s)
- Anna Aleksandrova
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Arif Mekhtiev
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Olga Timoshenko
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Elena Kugaevskaya
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Tatiana Gureeva
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Alisa Gisina
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Maria Zavialova
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Kirill Scherbakov
- Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Str., 119121 Moscow, Russia; (A.A.); (O.T.); (E.K.); (T.G.); (A.G.); (M.Z.); (K.S.)
| | - Anton Rudovich
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220084 Minsk, Belarus; (A.R.); (V.Z.); (V.K.)
| | - Vladimir Zhabinskii
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220084 Minsk, Belarus; (A.R.); (V.Z.); (V.K.)
| | - Vladimir Khripach
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220084 Minsk, Belarus; (A.R.); (V.Z.); (V.K.)
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Gorantla K, Krishnan A, Waheed SO, Varghese A, DiCastri I, LaRouche C, Paik M, Fields GB, Karabencheva-Christova TG. Novel Insights into the Catalytic Mechanism of Collagenolysis by Zn(II)-Dependent Matrix Metalloproteinase-1. Biochemistry 2024; 63:1925-1940. [PMID: 38963231 PMCID: PMC11309001 DOI: 10.1021/acs.biochem.4c00076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/14/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
Collagen hydrolysis, catalyzed by Zn(II)-dependent matrix metalloproteinases (MMPs), is a critical physiological process. Despite previous computational investigations into the catalytic mechanisms of MMP-mediated collagenolysis, a significant knowledge gap in understanding remains regarding the influence of conformational sampling and entropic contributions at physiological temperature on enzymatic collagenolysis. In our comprehensive multilevel computational study, employing quantum mechanics/molecular mechanics (QM/MM) metadynamics (MetD) simulations, we aimed to bridge this gap and provide valuable insights into the catalytic mechanism of MMP-1. Specifically, we compared the full enzyme-substrate complex in solution, clusters in solution, and gas-phase to elucidate insights into MMP-1-catalyzed collagenolysis. Our findings reveal significant differences in the catalytic mechanism when considering thermal effects and the dynamic evolution of the system, contrasting with conventional static potential energy surface QM/MM reaction path studies. Notably, we observed a significant stabilization of the critical tetrahedral intermediate, attributed to contributions from conformational flexibility and entropy. Moreover, we found that protonation of the scissile bond nitrogen occurs via proton transfer from a Zn(II)-coordinated hydroxide rather than from a solvent water molecule. Following C-N bond cleavage, the C-terminus remains coordinated to the catalytic Zn(II), while the N-terminus forms a hydrogen bond with a solvent water molecule. Subsequently, the release of the C-terminus is facilitated by the coordination of a water molecule. Our study underscores the pivotal role of protein conformational dynamics at physiological temperature in stabilizing the transition state of the rate-limiting step and key intermediates, compared to the corresponding reaction in solution. These fundamental insights into the mechanism of collagen degradation provide valuable guidance for the development of MMP-1-specific inhibitors.
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Affiliation(s)
- Koteswara
Rao Gorantla
- Department
of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States
| | - Anandhu Krishnan
- Department
of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States
| | - Sodiq O. Waheed
- Department
of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States
| | - Ann Varghese
- Department
of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States
| | - Isabella DiCastri
- Department
of Chemical Engineering, Michigan Technological
University, Houghton, Michigan 49931, United States
| | - Ciara LaRouche
- Department
of Chemical Engineering, Michigan Technological
University, Houghton, Michigan 49931, United States
| | - Meredith Paik
- Department
of Chemistry, Michigan Technological University, Houghton, Michigan 49931, United States
| | - Gregg B. Fields
- Department
of Chemistry and Biochemistry and I-HEALTH, Florida Atlantic University, Jupiter, Florida 33458, United States
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Li B, Mi J, Yuan Q. Fatty acid metabolism-related enzymes in colorectal cancer metastasis: from biological function to molecular mechanism. Cell Death Discov 2024; 10:350. [PMID: 39103344 DOI: 10.1038/s41420-024-02126-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/26/2024] [Accepted: 07/31/2024] [Indexed: 08/07/2024] Open
Abstract
Colorectal cancer (CRC) is a highly aggressive and life-threatening malignancy that metastasizes in ~50% of patients, posing significant challenges to patient survival and treatment. Fatty acid (FA) metabolism regulates proliferation, immune escape, metastasis, angiogenesis, and drug resistance in CRC. FA metabolism consists of three pathways: de novo synthesis, uptake, and FA oxidation (FAO). FA metabolism-related enzymes promote CRC metastasis by regulating reactive oxygen species (ROS), matrix metalloproteinases (MMPs), angiogenesis and epithelial-mesenchymal transformation (EMT). Mechanistically, the PI3K/AKT/mTOR pathway, wnt/β-catenin pathway, and non-coding RNA signaling pathway are regulated by crosstalk of enzymes related to FA metabolism. Given the important role of FA metabolism in CRC metastasis, targeting FA metabolism-related enzymes and their signaling pathways is a potential strategy to treat CRC metastasis.
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Affiliation(s)
- Biao Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Jing Mi
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Qi Yuan
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China.
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Du NN, Shao SJ, Feng JM, Wan H, Wu XQ. Evaluation of the clinical efficacy of Ru'ai Shuhou recipe for the prevention of lung metastases from breast cancer: a retrospective study based on propensity score matching. Front Pharmacol 2024; 15:1406862. [PMID: 39156102 PMCID: PMC11327059 DOI: 10.3389/fphar.2024.1406862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/18/2024] [Indexed: 08/20/2024] Open
Abstract
Background Breast cancer lung metastasis occurs at a high rate and at an early stage, and is the leading cause of death in breast cancer patients. The aim of this study was to investigate the effect of Ru'ai Shuhou Recipe (RSR) intervention on the occurrence of recurrent metastases, especially lung metastases, in postoperative patients with breast cancer. Materials and Methods A retrospective cohort study was implemented at Shuguang Hospital of Shanghai University of Traditional Chinese Medicine in China between January 2014 to January 2019. Female patients were included according to the propensity score matching (PSM) method and balanced on the basis of general and clinical information such as age, body mass index, neo-adjuvant therapy, and surgical approach. Patients with pathological diagnosis of breast cancer were included in this study. Breast cancer patients were divided into exposed and non-exposed groups according to whether they took RSR-based botanical drugs after surgery. Kaplan-Meier survival analysis and Cox survival analysis to explore the relationship between RSR and 5-year disease-free survival and incidence of lung metastases in breast cancer patients after surgery. Results 360 female patients were assessed and 190 patients were included in the study after PSM (95 in each of the exposed and non-exposed groups). Of the 190 patients after PSM, 55.79% were over 50 years of age. The mean follow-up time was 60.55 ± 14.82 months in the exposed group and 57.12 ± 16.37 months in the non-exposed group. There was no significant baseline characteristics difference between two groups. Kaplan-Meier analysis showed that the 5-year incidence of lung metastases was significantly lower in the exposed group, and the disease-free survival of patients was significantly longer. Cox univariate and multivariate analysis showed that neoadjuvant chemotherapy and lymph node metastasis were independent risk factors for the development of breast cancer lung metastasis, with risk ratios of 17.188 and 5.812, while RSR treatment was an independent protective factor against the development of breast cancer lung metastasis, with a risk ratio of 0.290. Conclusion Standard biomedical treatment combined with RSR intervention can better prevent breast cancer recurrence and metastasis, reduce the incidence of lung metastasis in patients, and improve long-term prognosis.
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Affiliation(s)
| | | | | | - Hua Wan
- Breast Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xue-Qing Wu
- Breast Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kumar I, Silva M, Choudhary DA, Ali SF, Rusak R, Cotzomi P, Wiecek S, Sato I, Khundoker R, Donmez B, Gabriel S, Bobila M, Leonida MD, Traba C. Small molecular exogenous modulators of active forms of MMPs. Biochimie 2024; 223:125-132. [PMID: 37944661 DOI: 10.1016/j.biochi.2023.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 09/13/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases, and their activity depends on calcium and zinc metal ions. These enzymes are expressed originally in zymogenic form, where the active site of proteins is closed by a prodomain which is removed during activation. A homeostatic balance of their activity is primarily regulated by a 'cysteine switch' located on a consensus sequence of the prodomain and natural endogenous inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). Breakage of this homeostasis may lead to various pathological conditions, which may require further activation and/or inhibition of these enzymes to regenerate that balance. Here, we report four modulators, more specifically, three inhibitors (I1, I2 and I3), and one exogenous activator (L) of the active form of human collagenase MMP-1 (without prodomain). The results were confirmed by binding studies using fluorescence-based enzyme assays.
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Affiliation(s)
- Ish Kumar
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA.
| | - Melissa Silva
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Dinesh A Choudhary
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Syeda F Ali
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Raymond Rusak
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Paulina Cotzomi
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Suzanne Wiecek
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Iwon Sato
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Rinat Khundoker
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Bora Donmez
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Samantha Gabriel
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Monica Bobila
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Mihaela D Leonida
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
| | - Christian Traba
- Department of Chemistry, Biochemistry & Physics, Fairleigh Dickinson University, 1000 River Rd, Teaneck, NJ, 07666, USA
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Sinha K, Parwez S, Mv S, Yadav A, Siddiqi MI, Banerjee D. Machine learning and biological evaluation-based identification of a potential MMP-9 inhibitor, effective against ovarian cancer cells SKOV3. J Biomol Struct Dyn 2024; 42:6823-6841. [PMID: 37504963 DOI: 10.1080/07391102.2023.2240416] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 07/08/2023] [Indexed: 07/29/2023]
Abstract
MMP-9, also known as gelatinase B, is a zinc-metalloproteinase family protein that plays a key role in the degradation of the extracellular matrix (ECM). The normal function of MMP-9 includes the breakdown of ECM, a process that aids in normal physiological processes such as embryonic development, angiogenesis, etc. Interruptions in these processes due to the over-expression or downregulation of MMP-9 are reported to cause some pathological conditions like neurodegenerative diseases and cancer. In the present study, an integrated approach for ML-based virtual screening of the Maybridge library was carried out and their biological activity was tested in an attempt to identify novel small molecule scaffolds that can inhibit the activity of MMP-9. The top hits were identified and selected for target-based activity against MMP-9 protein using the kit (Biovision K844). Further, MTT assay was performed in various cancer cell lines such as breast (MCF-7, MDA-MB-231), colorectal (HCT119, DL-D-1), cervical (HeLa), lung (A549) and ovarian cancer (SKOV3). Interestingly, one compound viz., RJF02215 exhibited anti-cancer activity selectively in SKOV3. Wound healing assay and colony formation assay performed on SKOV3 cell line in the presence of RJF02215 confirmed that the compound had a significant inhibitory effect on this cell line. Thus, we have identified a novel molecule that can inhibit MMP-9 activity in vitro and inhibits the proliferation of SKOV3 cells. Novel molecules based on the structure of RJF02215 may become a good value addition for the treatment of ovarian cancer by exhibiting selective MMP-9 activity.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Khushboo Sinha
- Cancer Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shahid Parwez
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shahana Mv
- Cancer Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Ananya Yadav
- Cancer Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Mohammad Imran Siddiqi
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dibyendu Banerjee
- Cancer Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Wu Y, Li X, Fu X, Huang X, Zhang S, Zhao N, Ma X, Saiding Q, Yang M, Tao W, Zhou X, Huang J. Innovative Nanotechnology in Drug Delivery Systems for Advanced Treatment of Posterior Segment Ocular Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403399. [PMID: 39031809 PMCID: PMC11348104 DOI: 10.1002/advs.202403399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/29/2024] [Indexed: 07/22/2024]
Abstract
Funduscopic diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), significantly impact global visual health, leading to impaired vision and irreversible blindness. Delivering drugs to the posterior segment of the eye remains a challenge due to the presence of multiple physiological and anatomical barriers. Conventional drug delivery methods often prove ineffective and may cause side effects. Nanomaterials, characterized by their small size, large surface area, tunable properties, and biocompatibility, enhance the permeability, stability, and targeting of drugs. Ocular nanomaterials encompass a wide range, including lipid nanomaterials, polymer nanomaterials, metal nanomaterials, carbon nanomaterials, quantum dot nanomaterials, and so on. These innovative materials, often combined with hydrogels and exosomes, are engineered to address multiple mechanisms, including macrophage polarization, reactive oxygen species (ROS) scavenging, and anti-vascular endothelial growth factor (VEGF). Compared to conventional modalities, nanomedicines achieve regulated and sustained delivery, reduced administration frequency, prolonged drug action, and minimized side effects. This study delves into the obstacles encountered in drug delivery to the posterior segment and highlights the progress facilitated by nanomedicine. Prospectively, these findings pave the way for next-generation ocular drug delivery systems and deeper clinical research, aiming to refine treatments, alleviate the burden on patients, and ultimately improve visual health globally.
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Affiliation(s)
- Yue Wu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xin Li
- Wenzhou Medical UniversityWenzhouZhejiang325035China
| | - Xueyu Fu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xiaomin Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | | | - Nan Zhao
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Xiaowei Ma
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Qimanguli Saiding
- Center for Nanomedicine and Department of AnesthesiologyBrigham and Women's Hospital, Harvard Medical SchoolBostonMA02115USA
| | - Mei Yang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Wei Tao
- Center for Nanomedicine and Department of AnesthesiologyBrigham and Women's Hospital, Harvard Medical SchoolBostonMA02115USA
| | - Xingtao Zhou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
| | - Jinhai Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye DiseasesChinese Academy of Medical SciencesShanghai200031China
- Shanghai Research Center of Ophthalmology and OptometryShanghai200031China
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Davis JA, Baker D, Peresleni T, Heiselman C, Kocis C, Demishev M, Garry DJ. Vaginal matrix metalloproteinase-9 (MMP-9) as a potential early predictor of preterm birth. J Perinat Med 2024; 52:591-596. [PMID: 38785035 DOI: 10.1515/jpm-2023-0429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 05/13/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVES To evaluate the differences in vaginal matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMPs) in pregnant patients with a history of prior preterm birth compared with controls. METHODS A prospective cohort pilot study recruited patients during prenatal care with history of prior spontaneous preterm birth (high-risk group) or no history of preterm birth (low-risk/controls). Inclusion criteria were singleton gestation at 11-16 weeks and between 18 and 55 years of age. Exclusion criteria were diabetes mellitus, hypertension, diseases affecting the immune response or acute vaginitis. A vaginal wash was performed at time of enrollment, and patients were followed through delivery. Samples were analyzed using semi-quantitative analysis of MMPS and TIMPS. The study was approved by the IRB and a p-value <0.05 was considered significant. RESULTS A total of 48 pregnant patients were recruited: 16 with a history of preterm birth (high-risk group) and 32 with no history of preterm birth (low-risk group/controls). Groups were similar in age, race, BMI, and delivery mode. The high-risk group had more multiparous women (100 vs. 68.8 %; p=0.02), a greater preterm birth rate (31.2 vs. 6.3 %; p=0.02), and a lower birth weight (2,885 ± 898 g vs. 3,480 ± 473 g; p=0.02). Levels of vaginal MMP-9 were greater in high-risk patients than low-risk patients (74.9 % ± 27.0 vs. 49.4 % ± 31.1; p=0.01). When dividing the cohort into patients that had a spontaneous preterm birth (7/48, 14.6 %) vs. those with a term delivery (41/48, 85.4 %), the vaginal MMP-9 remained elevated in the cohort that experienced a preterm birth (85.46 %+19.79 vs. 53.20 %+31.47; p=0.01). There were no differences in the other MMPS and in TIMPs between high and low-risk groups. CONCLUSIONS There was an increase in vaginal MMP-9 during early pregnancy in those at high risk for preterm birth and in those who delivered preterm, regardless of prior pregnancy outcome. Vaginal MMP-9 may have potential as a marker of increased risk of preterm birth.
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Affiliation(s)
- Jay A Davis
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - David Baker
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Tatyana Peresleni
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Cassandra Heiselman
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Christina Kocis
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Michael Demishev
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - David J Garry
- Department of Obstetrics & Gynecology and Reproductive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
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Chan KC, Basavaraj P, Tsai JC, Viehoever J, Hsieh BY, Li XY, Huang GJ, Huang WC. Evaluating the Therapeutic Effect of Hispidin on Prostate Cancer Cells. Int J Mol Sci 2024; 25:7857. [PMID: 39063105 PMCID: PMC11277327 DOI: 10.3390/ijms25147857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Androgen deprivation therapy (ADT) is the primary treatment for advanced prostate cancer (PCa). However, prolonged ADT inevitably results in therapy resistance with the emergence of the castration-resistant PCa phenotype (CRPC). Hence, there is an urgent need to explore new treatment options capable of delaying PCa progression. Hispidin (HPD) is a natural polyketide primarily derived from plants and fungi. HPD has been shown to have a diverse pharmacological profile, exhibiting anti-inflammatory, antiviral, cardiovascular and neuro-protective activities. However, there is currently no research regarding its properties in the context of PCa treatment. This research article seeks to evaluate the anti-cancer effect of HPD and determine the underlying molecular basis in both androgen-sensitive PCa and CRPC cells. Cell growth, migration, and invasion assays were performed via the MTS method, a wound healing assay and the transwell method. To investigate if HPD affected the expression of proteins, Western blot analysis was conducted. Furthermore, apoptosis was assessed by Annexin V-FITC/PI staining and Western blot analyses. HPD exhibited a favorable pharmaceutical profile to inhibit cell growth; disrupt the cell cycle; attenuate wound healing, migration and invasion; and induce apoptosis in PCa cells in vitro. The mechanistic results demonstrated that HPD reduced AR, MMP-2 and MMP-9 expression and activated the caspase-related pathway, leading to programmed cell death in PCa cells. We showed the anti-cancer effect of HPD on PCa cells and confirmed its feasibility as a novel therapeutic agent. This study provides significant insights into the delineation of the molecular mechanism of HPD in PCa cells and the development of an effective and safe therapy using HPD to eliminate PCa progression.
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Affiliation(s)
- Kai-Cheng Chan
- Graduate Institute of Cell Biology, College of Life Sciences, China Medical University, Taichung 40402, Taiwan; (K.-C.C.); (P.B.)
| | - Praveenkumar Basavaraj
- Graduate Institute of Cell Biology, College of Life Sciences, China Medical University, Taichung 40402, Taiwan; (K.-C.C.); (P.B.)
| | - Jui-Chen Tsai
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; (J.-C.T.); (B.-Y.H.); (X.-Y.L.)
| | - Jonathan Viehoever
- International Master’s Program of Biomedical, School of Medicine, China Medical University, Taichung 40402, Taiwan;
| | - Bing-Yan Hsieh
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; (J.-C.T.); (B.-Y.H.); (X.-Y.L.)
| | - Xin-Yu Li
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; (J.-C.T.); (B.-Y.H.); (X.-Y.L.)
| | - Guan-Jhong Huang
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan;
- Department of Food Nutrition and Healthy Biotechnology, Asia University, Taichung 41354, Taiwan
| | - Wen-Chin Huang
- Graduate Institute of Cell Biology, College of Life Sciences, China Medical University, Taichung 40402, Taiwan; (K.-C.C.); (P.B.)
- International Master’s Program of Biomedical, School of Medicine, China Medical University, Taichung 40402, Taiwan;
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40
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Jin J, Guo Q, Yan Z. The Role of Lutheran/Basal Cell Adhesion Molecule in Hematological Diseases and Tumors. Int J Mol Sci 2024; 25:7268. [PMID: 39000374 PMCID: PMC11242806 DOI: 10.3390/ijms25137268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/21/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Cell adhesion is a dynamic process that plays a fundamental role in cell proliferation, maintenance, differentiation, and migration. Basal cell adhesion molecule (BCAM), also known as Lutheran (Lu), belongs to the immunoglobulin superfamily of cell adhesion molecules. Lu/BCAM, which is widely expressed in red blood cells, endothelial cells, smooth muscle cells and epithelial cells across various tissues, playing a crucial role in many cellular processes, including cell adhesion, cell motility and cell migration. Moreover, Lu/BCAM, dysregulated in many diseases, such as blood diseases and various types of cancer, may act as a biomarker and target for the treatment of these diseases. This review explores the significance of Lu/BCAM in cell adhesion and its potential as a novel target for treating hematological diseases and tumors.
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Affiliation(s)
| | | | - Zhibin Yan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China; (J.J.); (Q.G.)
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Baik S, Heo H, Hong S, Jeong HS, Lee J, Lee H. Combination of Nicotinamide and Agastache rugosa Extract: A Potent Strategy for Protecting Hs68 Cells from UVB-Induced Photoaging. Prev Nutr Food Sci 2024; 29:162-169. [PMID: 38974585 PMCID: PMC11223918 DOI: 10.3746/pnf.2024.29.2.162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 07/09/2024] Open
Abstract
This study investigated the protective effects of nicotinamide (NAM) and Agastache rugosa extract (AR) against ultraviolet B (UVB)-induced photoaging in Hs68 cells. The results demonstrated that NAM and AR, alone or in combination, exhibited concentration-dependent protective effects against UVB radiation. The highest synergistic effect was observed at a NAM:AR ratio of 6:4. This combination exhibited a synergistic protective effect against UVB-induced photoaging. The sample concentration required for 80% cell survival was 9.70 μM and 131.16 ppm for NAM and AR, respectively. However, when combined, they exhibited strong synergistic effects with concentrations as low as 0.11 μM and 17.50 ppm. Moreover, 5.26 μM of NAM and 1,082.13 ppm of AR were required to inhibit 30% of reactive oxygen species, but the combination treatment required 0.62 μM and 95.49 ppm, respectively. This combination significantly reduced the production of matrix metalloproteinase and increased collagen production. These findings highlight the potential of combining NAM and AR as functional cosmetic materials to protect against UVB-induced photoaging. The synergistic effects observed in this study provide valuable information for developing novel strategies for cosmetic combinations that target UVB-mediated skin damage.
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Affiliation(s)
- Seungjoo Baik
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
| | - Huijin Heo
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
| | - Seonghwa Hong
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
| | - Heon Sang Jeong
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
| | - Junsoo Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
| | - Hana Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Chungbuk 28644, Korea
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De Silva S, Alli-Shaik A, Gunaratne J. Machine Learning-Enhanced Extraction of Biomarkers for High-Grade Serous Ovarian Cancer from Proteomics Data. Sci Data 2024; 11:685. [PMID: 38918474 PMCID: PMC11199488 DOI: 10.1038/s41597-024-03536-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 06/17/2024] [Indexed: 06/27/2024] Open
Abstract
Comprehensive biomedical proteomic datasets are accumulating exponentially, warranting robust analytics to deconvolute them for identifying novel biological insights. Here, we report a strategic machine learning (ML)-based feature extraction workflow that was applied to unveil high-performing protein markers for high-grade serous ovarian carcinoma (HGSOC) from publicly available ovarian cancer tissue and serum proteomics datasets. Diagnosis of HGSOC, an aggressive form of ovarian cancer, currently relies on diagnostic methods based on tissue biopsy and/or non-specific biomarkers such as the cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). Our newly developed ML-based approach enabled the identification of new serum proteomic biomarkers for HGSOC. The performance verification of these marker combinations using two independent cohorts affirmed their outperformance against known biomarkers for ovarian cancer including clinically used serum markers with >97% AUC. Our analysis also added novel biological insights such as enriched cancer-related processes associated with HGSOC.
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Affiliation(s)
- Senuri De Silva
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Asfa Alli-Shaik
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
| | - Jayantha Gunaratne
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore.
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
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Revert-Ros F, Ventura I, Prieto-Ruiz JA, Hernández-Andreu JM, Revert F. The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen. Int J Mol Sci 2024; 25:6523. [PMID: 38928229 PMCID: PMC11203716 DOI: 10.3390/ijms25126523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/01/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.
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Affiliation(s)
| | | | | | | | - Fernando Revert
- Mitochondrial and Molecular Medicine Research Group, Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain; (F.R.-R.); (I.V.); (J.A.P.-R.); (J.M.H.-A.)
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Wang J, Huang Y, Wu X, Li D. MicroRNA-939 amplifies Staphylococcus aureus-induced matrix metalloproteinase expression in atopic dermatitis. Front Immunol 2024; 15:1354154. [PMID: 38903509 PMCID: PMC11188349 DOI: 10.3389/fimmu.2024.1354154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 05/21/2024] [Indexed: 06/22/2024] Open
Abstract
Background Atopic dermatitis (AD) is a common chronic inflammatory skin diseases that seriously affects life quality of the patients. Staphylococcus aureus (S. aureus) colonization on the skin plays an important role in the pathogenesis of AD; however, the mechanism of how it modulates skin immunity to exacerbate AD remains unclear. MicroRNAs are short non-coding RNAs that act as post-transcriptional regulators of genes. They are involved in the pathogenesis of various inflammatory skin diseases. Methods In this study, we established miRNA expression profiles for keratinocytes stimulated with heat-killed S. aureus (HKSA). The expression of miR-939 in atopic dermatitis patients was analyzed by fluorescence in situ hybridization (FISH). miR-939 mimic was transfected to human primary keratinocyte to investigate its impact on the expression of matrix metalloproteinase genes (MMPs) in vitro. Subsequently, miR-939, along with Polyplus transfection reagent, was administered to MC903-induced atopic dermatitis skin to assess its function in vivo. Results MiR-939 was highly upregulated in HKSA-stimulated keratinocytes and AD lesions. In vitro studies revealed that miR-939 increased the expression of matrix metalloproteinase genes, including MMP1, MMP3, and MMP9, as well as the cell adhesion molecule ICAM1 in human primary keratinocytes. In vivo studies indicated that miR-939 increased the expression of matrix metalloproteinases to promote the colonization of S. aureus and exacerbated S. aureus-induced AD-like skin inflammation. Conclusions Our work reveals miR-939 is an important regulator of skin inflammation in AD that could be used as a potential therapeutic target for AD.
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Affiliation(s)
- Jiating Wang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yejing Huang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xinfeng Wu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Dongqing Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China
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Lai‐Foenander AS, Kuppusamy G, Manogoran J, Xu T, Chen Y, Tang SY, Ser H, Yow Y, Goh KW, Ming LC, Chuah L, Yap W, Goh B. Black soldier fly ( Hermetia illucens L.): A potential small mighty giant in the field of cosmeceuticals. Health Sci Rep 2024; 7:e2120. [PMID: 38831777 PMCID: PMC11144625 DOI: 10.1002/hsr2.2120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 04/04/2024] [Accepted: 04/27/2024] [Indexed: 06/05/2024] Open
Abstract
Background and Aims Natural products are widely used in the pharmaceutical and cosmetics industries due to their high-value bioactive compounds, which make for "greener" and more environmentally friendly ingredients. These natural compounds are also considered a safer alternative to antibiotics, which may result in antibiotic resistance as well as unfavorable side effects. The development of cosmeceuticals, which combine the cosmetic and pharmaceutical fields to create skincare products with therapeutic value, has increased the demand for unique natural resources. The objective of this review is to discuss the biological properties of extracts derived from larvae of the black soldier fly (BSF; Hermetia illucens), the appropriate extraction methods, and the potential of this insect as a novel active ingredient in the formulation of new cosmeceutical products. This review also addresses the biological actions of compounds originating from the BSF, and the possible association between the diets of BSF larvae and their subsequent bioactive composition. Methods A literature search was conducted using PubMed and Google Scholar to identify and evaluate the various biological properties of the BSF. Results One such natural resource that may be useful in the cosmeceutical field is the BSF, a versatile insect with numerous potential applications due to its nutrient content and scavenging behavior. Previous research has also shown that the BSF has several biological properties, including antimicrobial, antioxidant, anti-inflammatory, and wound healing effects. Conclusion Given the range of biological activities and metabolites possessed by the BSF, this insect may have the cosmeceutical potential to treat a number of skin pathologies.
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Affiliation(s)
- Ashley Sean Lai‐Foenander
- Biofunctional Molecule Exploratory Research Group, School of PharmacyMonash University MalaysiaBandar SunwayMalaysia
| | - Giva Kuppusamy
- Laboratory of Molecular Biology, Department of Research and DevelopmentGK Aqua Sdn Bhd, Port DicksonNegeri SembilanMalaysia
| | - Janaranjani Manogoran
- Laboratory of Molecular Biology, Department of Research and DevelopmentGK Aqua Sdn Bhd, Port DicksonNegeri SembilanMalaysia
| | - Tengfei Xu
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Yong Chen
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Siah Ying Tang
- Chemical Engineering Discipline, School of EngineeringMonash University Malaysia, Bandar SunwaySelangor Darul EhsanMalaysia
| | - Hooi‐Leng Ser
- Department of Biological SciencesSchool of Medical and Life Sciences, Sunway UniversityBandar SunwayMalaysia
| | - Yoon‐Yen Yow
- Department of Biological SciencesSchool of Medical and Life Sciences, Sunway UniversityBandar SunwayMalaysia
| | - Khang Wen Goh
- Faculty of Data Science and Information TechnologyINTI International UniversityNilaiMalaysia
| | - Long Chiau Ming
- Department of Medical SciencesSchool of Medical and Life Sciences, Sunway UniversityBandar SunwayMalaysia
| | - Lay‐Hong Chuah
- Biofunctional Molecule Exploratory Research Group, School of PharmacyMonash University MalaysiaBandar SunwayMalaysia
| | - Wei‐Hsum Yap
- School of BiosciencesTaylor's University, Subang JayaSelangorMalaysia
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP)Faculty of Health and Medical Sciences (FHMS), Taylor's University, Subang JayaSelangorMalaysia
| | - Bey‐Hing Goh
- Biofunctional Molecule Exploratory Research Group, School of PharmacyMonash University MalaysiaBandar SunwayMalaysia
- College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- Sunway Biofunctional Molecules Discovery Centre (SBMDC)School of Medical and Life Sciences, Sunway UniversitySunwayMalaysia
- Faculty of Health, Australian Research Centre in Complementary and Integrative MedicineUniversity of Technology SydneyUltimoNSWAustralia
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Sotirova Y, Kiselova-Kaneva Y, Vankova D, Tasinov O, Ivanova D, Popov H, Hristova M, Nikolova K, Andonova V. Tissue Regeneration and Remodeling in Rat Models after Application of Hypericum perforatum L. Extract-Loaded Bigels. Gels 2024; 10:341. [PMID: 38786258 PMCID: PMC11121646 DOI: 10.3390/gels10050341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/12/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
The wound-healing effect of St. John's Wort (SJW) is mainly attributed to hyperforin (HP), but its low stability restricts its topical administration. This study investigates how "free" HP-rich SJW extract (incorporated into a bigel; B/SJW) and extract "protected" by nanostructured lipid carriers (also included in a biphasic semisolid; B/NLC-SJW) affect tissue regeneration in a rat skin excision wound model. Wound diameter, histological changes, and tissue gene expression levels of fibronectin (Fn), matrix metalloproteinase 8 (MMP8), and tumor necrosis factor-alpha (TNF-α) were employed to quantify the healing progress. A significant wound size reduction was achieved after applying both extract-containing semisolids, but after a 21-day application period, the smallest wound size was observed in the B/NLC-SJW-treated animals. However, the inflammatory response was affected more favorably by the bigel containing the "free" SJW extract, as evidenced by histological studies. Moreover, after the application of B/SJW, the expression of Fn, MMP8, and TNF-α was significantly higher than in the positive control. In conclusion, both bigel formulations exhibited beneficial effects on wound healing in rat skin, but B/SJW affected skin restoration processes in a comprehensive and more efficient way.
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Affiliation(s)
- Yoana Sotirova
- Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria;
| | - Yoana Kiselova-Kaneva
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria (O.T.); (D.I.)
| | - Deyana Vankova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria (O.T.); (D.I.)
| | - Oskan Tasinov
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria (O.T.); (D.I.)
| | - Diana Ivanova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria (O.T.); (D.I.)
| | - Hristo Popov
- Department of General and Clinical Pathology, Forensic Medicine and Deontology, Faculty of Medicine, Medical University of Varna, 9000 Varna, Bulgaria;
| | - Minka Hristova
- Department of Physiology and Pathophysiology, Faculty of Medicine, Medical University of Varna, 9000 Varna, Bulgaria;
| | - Krastena Nikolova
- Department of Physics and Biophysics, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria;
| | - Velichka Andonova
- Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria;
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Lu DD, Yuan L, Wang ZZ, Zhao JJ, Du YH, Ning N, Chen GQ, Huang SC, Yang Y, Zhang Z, Nan Y. To explore the mechanism of Yigong San anti-gastric cancer and immune regulation. World J Gastrointest Oncol 2024; 16:1965-1994. [PMID: 38764819 PMCID: PMC11099436 DOI: 10.4251/wjgo.v16.i5.1965] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/21/2024] [Accepted: 02/20/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Yigong San (YGS) is a representative prescription for the treatment of digestive disorders, which has been used in clinic for more than 1000 years. However, the mechanism of its anti-gastric cancer and regulate immunity are still remains unclear. AIM To explore the mechanism of YGS anti-gastric cancer and immune regulation. METHODS Firstly, collect the active ingredients and targets of YGS, and the differentially expressed genes of gastric cancer. Secondly, constructed a protein-protein interaction network between the targets of drugs and diseases, and screened hub genes. Then the clinical relevance, mutation and repair, tumor microenvironment and drug sensitivity of the hub gene were analyzed. Finally, molecular docking was used to verify the binding ability of YGS active ingredient and hub genes. RESULTS Firstly, obtained 55 common targets of gastric cancer and YGS. The Kyoto Encyclopedia of Genes and Genomes screened the microtubule-associated protein kinase signaling axis as the key pathway and IL6, EGFR, MMP2, MMP9 and TGFB1 as the hub genes. The 5 hub genes were involved in gastric carcinogenesis, staging, typing and prognosis, and their mutations promote gastric cancer progression. Finally, molecular docking results confirmed that the components of YGS can effectively bind to therapeutic targets. CONCLUSION YGS has the effect of anti-gastric cancer and immune regulation.
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Affiliation(s)
- Dou-Dou Lu
- School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Zhao-Zhao Wang
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jian-Jun Zhao
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Hua Du
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Na Ning
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Guo-Qing Chen
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shi-Cong Huang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Yang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Zhe Zhang
- Department of Chinese Medical Gastrointestinal, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yi Nan
- Key Laboratory of Ningxia Minority Medicine Modernization Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Azevedo VAN, De Assis EIT, Silva AWB, Costa FDC, Souza LF, Silva JRV. α-Pinene Improves Follicle Morphology and Increases the Expression of mRNA for Nuclear Factor Erythroid 2-Related Factor 2 and Peroxiredoxin 6 in Bovine Ovarian Tissues Cultured In Vitro. Animals (Basel) 2024; 14:1443. [PMID: 38791661 PMCID: PMC11117312 DOI: 10.3390/ani14101443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Oxidative stress during in vitro of ovarian tissues has adverse effects on follicle survival. α-pinene is a monoterpenoid molecule with antioxidant activity that has great potential to maintain cell survival in vitro. This study investigated the effect of α-pinene (1.25, 2.5, 5.0, 10.0, or 20.0 μg/mL) on primordial follicle growth and morphology, as well as on stromal cells and collagen fibers in bovine ovarian slices cultured for six days. The effect of α-pinene on transcripts of catalase (CAT), superoxide dismutase (SOD), peroxiredoxin 6 (PRDX6), glutathione peroxidase (GPX1), and nuclear factor erythroid 2-related factor 2 (NRF2) was investigated by real-time PCR. The tissues were processed for histological analysis to evaluate follicular growth, morphology, stromal cell density, and collagen fibers. The results showed that 2.5, 5.0, or 10.0 µg/mL α-pinene increased the percentages of normal follicles but did not influence follicular growth. The α-pinene (10.0 µg/mL) kept the stromal cell density and collagen levels in cultured bovine ovarian tissue like uncultured tissues. Ovarian tissues cultured in control medium had reduced expression of mRNA for NRF2, SOD, CAT, GPX1, and PRDX6, but α-pinene (10.0 µg/mL) increased mRNA levels for NRF2 and PRDX6. In conclusion, 10.0 µg/mL α-pinene improves the follicular survival, preserves stromal cell density and collagen levels, and increases transcripts of NRF2 and PRDX6 after in vitro culture of bovine ovarian tissue.
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Affiliation(s)
| | - Ernando Igo Teixeira De Assis
- Laboratory of Biotechnology and Physiology of Reproduction, Federal University of Ceara, Sobral 62041-040, CE, Brazil
| | - Anderson Weiny Barbalho Silva
- Laboratory of Biotechnology and Physiology of Reproduction, Federal University of Ceara, Sobral 62041-040, CE, Brazil
| | - Francisco Das Chagas Costa
- Laboratory of Biotechnology and Physiology of Reproduction, Federal University of Ceara, Sobral 62041-040, CE, Brazil
| | - Layana Freitas Souza
- Laboratory of Biochemistry and Gene Expression, State University of Ceara, Fortaleza 60714-903, CE, Brazil
| | - José Roberto Viana Silva
- Laboratory of Biotechnology and Physiology of Reproduction, Federal University of Ceara, Sobral 62041-040, CE, Brazil
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Huang Y, Yan B, Meng C, Zhang L, Wang C. Matrix metalloproteinases in chronic rhinosinusitis. Expert Rev Clin Immunol 2024; 20:547-558. [PMID: 38251631 DOI: 10.1080/1744666x.2024.2302362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Matrix metalloproteinases (MMPs) are a group of enzymes that are essential in maintaining extracellular matrix (ECM) homeostasis, regulating inflammation and tissue remodeling. In chronic rhinosinusitis (CRS), the overexpression of certain MMPs can contribute to chronic nasal tissue inflammation, ECM remodeling, and tissue repair. AREAS COVERED This review provides a comprehensive overview of the biological characteristics and functions of the MMP family, particularly focusing on the expression and activity of MMPs in patients with CRS, and delves into their role in the pathogenesis of CRS and their potential as therapeutic targets. EXPERT OPINION MMPs are important in tissue remodeling and have been implicated in the pathophysiology of CRS. Previous studies have shown that the expression of MMPs is upregulated in the nasal mucosa of patients with CRS and positively correlates with the severity of CRS. However, there is still a large gap in the research content of MMP in CRS, and the specific expression and pathogenic mechanism of MMP still need to be clarified. The significance and value of the ratio of MMP to tissue inhibitors of metalloproteinase (TIMP) in diseases still need to be demonstrated. Moreover, further studies are needed to assess the efficacy and safety of biologics that target MMPs in patients with CRS.
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Affiliation(s)
- Yuqing Huang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Bing Yan
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Chen Meng
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Luo Zhang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China
| | - Chengshuo Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Zhi S, Huang M, Cheng K. Enzyme-responsive design combined with photodynamic therapy for cancer treatment. Drug Discov Today 2024; 29:103965. [PMID: 38552778 DOI: 10.1016/j.drudis.2024.103965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/09/2024] [Accepted: 03/22/2024] [Indexed: 04/07/2024]
Abstract
Photodynamic therapy (PDT) is a noninvasive cancer treatment that has garnered significant attention in recent years. However, its application is still hampered by certain limitations, such as the hydrophobicity and low targeting of photosensitizers (PSs) and the hypoxia of the tumor microenvironment. Nevertheless, the fusion of enzyme-responsive drugs with PDT offers novel solutions to overcome these challenges. Utilizing the attributes of enzyme-responsive drugs, PDT can deliver PSs to the target site and selectively release them, thereby enhancing therapeutic outcomes. In this review, we spotlight recent advances in enzyme-responsive materials for cancer treatment and primarily delineate their application in combination with PDT.
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Affiliation(s)
- Siying Zhi
- Guangdong Provincial Key Laboratory of New Drug Screening and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Meixin Huang
- Guangdong Provincial Key Laboratory of New Drug Screening and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kui Cheng
- Guangdong Provincial Key Laboratory of New Drug Screening and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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