|
1
|
Gao X, Qian B, Yuan T, Pan D, Liang Z, Yin Y, Liu S, Li X, Zhao D, Zhang H. Ginseng extract and total ginsenosides protect the function of hematopoietic stem cells by activating the Notch and Wnt signal pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119798. [PMID: 40216043 DOI: 10.1016/j.jep.2025.119798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/31/2025] [Accepted: 04/09/2025] [Indexed: 04/17/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax ginseng C.A. Meyer (ginseng), a traditional Chinese medicine, is famous for "Qi-tonifying" effect and widely used for healthcare and therapeutic effects in China. Modern pharmacology showed that Ginseng had a potential impact on hematopoietic stem cells (HSCs) that promote the regeneration of all blood cells in the bone marrow. The "Qi-tonifying" effect of ginseng might have close correlation with hematopoietic function. However, the protective effect of ginseng on HSCs has been rarely studied. AIM OF THE STUDY To elucidate the difference of chemical composition and the effects of ginseng extract (GE), total ginsenosides (TG) and total polysaccharides (TP) on HSCs of cyclophosphamide (CYP)-induced mice. MATERIALS AND METHODS The ginsenosides, monosaccharide and molecular distribution of GE, TG, and TP were detected. We established the mouse myelosuppression model induced by CYP. Eight ginsenosides in mice plasma were detected with high-performance liquid chromatography-mass spectrometer (MS)/MS in GE and TG group. Blood cell parameters (red blood cell, hemoglobin, reticulocyte, platelet, white blood cell, neutrophil, and lymphocyte) of plasma, oxidative stress indicators (superoxide dismutase, catalase, glutathione peroxidase, lactate dehydrogenase, malondialdehyde, and myeloperoxidase) of liver, cell differentiation marker (CD33, and GR-1) and colony forming of HSCs were detected. Ribonucleic acid (RNA)-sequencing analysis was performed on purified HSCs to find differentially expressed genes (DEGs). And the expression of DEGs was verified by quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemical (IHC). RESULTS Our results showed that 24 and 34 ginsenosides were detected in the GE and TG, and the total sugar content was 72.28 %, 4.68 %, and 89.79 % in GE, TG and TP, respectively. The weight-average molar mass/number-average molar mass (Mw/Mn) values of GE and TP were 2.96 and 1.23. TP showed homogeneous polysaccharide. The results of animal experiments showed that Rb1, Rc, Rb2, Rb3, and Rd of mouse serum in TG group was 22.91, 11.64, 10.73, 9.36, and 8.61 times in GE group, respectively. GE, TG and TP obviously elevated the numbers of blood cells, and improved oxidative stress indicator of liver. The results of RNA-sequencing analysis showed that DEGs in GE, TG and TP groups were primarily focused on signaling pathways related to HSCs. GE and TG obviously promoted the expression of Notch1, Notch2 and Jag1, and inhibited the expression of Hes1 of HSCs in model mice via activating Notch signal pathway. Meanwhile, GE and TG also obviously promoted the expression of Wnt7b, Wnt10b, and Fzd6 of HSCs by activating Wnt signal pathway. However, TP hardly activated the expression of these genes in Notch and Wnt signal pathways. Moreover, TG significantly increased the expression of CD33, CD38, CD14, CD4, CD19 and Gp1bα, and GE remarkably increased the expressions of CD34, CD14, CD4, and Gp1bα. GE and TG significantly increased the Gr-1hi and decreased the Gr-1neg. However, TP played less role in HSCs. CONCLUSIONS This study found that TG and GE showed a strong protection on HSCs in model mice induced by CYP via activating the Notch and Wnt signal pathways, however, TP could not activate HSCs. Therefore, we think that ginsenosides from GE and TG are important chemical components in protecting the function of HSCs by activating the Notch and Wnt signal pathways.
Collapse
Affiliation(s)
- Xiang Gao
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Benxin Qian
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Tongyi Yuan
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Daian Pan
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Zuguo Liang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Yifei Yin
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Songyan Liu
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - He Zhang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, China.
| |
Collapse
|
|
2
|
Fernandes C, Miranda MCC, Roque CR, Paguada ALP, Mota CAR, Florêncio KGD, Pereira AF, Wong DVT, Oriá RB, Lima-Júnior RCP. Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis? Pharmaceuticals (Basel) 2024; 17:1020. [PMID: 39204125 PMCID: PMC11357004 DOI: 10.3390/ph17081020] [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: 05/29/2024] [Revised: 07/24/2024] [Accepted: 08/01/2024] [Indexed: 09/03/2024] Open
Abstract
Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, a community of microorganisms living in or on the human body, is a critical determinant of drug response and toxicity. Factors such as diet, lifestyle, exposure to xenobiotics, antibiotics use, illness, and genetics can influence the composition of the microbiota. Changes in the intestinal microbiota are particularly influential in drug responsiveness, especially in cancer chemotherapy. The microbiota can modulate an individual's response to a drug, affecting its bioavailability, clinical effect, and toxicity, affecting treatment outcomes and patient quality of life. For instance, the microbiota can convert drugs into active or toxic metabolites, influencing their efficacy and side effects. Alternatively, chemotherapy can also alter the microbiota, creating a bidirectional interplay. Probiotics have shown promise in modulating the microbiome and ameliorating chemotherapy side effects, highlighting the potential for microbiota-targeted interventions in improving cancer treatment outcomes. This opinion paper addresses how environmental factors and chemotherapy-induced dysbiosis impact cancer chemotherapy gastrointestinal toxicity.
Collapse
Affiliation(s)
- Camila Fernandes
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | | | - Cássia Rodrigues Roque
- Laboratory of Tissue Healing, Ontogeny, and Nutrition, Department of Morphology, and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza 60430-170, Brazil; (C.R.R.); (R.B.O.)
| | - Ana Lizeth Padilla Paguada
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | - Carlos Adrian Rodrigues Mota
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | - Katharine Gurgel Dias Florêncio
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | - Anamaria Falcão Pereira
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | - Deysi Viviana Tenazoa Wong
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| | - Reinaldo Barreto Oriá
- Laboratory of Tissue Healing, Ontogeny, and Nutrition, Department of Morphology, and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza 60430-170, Brazil; (C.R.R.); (R.B.O.)
| | - Roberto César Pereira Lima-Júnior
- Department of Physiology and Pharmacology, and Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceara, Rua Cel Nunes de Melo, 1000, Fortaleza 60430-270, Brazil; (C.F.); (A.L.P.P.); (C.A.R.M.); (K.G.D.F.); (A.F.P.); (D.V.T.W.)
| |
Collapse
|
|
3
|
Giram P, Nimma R, Bulbule A, Yadav AS, Gorain M, Venkata Radharani NN, Kundu GC, Garnaik B. Poly(d,l-lactide- co-glycolide) Surface-Anchored Biotin-Loaded Irinotecan Nanoparticles for Active Targeting of Colon Cancer. ACS OMEGA 2024; 9:3807-3826. [PMID: 38284072 PMCID: PMC10809773 DOI: 10.1021/acsomega.3c07833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/30/2024]
Abstract
A poly(d,l-lactide-co-glycolide) (PLGA) copolymer was synthesized using the ring-opening polymerization of d,l-lactide and glycolide monomers in the presence of zinc proline complex in bulk through the green route and was well characterized using attenuated total reflectance-Fourier transform infrared, 1H and 13C nuclear magnetic resonance, gel permeation chromatography, differential scanning calorimetry, X-ray diffraction, matrix-assisted laser desorption/ionization time-of-flight, etc. Furthermore, PLGA-conjugated biotin (PLGA-B) was synthesized using the synthesized PLGA and was employed to fabricate nanoparticles for irinotecan (Ir) delivery. These nanoparticles (PLGA-NP-Ir and PLGA-B-NP-Ir) were tested for physicochemical and biological characteristics. PLGA-B-NP-Ir exhibited a stronger cellular uptake and anticancer activity as compared to PLGA-NP-Ir in CT-26 cancer cells (log p < 0.05). The accumulation and retention of fluorescence-labeled nanoparticles were observed to be better in CT-26-inoculated solid tumors in Balb/c mice. The PLGA-B-NP-Ir-treated group inhibited tumor growth significantly more (log p < 0.001) than the untreated control, PLGA-NP-Ir, and Ir-treated groups. Furthermore, no body weight loss, hematological, and blood biochemical tests demonstrated the nanocarriers' nontoxic nature. This work presents the use of safe PLGA and the demonstration of a proof-of-concept of biotin surface attached PLGA nanoparticle-mediated active targeted Ir administration to combat colon cancer. To treat colon cancer, PLGA-B-NP-Ir performed better due to specific active tumor targeting and greater cellular uptake due to biotin.
Collapse
Affiliation(s)
- Prabhanjan
S. Giram
- Polymer
Science and Engineering Division, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
- Academy
of Scientific and Innovative Research AcSIR Headquarters, CSIR-HRDC Campus Sector 19, Kamla
Nehru Nagar, Ghaziabad, Uttar
Pradesh 201 002, India
| | - Ramakrishna Nimma
- Laboratory
of Tumor, Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science, Pune 411007, India
| | - Anuradha Bulbule
- Laboratory
of Tumor, Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science, Pune 411007, India
| | - Amit Singh Yadav
- Laboratory
of Tumor, Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science, Pune 411007, India
| | - Mahadeo Gorain
- Laboratory
of Tumor, Biology, Angiogenesis and Nanomedicine Research, National Center for Cell Science, Pune 411007, India
| | | | - Gopal C. Kundu
- School
of Biotechnology and Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Institute of Eminence, Bhubaneswar 751 024, India
| | - Baijayantimala Garnaik
- Polymer
Science and Engineering Division, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
- Academy
of Scientific and Innovative Research AcSIR Headquarters, CSIR-HRDC Campus Sector 19, Kamla
Nehru Nagar, Ghaziabad, Uttar
Pradesh 201 002, India
| |
Collapse
|
|
4
|
Yue F, Zeng X, Wang Y, Fang Y, Yue M, Zhao X, Zhu R, Zeng Q, Wei J, Chen T. Bifidobacterium longum SX-1326 ameliorates gastrointestinal toxicity after irinotecan chemotherapy via modulating the P53 signaling pathway and brain-gut axis. BMC Microbiol 2024; 24:8. [PMID: 38172689 PMCID: PMC10763180 DOI: 10.1186/s12866-023-03152-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial. METHODS In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria. RESULTS Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.
Collapse
Affiliation(s)
- Fenfang Yue
- School of Life Science, Nanchang University, Nanchang, 330031, China
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Xiangdi Zeng
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Yufan Wang
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Yilin Fang
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Mengyun Yue
- Department of Neurology, The First Affiliated Hospital, Jiang Xi Medical College, Nanchang University, Nanchang, 330031, China
| | - Xuanqi Zhao
- School of Life Science, Nanchang University, Nanchang, 330031, China
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Ruizhe Zhu
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Qingwei Zeng
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Jing Wei
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China
| | - Tingtao Chen
- School of Life Science, Nanchang University, Nanchang, 330031, China.
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, JiangXi Medical College, Nanchang University, Nanchang, 330031, China.
| |
Collapse
|
|
5
|
Jenvrin A, Perret A, Palmieri LJ, Soularue E, Broudin C, Rance B, Taieb J, Gallois C. Chemotherapy-induced ileitis associated or not with colitis in digestive oncology patients: An AGEO multicentre study. Dig Liver Dis 2023; 55:1426-1433. [PMID: 37045619 DOI: 10.1016/j.dld.2023.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 02/06/2023] [Accepted: 03/07/2023] [Indexed: 04/14/2023]
Abstract
BACKGROUND The characteristics and management of ileitis induced by chemotherapy in cancer patients are poorly described in the literature. METHODS This retrospective multicentre study enroled patients hospitalized in a digestive oncology unit for a symptomatic chemotherapy-induced ileitis. RESULTS Forty-three patients were included, with a regimen based on fluoropyrimidine and/or irinotecan in 95% of cases. Five patients were excluded due to the diagnosis of infectious ileitis (Clostridium difficile in 3 patients, Campylobacter jejuni in 1 patient and cytomegalovirus in 1 patient). The most frequently described symptoms were diarrhoea (77% including 54% of grade 3-4 diarrhoea), abdominal pain (58%), fever (51%) and vomiting (56%). An ileo-colonoscopy was performed in 35% of patients and did not show any specific results or severity criteria. The ileitis was complicated by bowel perforation and/or obstruction in 3 patients. Disease progression was favourable in 1-2 weeks in the vast majority of cases, on symptomatic treatment, allowing resumption of the chemotherapy regimen involved in 67% of patients. CONCLUSION Chemotherapy-induced ileitis is a rare complication that most often involves fluoropyri-midine- and/or irinotecan-based regimens. In most cases, endoscopic examinations were not contributory and do not seem useful in the event of non-severe symptomatology which most often develops favourably on symptomatic therapy, allowing resumption of the chemotherapy involved.
Collapse
Affiliation(s)
- Anaïs Jenvrin
- Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France
| | - Audrey Perret
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - Lola-Jade Palmieri
- Assistance Publique-Hôpitaux de Paris, Gastroenterology and Digestive Oncology Department, Cochin Hospital, Paris, France
| | - Emilie Soularue
- Institut Mutualiste Montsoutris, Department of Medical Oncology, Paris, France
| | - Chloé Broudin
- Paris University; Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France
| | - Bastien Rance
- Université Paris Cité, Inserm, Centre de Recherche des Cordeliers; Assistance Publique-Hôpitaux de Paris, Department of Medical Bioinformatics, Hôpital Européen Georges Pompidou, Paris, France
| | - Julien Taieb
- Paris Cité University; Siric CARPEM; Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France
| | - Claire Gallois
- Paris Cité University; Siric CARPEM; Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.
| |
Collapse
|
|
6
|
Wang L, Sun Z, Shan X, Peng C, Ding H, Feng S, Zhao C, Wang X, Wu J. MicroRNA-223 Inhibits Soybean Glycinin- and β-Conglycinin-Induced Apoptosis of IPEC-J2 Cells by Targeting NLRP-3 in the IEL/IPEC-J2 Co-culture System. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:13745-13756. [PMID: 37682935 DOI: 10.1021/acs.jafc.3c01581] [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: 09/10/2023]
Abstract
The apoptosis of intestinal porcine epithelial cells induced by soybean antigen protein allergy is one of the most important mechanisms responsible for enteritis. MicroRNAs (miRNAs) affect the cellular and physiological functions of all multicellular organisms. We hypothesize that microRNA-223 inhibits soybean glycinin- and β-conglycinin-induced apoptosis of intestinal porcine enterocytes (IPEC-J2) by targeting the NLR family pyrin domain containing 3 (NLRP-3). Using the intestinal interepithelial lymphocyte (IEL)/IPEC-J2 co-culture system as an in vitro model, we investigate the role of microRNA-223 in the regulation of soybean glycinin- and β-conglycinin-induced apoptosis. In co-cultured IEL/IPEC-J2 cells incubated with glycinin or β-conglycinin, microRNA-223 decreased NLRP-3, ASC, caspase-1, caspase-3, FAS, BCL-2, and APAF-1 expressions in IPEC-J2 cells; decreased cytokine and cyclooxygenase-2 levels; significantly increased cell activity; and inhibited apoptosis. These data supported a novel antiallergic mechanism to mitigate the sensitization of soybean antigenic protein, which involves the upregulation of microRNA-223-targeting NLRP-3.
Collapse
Affiliation(s)
- Lei Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Zhifeng Sun
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Xinggen Shan
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Chenglu Peng
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hongyan Ding
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Shibin Feng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Chang Zhao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Xichun Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Jinjie Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| |
Collapse
|
|
7
|
Luisa Valerio de Mello Braga L, Simão G, Silva Schiebel C, Caroline Dos Santos Maia A, Mulinari Turin de Oliveira N, Barbosa da Luz B, Rita Corso C, Soares Fernandes E, Maria Ferreira D. Rodent models for anticancer toxicity studies: contributions to drug development and future perspectives. Drug Discov Today 2023:103626. [PMID: 37224998 DOI: 10.1016/j.drudis.2023.103626] [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: 08/12/2022] [Revised: 05/08/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023]
Abstract
Antineoplastic treatment induces a type of gastrointestinal toxicity known as mucositis. Findings in animal models are usually easily reproducible, and standardized treatment regimens are often used, thus supporting translational science. Essential characteristics of mucositis, including intestinal permeability, inflammation, immune and oxidative responses, and tissue repair mechanisms, can be easily investigated in these models. Given the effects of mucositis on the quality of life of patients with cancer, and the importance of experimental models in the development of more effective new therapeutic alternatives, this review discusses progress and current challenges in using experimental models of mucositis in translational pharmacology research. Teaser Experimental models for studying gastrointestinal mucositis have provided a wealth of information improving the understanding of antineoplastic toxicity.
Collapse
Affiliation(s)
- Lara Luisa Valerio de Mello Braga
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Gisele Simão
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Carolina Silva Schiebel
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Andressa Caroline Dos Santos Maia
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Natalia Mulinari Turin de Oliveira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Bruna Barbosa da Luz
- Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Claudia Rita Corso
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Elizabeth Soares Fernandes
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Daniele Maria Ferreira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil.
| |
Collapse
|
|
8
|
Lee YM, Chen YH, Ou DL, Hsu CL, Liu JH, Ko JY, Hu MCT, Tan CT. SN-38, an active metabolite of irinotecan, enhances anti-PD-1 treatment efficacy in head and neck squamous cell carcinoma. J Pathol 2023; 259:428-440. [PMID: 36641765 DOI: 10.1002/path.6055] [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: 03/26/2022] [Revised: 12/08/2022] [Accepted: 01/12/2023] [Indexed: 01/16/2023]
Abstract
Anti-programmed cell death 1 (anti-PD-1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN-38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand-1 (PD-L1) expression in breast and ovarian tumor models. We analyzed the SN-38-mediated activation of natural killer cells in vitro and explored the efficacy of SN-38 in combination with anti-PD-1 for treatment in vivo. In vitro, SN-38 enhanced the expression of FoxO3a and reduced the expression of c-Myc and PD-L1 dose-dependently in tumor cells. Low-dose SN-38 increased interferon-γ secretion by NK cells and promoted NK cell-mediated cytotoxicity in tumor cells. In vivo studies revealed that at non-cytotoxic drug concentrations, SN-38 significantly enhanced anti-PD-1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T-cell infiltration in post-treatment tumors. RNA-seq analysis indicated that SN-38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Yi-Mei Lee
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.,Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Hsin Chen
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.,Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Da-Liang Ou
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,YongLin Institute of Health, National Taiwan University, Taipei, Taiwan
| | - Chia-Lang Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Hua Liu
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.,Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Jenq-Yuh Ko
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
| | - Mickey C-T Hu
- Panorama Institute of Molecular Medicine, Sunnyvale, CA, USA.,Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ching-Ting Tan
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.,Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.,Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Otolaryngology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| |
Collapse
|
|
9
|
Huang J, Hwang AYM, Jia Y, Kim B, Iskandar M, Mohammed AI, Cirillo N. Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models. Int J Mol Sci 2022; 23:15434. [PMID: 36499758 PMCID: PMC9737148 DOI: 10.3390/ijms232315434] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen's Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Nicola Cirillo
- Melbourne Dental School, The University of Melbourne, Carlton, VIC 3053, Australia
| |
Collapse
|
|
10
|
Jiang ZF, Wu W, Hu HB, Li ZY, Zhong M, Zhang L. P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption. World J Gastroenterol 2022; 28:5265-5279. [PMID: 36185635 PMCID: PMC9521516 DOI: 10.3748/wjg.v28.i36.5265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/20/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
The intestinal mucosa is a highly compartmentalized structure that forms a direct barrier between the host intestine and the environment, and its dysfunction could result in a serious disease. As T cells, which are important components of the mucosal immune system, interact with gut microbiota and maintain intestinal homeostasis, they may be involved in the process of intestinal barrier dysfunction. P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effects of extracellular adenosine triphosphate and is expressed by most innate or adaptive immune cells, including T cells. Current evidence has demonstrated that P2X7R is involved in inflammation and mediates the survival and differentiation of T lymphocytes, indicating its potential role in the regulation of T cell function. In this review, we summarize the available research about the regulatory role and mechanism of P2X7R on the intestinal mucosa-derived T cells in the setting of intestinal barrier dysfunction.
Collapse
Affiliation(s)
- Zhi-Feng Jiang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Wei Wu
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Han-Bing Hu
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Lin Zhang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| |
Collapse
|
|
11
|
Kaliannan K, Donnell SO, Murphy K, Stanton C, Kang C, Wang B, Li XY, Bhan AK, Kang JX. Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome. Int J Mol Sci 2022; 23:5332. [PMID: 35628140 PMCID: PMC9140600 DOI: 10.3390/ijms23105332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/02/2022] [Accepted: 05/06/2022] [Indexed: 02/04/2023] Open
Abstract
Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.
Collapse
Affiliation(s)
- Kanakaraju Kaliannan
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Shane O. Donnell
- School of Microbiology, University College Cork, T12 K8AF Cork, Ireland; (S.O.D.); (C.S.)
- Teagasc Moorepark Food Research Centre, Fermoy, P61 C996 Co. Cork, Ireland
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Kiera Murphy
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Catherine Stanton
- School of Microbiology, University College Cork, T12 K8AF Cork, Ireland; (S.O.D.); (C.S.)
- Teagasc Moorepark Food Research Centre, Fermoy, P61 C996 Co. Cork, Ireland
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Chao Kang
- Department of Nutrition, The General Hospital of Western Theater Command, Chengdu 610000, China;
| | - Bin Wang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Xiang-Yong Li
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Atul K. Bhan
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
| | - Jing X. Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| |
Collapse
|
|
12
|
Giram PS, Wang JTW, Walters AA, Rade PP, Akhtar M, Han S, Faruqu FN, Abdel-Bar HM, Garnaik B, Al-Jamal KT. Green synthesis of methoxy-poly(ethylene glycol)-block-poly(l-lactide-co-glycolide) copolymer using zinc proline as a biocompatible initiator for irinotecan delivery to colon cancer in vivo. Biomater Sci 2021; 9:795-806. [PMID: 33206082 DOI: 10.1039/d0bm01421d] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Poly(lactic-co-glycolic acid) (PLGA) is the most commonly described biocompatible copolymer used in biomedical applications. In this work, a green synthetic approach based on the biocompatible zinc proline complex, as an initiator for PLGA synthesis, is reported for the first time for the synthesis of methoxy-poly(ethylene glycol)-block-poly(l-lactic-co-glycolic acid) (mPEG-PLGA). mPEG-PLGA with controlled molecular weight and narrow polydispersity was synthesised. Its potential for delivery of irinotecan (Ir), a poorly water-soluble chemotherapeutic drug used for the treatment of colon and pancreatic cancer, was studied. Nanoparticles of controlled size (140-160 nm), surface charge (∼-10 mV), release properties and cytotoxicity against CT-26 (colon) and BxPC-3 (pancreatic) cancer cells, were prepared. Tumor accumulation was confirmed by optical imaging of fluorescently labelled nanoparticles. Unlike Tween® 80 coated NP-Ir, the Pluronic® F-127 coated NP-Ir exhibits significant tumor growth delay compared to untreated and blank formulation treated groups in the CT-26 subcutaneous tumor model, after 4 treatments of 30 mg irinotecan per kg dose. Overall, this proof-of-concept study demonstrates that the newly synthesized copolymer, via a green route, is proven to be nontoxic, requires fewer purification steps and has potential applications in drug delivery.
Collapse
Affiliation(s)
- Prabhanjan S Giram
- Polymer Science and Engineering Division, CSIR-National Chemical Laboratory, Pune-411008, India.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Antidiarrheal Effect of Sechang-Zhixie-San on Acute Diarrhea Mice and Network Pharmacology Deciphering Its Characteristics and Potential Mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8880298. [PMID: 33381214 PMCID: PMC7749774 DOI: 10.1155/2020/8880298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/05/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022]
Abstract
Sechang-Zhixie-San (SCZX) is an ancient prescription used for pediatric diarrhea by the Yi people in China, which consists of Rodgersia sambucifolia Hemsley (known as Yantuo and abbreviated as YT) and Bentonite (BN). Now, it is also a Chinese patent medicine used in the clinic to treat infantile diarrhea. Besides evaluating the antidiarrheal effect of SCZX on diarrhea mice induced by Folium Sennae, the purpose of this study is to outline the characteristics of the antidiarrheal effect and reveal the potential mechanisms of SCZX through the analysis of the mechanism and active components of YT via network pharmacology and molecular docking, combined with the research progress of BN obtained from the literature. SCZX (3.12 and 12.48 g/kg) effectively inhibited diarrhea in mice, significantly lowering the loose stool rate (LSR), loose stool level (LSL), and loose stool index (LSI). Using network pharmacology, the "herb-compound-target-pathway-pharmacological action" network was mapped to indicate the antidiarrheal mechanism of YT. And the docking results revealed that 4 components of YT including quercetin, geranyl-1-O-α-L-arabinopyranosyl-(1 ⟶ 6)-β-D-glucopyranoside, 3α-O-(E)-p-hydroxy-cinnamoyl-olean-12-en-27-oic acid, and daucosterol showed significant docking activities with STAT3, EGFR, and SLC10A2, involving 11 pathways such as Th17 cell differentiation, Jak-STAT signaling pathway, ErbB signaling pathway, and HIF-1 signaling pathway. According to our research results and literature reports, the antidiarrheal could be summarized into five aspects: inhibiting intestinal inflammation, acting as a barrier to the intestinal mucosal, regulating water and ion transport, involving the purification of intestinal microorganisms, and intestinal transmission, which might be dependent on multiple proteins and intervention in multiple pathways.
Collapse
|
|
14
|
The Alpha-Lipoic Acid Improves Survival and Prevents Irinotecan-Induced Inflammation and Intestinal Dysmotility in Mice. Pharmaceuticals (Basel) 2020; 13:ph13110361. [PMID: 33152996 PMCID: PMC7692584 DOI: 10.3390/ph13110361] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 01/07/2023] Open
Abstract
Irinotecan, an anticancer drug, induces diarrhea and intestinal inflammation, resulting in an increase in the cost of care and in treatment delays. In this study, we investigated whether alpha-lipoic acid (α-LA) could improve irinotecan-mediated intestinal inflammation, diarrhea and dysmotility. Intestinal mucositis was induced by irinotecan injection (75 mg/kg, i.p., for 4 days) in Swiss mice. α-LA (50, 100 or 200 mg/kg, gavage) was administered daily 1 h before the injection of irinotecan. Duodenum tissues were obtained for inflammation and proliferation analysis. The outcomes: diarrhea, intestinal dysmotility, weight body loss and survival were evaluated. Compared with the control condition, irinotecan diminished (p < 0.05) intestinal villus height, caused a loss of crypt integrity and intense inflammatory cell infiltration, increased myeloperoxidase (MPO), IL-6 and IL-1β levels and decreased reduced glutathione (GSH) levels in duodenum segments and increased gastric retention and decreased liquid retention in the medial intestinal segment, resulting in increased intestinal transit, severe diarrhea and reduced survival (approximately 72%). Furthermore, α-LA (200 mg/kg) pretreatment ameliorated (p < 0.05) these irinotecan-induced effects. Our findings show that α-LA reduced irinotecan-induced inflammation, intestinal dysmotility and diarrhea, resulting in improved survival. α-LA may be a useful therapeutic agent for the treatment of gut dysmotility in patients with intestinal mucositis associated with irinotecan treatment.
Collapse
|
|
15
|
Irinotecan-induced intestinal mucositis in mice: a histopathological study. Cancer Chemother Pharmacol 2020; 87:327-336. [PMID: 33130913 DOI: 10.1007/s00280-020-04186-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/19/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Intestinal mucositis is an important adverse effect of antineoplastic therapy, which remains without adequate treatment. The present study aimed to carry out a complete evaluation of the histopathological changes during irinotecan-induced intestinal mucositis, using the protocol most found in the pharmacological reports nowadays to better understand irinotecan toxicity and support future studies on drug discovery. METHODS Intestinal mucositis was induced by treating swiss mice for 4 days with irinotecan (75 mg/kg, i.p.). After 72 h post irinotecan, the mice were sacrificed and the small intestine and colon were excised to performed histological analysis by stained tissue with hematoxylin/eosin (H&E). RESULTS Histoarchitecture loss, villus/crypt ratio reduction, atrophy of the muscular layer, hypertrophy in the submucosal and mucous layers, ruptures in the epithelium, as well as extent cellular infiltrate and presence of micro abscesses and the fusion of the crypts were observed in the histological analysis. Moreover, duodenum and colon had increased intraepithelial lymphocytes and mitotic figures. However, submucosal ganglia were decreased in the duodenum and increased in the colon. CONCLUSIONS The data obtained in the present study provides new evidence that irinotecan-induced intestinal mucositis highly affects small intestine and colon, further contributing to establish criteria in light of the histopathological changes induced by irinotecan during intestinal mucositis and facilitating inter-study comparisons.
Collapse
|
|
16
|
Chen C, Zhang Q, Yu W, Chang B, Le AD. Oral Mucositis: An Update on Innate Immunity and New Interventional Targets. J Dent Res 2020; 99:1122-1130. [PMID: 32479139 DOI: 10.1177/0022034520925421] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oral mucositis (OM), a common debilitating toxicity associated with chemo- and radiation therapies, is a significant unmet clinical need for head and neck cancer patients. The biological complexities of chemoradiotherapy-induced OM involve interactions among disrupted tissue structures, inflammatory infiltrations, and oral microbiome, whereby several master inflammatory pathways constitute the complicated regulatory networks. Oral mucosal damages triggered by chemoradiotherapy-induced cell apoptosis were further exacerbated by the amplified inflammatory cascades dominantly governed by the innate immune responses. The coexistence of microbiome and innate immune components in oral mucosal barriers indicates that a signaling hub coordinates the interaction between environmental cues and host cells during tissue and immune homeostasis. Dysbiotic shifts in oral microbiota caused by cytotoxic cancer therapies may also contribute to the progression and severity of chemoradiotherapy-induced OM. In this review, we have updated the mechanisms involving innate immunity-governed inflammatory cascades in the pathobiology of chemoradiotherapy-induced OM and the development of new interventional targets for the management of this severe morbidity in head and neck cancer patients.
Collapse
Affiliation(s)
- C Chen
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Q Zhang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - W Yu
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - B Chang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - A D Le
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
17
|
Deng C, Lou Y, Gao Y, Deng B, Su F, Jia L. Efficacy and safety of Shengjiang Xiexin decoction in prophylaxis of chemotherapy-related diarrhea in small cell lung cancer patients: study protocol for a multicenter randomized controlled trial. Trials 2020; 21:370. [PMID: 32357899 PMCID: PMC7193543 DOI: 10.1186/s13063-020-04275-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 03/24/2020] [Indexed: 12/27/2022] Open
Abstract
Background Diarrhea is a common adverse reaction in patients with cancer receiving chemotherapy, for which there is currently no effective method of treatment. Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medicine (TCM) formula, has shown efficacy in alleviating irinotecan-induced diarrhea in preliminary clinical studies. The current study is designed to assess the efficacy and safety of SXD for prophylaxis against irinotecan-induced diarrhea. Additionally, we employ a new approach to analyze and evaluate the data based on the patients’ uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype, which predicts the risk of diarrhea. Methods and design A prospective, double-blind, randomized, placebo-controlled trial will be conducted in patients with small cell lung cancer (SCLC) from five hospitals in China. For this study, 100 irinotecan-naïve patients will be randomly allocated to either the SXD or placebo arms in a 1:1 ratio. Stratified randomization will be used to divide subjects by UGT1A1 genotype into groups with differing risk of diarrhea. The trial will consist of two cycles of chemotherapy with 14 days of oral administration of SXD or placebo administered beginning between 3 days before and up to 11 days after initiation of each chemotherapy cycle. The primary study outcome is the incidence of diarrhea. Secondary outcomes include the degree of diarrhea, the degree of neutropenia, the rate of alterations in chemotherapy regimens, the amount of antidiarrheal drug taken, the rate of hospitalization, and evaluation of chemotherapy efficacy. Discussion This study is the first to use the UGT1A1 genotype to stratify patients into groups based on their risk of diarrhea, and to provide a complete assessment of chemotherapy-related diarrhea (CRD), including records of diarrhea duration, grading the severity of diarrhea, and evaluating concomitant symptoms. Study results will provide high-level clinical evidence on the use of SXD as prophylaxis for CRD. Trial registration Chinese Clinical Trial Register: ChiCTR1800018490. Registered on 20 September 2018. Retrospectively registered. http://www.chictr.org.cn/edit.aspx?pid=25250&htm=4c
Collapse
Affiliation(s)
- Chao Deng
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China
| | - Yanni Lou
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China
| | - Yu Gao
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China.,Beijing University of Chinese Medicine, No.11, East Road, North Third Ring Road, Chao Yang District, Beijing, 100029, China
| | - Bo Deng
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China
| | - Fei Su
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China
| | - Liqun Jia
- Department of medical oncology, integrated traditional Chinese and Western Medicine, China-Japan Friendship Hospital, No.2, East Street, Ying Hua Yuan, Chao Yang District, Beijing, 100029, China.
| |
Collapse
|
|
18
|
Zhu XH, Lang HD, Wang XL, Hui SC, Zhou M, Kang C, Yi L, Mi MT, Zhang Y. Synergy between dihydromyricetin intervention and irinotecan chemotherapy delays the progression of colon cancer in mouse models. Food Funct 2019; 10:2040-2049. [PMID: 30907395 DOI: 10.1039/c8fo01756e] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) is the third highest cause of cancer-related death and the main option for prolonged survival is chemotherapeutic intervention. There is increasing interest in dietary intervention using natural agents to enhance the sensitivity of such invasive chemical treatment. In this study, the chemotherapeutic efficacy of dihydromyricetin (DMY) intervention on treatments involving irinotecan (CPT-11) or gemcitabine (GM) was evaluated in an AOM/DSS-induced colitis-associated colon cancer model and a Min (Apc Min/+) mice model. Our data showed that DMY could promote the CPT-11 effect both in the mouse model of AOM/DSS and Apc Min/+ cancer and had no influence on the GM effect. In AOM/DSS cancer, tumors were sensitive to 100 mg kg-1 DMY chemotherapy under 100 mg kg-1 or 200 mg kg-1 CPT-11. DMY-driven CPT-11 chemotherapy induced enhanced IgG levels and the reduction of Fusobacterium abundance in the gut. In the Min model, CPT-11 with 20 mg kg-1 DMY prevented tumor formation but not with 100 mg kg-1 DMY. Mechanically, chloride ion-dependent CFTR, CLCN4, and CLIC4 signaling are not involved in DMY mediated chemotherapeutic colon tumorigenesis. These results suggested that a suitable dose of DMY could act as a coadjuvant to CPT-11 chemotherapy.
Collapse
Affiliation(s)
- Xiao-Hui Zhu
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Army Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, P.R. China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside. Cancers (Basel) 2019; 11:cancers11060857. [PMID: 31226812 PMCID: PMC6627284 DOI: 10.3390/cancers11060857] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/10/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Mucositis is one of the most common debilitating side effects related to chemotherapy (CT), radiation therapy (RT), targeted agents and immunotherapy. It is a complex process potentially involving any portion of the gastrointestinal tract and injuring the mucosa, leading to inflammatory or ulcerative lesions. Mechanisms and clinical presentation can differ according both to the anatomic site involved (oral or gastrointestinal) and the treatment received. Understanding the pathophysiology and management of mucosal injury as a secondary effect of anti-cancer treatment is an important area of clinical research. Prophylaxis, early diagnosis, and adequate management of complications are essential to increase therapeutic success and, thus, improve the survival outcomes of cancer patients. This review focuses on the pathobiology and management guidelines for mucositis, a secondary effect of old and new anti-cancer treatments, highlighting recent advances in prevention and discussing future research options.
Collapse
|
|
20
|
Qiu Y, Zhang J, Ji R, Zhou Y, Shao L, Chen D, Tan J. Preventative effects of selenium-enriched Bifidobacterium longum on irinotecan-induced small intestinal mucositis in mice. Benef Microbes 2019; 10:569-577. [PMID: 30964326 DOI: 10.3920/bm2018.0096] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intestinal mucositis is a frequent side effect in cancer patients who are treated with chemotherapy. There are no effective treatment strategies to date. To find a novel way to alleviate mucositis, the effects of selenium-enriched Bifidobacterium longum (Se-B. longum) in preventing irinotecan (CPT-11)-induced intestinal mucositis in a mouse model were investigated. We tested the ability of Se-B. longum (Se 0.6 mg/kg, 5×108 cfu/mice) to reduce small intestinal mucositis induced by CPT-11 (75 mg/kg, daily) injected intraperitoneally for four consecutive days in mice. Se-B. longum significantly decreased mortality induced by CPT-11 from 71.4% to 16.7%. CPT-11 induced body weight loss, which was alleviated by preventative and simultaneous administration of Se-B. longum. Se-B. longum significantly decreased the severity of diarrhoea from 11 to 4% compared to the CPT-11 group. Inflammation, including intestinal shortening and upregulation of tumour necrosis factor-α and interleukin-1β induced by CPT- 11, were prevented by Se-B. longum. Se-B. longum is effective in preventing small intestinal mucositis induced by CPT-11 and therefore has potential to be used clinically by cancer patients.
Collapse
Affiliation(s)
- Y Qiu
- 1 School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 201203, China P.R.,3 Pharmacy Department, Shanghai Tenth People's hospital, 301 Yanchang Middle Road, Shanghai 201203, China P. R
| | - J Zhang
- 2 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China P.R
| | - R Ji
- 2 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China P.R
| | - Y Zhou
- 2 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China P.R
| | - L Shao
- 4 Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201203, China P.R
| | - D Chen
- 1 School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 201203, China P.R
| | - J Tan
- 2 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China P.R
| |
Collapse
|
|
21
|
Kotsiou OS, Gourgoulianis KI, Zarogiannis SG. IL-33/ST2 Axis in Organ Fibrosis. Front Immunol 2018; 9:2432. [PMID: 30405626 PMCID: PMC6207585 DOI: 10.3389/fimmu.2018.02432] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.
Collapse
Affiliation(s)
- Ourania S. Kotsiou
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Konstantinos I. Gourgoulianis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Sotirios G. Zarogiannis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| |
Collapse
|