Age-related macular degeneration (AMD) is a debilitating retinal disorder that may lead to progressive vision loss. One contributing factor to AMD pathogenesis is excessive blue light (BL) exposure. In this study, we investigated the therapeutic potential of exosomes derived from human umbilical cord blood mesenchymal stem cells (hUCMSC-EXs) in addressing BL-induced damage to ARPE-19 human retinal pigment epithelial (RPE) cells and explored the underlying mechanisms. Our findings revealed that BL exposure induced morphological alterations in ARPE-19 cells, accompanied by a time-dependent decline in cell viability, increased apoptosis, heightened oxidative stress, and inflammatory responses; however, hUCMSC-EXs dose-dependently mitigated BL-induced ARPE-19 cell damage. Interestingly, hUCMSC-EXs were found to suppress the upregulation of fibroblast growth factor 2 (FGF2) in BL-exposed ARPE-19 cells. Furthermore, FGF2 overexpression partially counteracted the inhibitory effects of hUCMSC-EXs on FGF2 expression and compromised the protective benefits of hUCMSC-EXs against BL-induced ARPE-19 cell damage. In conclusion, our results suggest that hUCMSC-EXs shield ARPE-19 cells from BL-induced harm by inhibiting FGF2 expression.

Endometriosis is a chronic estrogen-dependent inflammatory disease that significantly affects women's health. Polygala fallax Hemsl. (PFH), a traditional Zhuang medicine, has been frequently used for gynecological disorders. This study investigated the therapeutic effects and mechanisms of the alcohol extract of Polygala fallax Hemsl. (ae-PFH) in a rat model of endometriosis, as well as its potential for combination therapy. SD rats were divided into seven groups: control, model, PFH, mifepristone, PFH combined with mifepristone, exosomes, and PFH combined with exosomes. After 21 days of treatment, body weight, organ coefficients, and histopathological changes in uterine and ovarian tissues were analyzed. UPLC-Q-Exactive Orbitrap-MS identified active components in ae-PFH and serum samples, followed by molecular docking with key disease target proteins. Serum levels of inflammatory cytokines and hormones were measured using ELISA, while protein and mRNA expression of key regulatory factors were assessed via Western blot and q-PCR. Ae-PFH reduced lesion size and suppressed inflammation, angiogenesis, and pain by inhibitied the PI3K/AKT pathway. Additionally, in combination therapy, ae-PFH significantly enhanced therapeutic effects of mifepristone or exosomes derived from umbilical cord mesenchymal stem cells. These findings indicated that ae-PFH presentd a promising medical method for the treatment of endometriosis, exhibiting innovative potentiality for combination therapy.

Type 2 diabetes (T2D) is a chronic disease characterized by long-term insulin resistance (IR) and pancreatic β-cell dysfunction. Conventional T2D medication ignores pancreatic β-cell damage. In this study, we designed an oral glucose-responsive nanoparticle for pancreatic β-cell regeneration and treatment of T2D. It was formed by carboxymethyl chitosan (CMC) grafted with 3-aminophenylboronic acid (APBA) as the shell and small-molecule citrus pectin (MCP) spheres encapsulating artemisinin (Art) connected by borate ester bonds. The prepared CMC-APBA wrapped Art-loaded MCP nanoparticles (CAM@Art) had therapeutic effects for the treatment of IR, antioxidant and promotion of pancreatic α-cell differentiation in vitro experiments. In addition, in vivo experiments showed that CAM@Art could reduce blood glucose, oxidative stress and inflammation levels and reverse IR in diabetic rats. Importantly, pancreatic β-cell regeneration was found in islets in vivo. Mechanistically, CAM@Art promotes pancreatic α-cell differentiation by promoting overexpression of the transcription factor Pax4 and ectopic expression of Arx. The results suggest that the present study provides a promising therapeutic strategy for the treatment of diabetic pancreatic β-cell dysfunction.

Sustained hyperglycemia induces complex pathological microenvironment in diabetic wounds, significantly hindering wound healing. Most current therapeutic approaches (e.g., hydrogel dressings) have paid little attention to the effect of blood glucose levels on diabetic wound healing. In this study, a synergetic therapeutic strategy including a wound microenvironment responsive, multifunctional hydrogel and the exosome-mediated glucose regulation is developed for diabetic wound treatment. First, a gelatin-dopamine (Gel-DA) crosslinked hyaluronic acid-phenylboronic acid (HA-PBA) hydrogel (GDHP) is constructed with good injectable, self-healing, and adhesive abilities. Such GDHP hydrogel not only can effectively relieve oxidative stress and reduce inflammation, but also promote keratinocyte migration. Then, ciprofloxacin hydrochloride (CIP·H) is loaded to prepare the GDHPC hydrogel that may respond to diabetic wound microenvironment (e.g., low pH, high glucose and reactive oxygen species) and degrade for controlled release of CIP·H, showing on-demand antibacterial properties. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-exos) are administered via tail vein injection in diabetic mice, which may repair injured pancreatic islets by modulating the pancreatic immune microenvironment, thus promoting insulin secretion and further reducing blood glucose levels. By applying this synergetic therapeutic strategy, the full-thickness cutaneous wounds in type 1 diabetic mice heal well and quickly compared to that treated with the GDHPC hydrogel and the hucMSC-exos alone. This promotion effect on wound healing may associate with reducing inflammation and promoting angiogenesis. This study sheds new light on the development of a dual-action strategy that can effectively maintain glucose homeostasis, improve the wound microenvironment, and consequently promote inside-out repair of diabetic wounds, offering a promising therapeutic avenue for future diabetic wound treatment.

Exosomes secreted by mesenchymal stem cells (MSCs) have been considered as a novel biological therapy for myocardial ischemia/reperfusion injury (MIRI). However, the underlying mechanism of exosomes has not been completely established, especially in the early stage of MIRI. In this study, we primarily investigated the protective effect of exosomes on MIRI from both in vitro and ex vivo perspectives. Bioinformatic analysis was conducted to identify exosomal miRNA associated with myocardial protection, Genes and proteins related to functional studies and myocardial energy metabolism were analyzed and evaluated using techniques such as Polymerase Chain Re-action (PCR), Western blotting, double luciferase biochemical techniques, flow cytometry assay, etc. It was discovered that exosomes ameliorated cardiomyocyte injury t by delivery of miR-132-3p.This process reduced the expression of Phosphatase and tensin homolog (PTEN) mRNA and protein, enhanced the expression of phosphorylated protein kinase (pAKT), regulated the insulin signaling pathway, facilitated intracellular Glucose transporter 4 (GLUT4) protein membrane translocation, and enhanced glucose uptake and Adenosine Triphosphate (ATP) production. This study confirmed, for the first time, that MSC-EXO can provide myocardial protection in the early stages of MIRI through miR-132/PTEN/AKT pathway. This research establishes a theoretical and experimental foundation for the clinical application of MSC-derived exosomes.

Diabetes mellitus (DM) is a chronic widespread metabolic disorder, involving a high blood glucose level which causes multiple serious complications including liver, kidney, brain and peripheral nerves damage. Due to the undesirable side effects of the anti-diabetic drugs, the current studies directed to use stem cells and exosomes to overcome the limitations of traditional therapy. We aimed to compare the antidiabetic effect of Bone marrow mesenchymal stem cells (BMMSCs) and its derived exosomes against diabetic hepatopathy induced by streptozotocin (STZ) in albino rats. Our study was conducted on 28 male albino rats divided into 4 groups {control negative non diabetic group, control positive diabetic group, exosomes treated group received (5 × 109 particle/rat) through tail vein twice per week for one month} and Stem cell treated group received (107) BMMSCs through tail vein twice per week for one month. Hepatic structure together with blood glucose level, liver function enzymes were assayed in addition to a lipid profile tests, oxidative stress, and gene expression. Both treated groups by exosomes and stem cells expressed significantly low levels of fasting blood glucose, liver function parameters (ALT, AST, ALP), lipid profile tests (cholesterol and triglycerides), lipid peroxidation index (MDA), with substantial reduction in IL-1β expression compared to diabetic group. Significantly downregulating the VEGF and elevation of eNOS genes and GSH which suggest the effective role provided by BMMSCs and its derived exosomes for treatment of diabetic hepatopathy. Although, the results of both groups showed near average outcomes, the exosome treated group significantly enhanced liver function enzymes and triglyceride, cholesterol level compared to stem cells treated group. These findings were reinforced by the histopathological and immunohistochemistry examination. The latter showed slight but non-significant improvements in VEGF, eNOS, and IL-1β expression. These minor differences together with practical advantages of exosomes make it preferable over BMMSCs in treatment of diabetic hepatopathy.

The pancreas is made of two compartments: the exocrine pancreas, a source of digestive enzymes, and the endocrine islets which produce vital hormones. Distinct diseases could arise in the pancreas such as diabetes, neuroendocrine tumors, pancreatitis, and pancreatic cancers. Various treatment methods are being researched against these diseases. Treatment with recombinant proteins, therapeutic antibodies, vaccination, gene therapy, tissue engineering, and stem cell treatment are treatment methods. Furthermore, biomarkers are important for both treatment and diagnosis. However, some of the treatment methods mentioned above have not yet been applied to some pancreatic diseases. This review provides insights into the latest advancements in diagnosis and treatment for pancreatic diseases within the scope of medical biotechnology. In addition, some methods that are not yet used for treatment purposes for pancreatic diseases but are used in other diseases that occur in different organs due to similar reasons have been investigated. In this context, possible diagnosis and treatment methods for pancreatic diseases are interpreted. The first aim of this review is to bring together and present the current diagnosis and treatment methods for pancreatic diseases. The second aim is to highlight methods that may have treatment potential by comparing pancreatic diseases that cannot be treated with similar diseases.

Graft-versus-host disease (GvHD) is a prevalent complication following allogeneic hematopoietic stem cell transplantation (HSCT) and is characterized by relatively high morbidity and mortality rates. GvHD can result in extensive systemic damage in patients following allogeneic HSCT (allo-HSCT), with the skin, gastrointestinal tract, and liver frequently being the primary target organs affected. The severe manifestations of acute intestinal GvHD often indicate a poor prognosis for patients after allo-HSCT. Endoscopy and histopathological evaluation remain employed to diagnose GvHD, and auxiliary examinations exclude differential diagnoses. Currently, reliable serum biomarkers for the diagnosis and differential diagnosis of GvHD are scarce. As an essential part of standard transplant protocols, early application of immunosuppressive drugs effectively prevents GvHD. Among them, steroids represent first-line therapeutic agents, and the JAK2 inhibitor ruxolitinib represents the second-line therapeutic agent. Currently, no efficacious treatment modality exists for steroid-resistant aGvHD. Therefore, the diagnosis and treatment of GvHD still face significant medical demands. Extracellular vesicles (EVs) are nanometer to micrometer-scale biomembrane vesicles containing various bioactive components, such as proteins, nucleotides, and metabolites. Distinctive changes in serum-derived EV components occur in patients after allo-HSCT; Hence, EVs are expected to be potential biomarkers for diagnosing and treating GvHD. Furthermore, cell-free therapeutics characterized by EVs derived from mesenchymal stem cells (MSCs) have manifested remarkable therapeutic efficacy in preclinical models and preclinical trials of GvHD. Customized engineered EVs with fewer toxic and side effects for the combined treatment of GvHD hold broad prospects for clinical translation. This review article examines the potential value of translating EVs into clinical applications for the diagnosis and treatment of GvHD. It summarizes the latest advancements and prospects of engineered EVs applying GvHD.

Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are nanoscale lipid bilayer vesicles secreted by mesenchymal stem cells. They inherit the parent cell's attributes, facilitating tissue repair and regeneration, promoting angiogenesis, and modulating the immune response, while offering advantages like reduced immunogenicity, straightforward administration, and enhanced stability for long-term storage. These characteristics elevate MSC-EVs as highly promising in cell-free therapy with notable clinical potential. It is critical to delve into their pharmacokinetics and thoroughly elucidate their intracellular and in vivo trajectories. A detailed summary and evaluation of existing tracing strategies are needed to establish standardized protocols. Here, we have summarized and anticipated the research progress of MSC-EVs in various biomedical imaging techniques, including fluorescence imaging, bioluminescence imaging, nuclear imaging (PET, SPECT), tomographic imaging (CT, MRI), and photoacoustic imaging. The challenges and prospects of MSC-EV tracing strategies, with particular emphasis on clinical translation, have been analyzed, with promising solutions proposed.

The occurrence of diabetic kidney disease (DKD), a critical microvascular issue in diabetes, is progressively on the rise. In recent years, long noncoding RNAs (lncRNAs) have garnered considerable attention as a novel and critical layer of biological regulation. Our knowledge regarding the roles and underlying mechanisms of lncRNAs in various diseases, including DKD, continues to evolve. Similarly, microRNAs (miRNAs), which are small noncoding RNAs, have been recognized as crucial contributors to cellular processes and disease pathogenesis. Emerging studies have highlighted the complex interactions between lncRNAs and miRNAs, particularly in the context of DKD, underscoring their importance in complex human diseases. Renal intrinsic cell damage is an important cause of inducing DKD. Persistent high glucose stimulation leads to remodeling of renal intrinsic cells and a cascade of pathological changes. This article aims to review recent literature on the lncRNAs-mediated regulation of miRNAs affecting renal intrinsic cells in DKD and to propose novel molecular-level therapeutic strategies for DKD. Through in-depth investigation of this dynamic molecular interaction, we can gain a profound understanding of the potential mechanisms underlying diabetic nephropathy, potentially identifying new targets for therapeutic intervention and paving the way for personalized and effective treatments.

Extracellular vesicles (EVs) participate in intercellular communication and play an essential role in physiological and pathological processes. In recent years, EVs have garnered significant attention as cell-free therapeutic alternatives, vectors for drug and gene delivery, biomarkers for disease diagnosis and prognosis, vaccine development, and nutraceuticals. The biodistribution of EVs critically influences their efficacy and toxicity. Therefore, this review aims to discuss the main factors influencing the biodistribution of unmodified EVs, highlighting their distribution patterns, advantages, limitations, and applications under different routes of administration. In addition, we provide a comprehensive discussion of the currently available sources of EVs and summarize the current status of the therapeutic potentials of EVs. By optimizing administration routes and selecting appropriate EV sources, we aim to offer valuable insights to enhance the delivery efficiency and therapeutic efficacy of EVs to target tissues.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission.

We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice.

We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation.

The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD.

Background/Objective: Diabetes mellitus (DM) remains a major global health challenge due to its chronic nature and associated complications. Traditional diagnostic approaches, though effective, often lack the sensitivity required for early-stage detection. Recent advancements in molecular biology have identified RNA molecules, particularly non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as promising biomarkers for diabetes. This review aims to explore the role of RNA-based biomarkers in the diagnosis, prognosis, and management of diabetes, highlighting their potential to revolutionize diabetes care.Method: A comprehensive literature review was conducted using electronic databases including PubMed, Scopus, and Web of Science. Articles published up to 2024 were screened and analyzed to extract relevant findings related to RNA-based diagnostics in diabetes. Emphasis was placed on studies demonstrating clinical utility, mechanistic insights, and translational potential of RNA molecules.Results: Numerous RNA species, particularly miRNAs such as miR-375, miR-29, and lncRNAs like H19 and MEG3, exhibit altered expression patterns in diabetic patients. These molecules are involved in key regulatory pathways of glucose metabolism, insulin resistance, and β-cell function. Circulating RNAs are detectable in various biofluids, enabling non-invasive diagnostic approaches. Emerging technologies, including RNA sequencing and liquid biopsy platforms, have enhanced the sensitivity and specificity of RNA detection, fostering the development of novel diagnostic tools and personalized therapeutic strategies.Conclusion: RNA-based biomarkers hold significant promise in advancing early detection, risk stratification, and therapeutic monitoring in diabetes care. Despite current challenges such as standardization and clinical validation, the integration of RNA diagnostics into routine clinical practice could transform diabetes management, paving the way for precision medicine approaches. Further research and multi-center trials are essential to validate these biomarkers and facilitate their regulatory approval and clinical implementation.

There's a scarcity of drugs effective against nonalcoholic steatohepatitis (NASH). Exosomes from Human umbilical cord mesenchymal stem cells (huc-MSCs) show potential in managing glycolipid metabolism and the immune response. Therefore, further investigations are required to explore their application in NASH and the underlying mechanisms.

C57BL/6J mice were fed with a western diet for 12 weeks to induce NASH, and huc-MSCs exosomes (MSCs-exo) were administered during the feeding period. The effect of MSCs-exo was evaluated by monitoring changes in body weight, fat distribution, blood glucose, and insulin levels, and analyzing pathological alterations in liver tissue. Mechanism investigations were carried out using flow cytometry, immunofluorescence staining, and other experimental techniques.

MSCs-exo could reduce liver fat, inflammation, fibrosis, and improved metabolism to alleviate the progression of NASH. Besides, MSCs-exo could decrease macrophage accumulation in the liver, encouraging M2 over M1 macrophage polarization. Furthermore, our study found that MSCs-exo had a high expression of miR-24-3p, which may regulate macrophage polarization by targeting the interferon-stimulated genes (STING) gene in macrophages, with its overexpression amplifying MSCs-exo's NASH benefits.

These findings suggest that the therapeutic effect of MSCs-exo on NASH may be attributed to the regulation of macrophage M2 polarization through miR-24-3p targeting STING. This provides a scientific basis for future clinical application.

This work compared the potential effects of bone marrow mesenchymal stem cells (BM-MSCs) with BM-MSCs-derived exosomes against impaired autophagy in streptozotocin (STZ)-induced diabetic rats.

Three days after STZ injection, a single dose of (3 ​× ​10^6) BM- MSCs or BM-MSCs-derived exosomes (80 μg/rat) was administered to evaluate their effects against nondiabetic and diabetic control rats. We assessed pancreatic structure via light and electron microscopy and evaluated its staining for insulin and the autophagy marker P62 immunohistochemically. Moreover, autophagy marker LC3 gene expression was examined by PCR.

Both BM-MSCs and BM-MSCs derived exosomes showed histological restoration of pancreatic tissues. Both treatments markedly increased the amount of insulin and significantly decreased the autophagy markers P62 and LC3.

Our findings suggest that both BM-MSCs and BM-MSCs-derived exosomes provides a potential alternative to modulate diabetes mellitus.

Type1 Diabetes (T1D) is an autoimmune disorder characterised by the loss of pancreatic β-cells. This β cell loss occurs primarily through inflammatory pathways culminating in apoptosis. Mesenchymal stromal cells (MSCs) have been heavily studied for therapeutic applications due to their regenerative, anti-apoptotic, immunomodulatory, and anti-inflammatory properties. The therapeutic effects of MSCs are mediated through cell-to-cell contact, differentiation, and the release of paracrine factors, which include the release of extracellular vesicles (EVs). Culturing MSCs in hypoxia, a low oxygen tension state more analogous to their physiological environment, seems to increase the therapeutic efficacy of MSC cell therapy, enhancing their immunomodulatory, anti-inflammatory, and anti-fibrotic properties. This is also the case with MSC-derived EVs, which show altered properties based on the parent cell preconditioning. In this review, we examine the evidence supporting the potential application of hypoxic preconditioning in strengthening MSC-EVs for treating the inflammatory and apoptotic causes of β cell loss in T1D.

Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.

Diabetes mellitus with nonalcoholic fatty liver disease (DM-NAFLD) represents a complex metabolic syndrome with significant clinical challenges. This study explores the therapeutic potential and underlying mechanisms of umbilical cord-derived mesenchymal stem cells (UCMSCs)-derived extracellular vesicles (EVs) in DM-NAFLD.

UCMSCs-EVs were isolated and characterized. DM-NAFLD mouse model was developed through high-energy diet and streptozotocin injection. Additionally, primary mouse hepatocytes were exposed to high glucose to simulate cellular conditions. Hepatic tissue damage, body weight changes, lipid levels, glucose and insulin homeostasis, and hepatic lipid accumulation were evaluated. The interaction between UCMSCs-EVs and hepatocytes was assessed, focusing on the localization and function of circ-Tulp4. The study also investigated the expression of circularRNA TUB-like protein 4 (circ-Tulp4), heterogeneous nuclear ribonucleoprotein C (HNRNPC), abhydrolase domain containing 6 (ABHD6), cleaved Caspase-1, NLR family pyrin domain containing 3 (NLRP3) and cleaved N-terminal gasdermin D (GSDMD-N). The binding of circ-Tulp4 to lysine demethylase 6B (KDM6B) and the subsequent epigenetic regulation of ABHD6 by H3K27me3 were analyzed.

Circ-Tulp4 was reduced, while HNRNPC and ABHD6 were elevated in DM-NAFLD models. UCMSCs-EVs attenuated hepatic steatosis and inhibited the NLRP3/cleaved Caspase-1/GSDMD-N pathway. EVs delivered circ-Tulp4 into hepatocytes, thereby restoring circ-Tulp4 expression. Elevated circ-Tulp4 enhanced the recruitment of H3K27me3 to the HNRNPC promoter through interaction with KDM6B, thus suppressing HNRNPC and ABHD6. Overexpression of HNRNPC or ABHD6 counteracted the protective effects of UCMSCs-EVs, exacerbating pyroptosis and hepatic steatosis in DM-NAFLD.

UCMSCs-EVs deliver circ-Tulp4 into hepatocytes, where circ-Tulp4 inhibits the HNRNPC/ABHD6 axis, thereby reducing pyroptosis and alleviating DM-NAFLD. These findings provide a novel therapeutic avenue for targeting DM-NAFLD through modulation of cell pyroptosis.

Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2 pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.

Painful diabetic neuropathy (PDN) is a challenging complication of diabetes with patients experiencing a painful and burning sensation in their extremities. Existing treatments provide limited relief without addressing the underlying mechanisms of the disease. PDN involves the gradual degeneration of nerve fibers in the skin. Keratinocytes, the most abundant epidermal cell type, are closely positioned to cutaneous nerve terminals, suggesting the possibility of bi-directional communication. Extracellular vesicles are lipid-bilayer encapsulated nanovesicles released from many cell types that mediate cell to cell communication. The role of keratinocyte-derived extracellular vesicles (KDEVs) in influencing signaling between the skin and cutaneous nerve terminals and their contribution to the genesis of PDN has not been explored. In this study, we characterized KDEVs in a well-established high-fat diet mouse model of PDN using primary adult mouse keratinocyte cultures. We obtained highly enriched KDEVs through size-exclusion chromatography and then analyzed their molecular cargo using proteomic analysis and small RNA sequencing. We found significant differences in the protein and microRNA content of high-fat diet KDEVs compared to KDEVs obtained from control mice on a regular diet, including pathways involved in axon guidance and synaptic transmission. Additionally, using an in vivo conditional extracellular vesicle reporter mouse model, we demonstrated that epidermal-originating GFP-tagged KDEVs are retrogradely trafficked into the dorsal root ganglion (DRG) neuron cell bodies. This study presents the first comprehensive isolation and molecular characterization of the KDEV protein and microRNA cargo in RD and HFD mice. Our findings suggest a potential novel communication pathway between keratinocytes and DRG neurons in the skin, which could have implications for PDN.

Metabolic syndrome (MetS) is characterized by abdominal obesity, increased blood pressure (BP), fasting blood glucose (FBG) and triglyceride levels, and reduced high-density lipoprotein (HDL) levels. This study aims to investigate the efficacy of the Wharton's jelly mesenchymal stem cells (WJMSCs)-derived small extracellular vesicles' (sEVs) preparations in managing MetS.

Twenty-four rats were fed with a high-fat and high-fructose diet to induce MetS for 16 weeks and randomized into three groups (n = 8/group): a MetS Control group treated with normal saline, MetS Low Dose (LD) group treated with a LD of sEVs preparations (3 × 109 particle/rat), and MetS High Dose (HD) group treated with a HD of sEVs preparations (9 × 109 particles/rat). The Control Non-Disease (ND) group was given a standard rat diet and autoclaved tap water with normal saline as treatment. Treatments were given via intravenous injection every three weeks for twelve weeks. Rats were assessed every six weeks for physical measurements, FBG, lipid profiles, CRP, leptin, adiponectin, and BP. Necropsy evaluation was performed on the lungs, liver, spleen, and kidney.

Significant reductions in FBG, triglycerides, BP, and increased HDL levels were observed in the treated groups compared to the control group. However, significant abdominal circumference (AC) improvement was not observed in the treated groups. Non-significant associations were found between fasting CRP, leptin, and adiponectin levels with MetS rats after treatment. In addition, sEVs preparations improved inflammation and hemorrhage in the lung and mineralisation in the renal of the treated group.

Human fetal WJMSCs-derived sEVs preparations improve all the clusters of MetS in rats except AC and could be further explored as a treatment for MetS.

The global issue of aging populations has become increasingly prominent, thus the research and development for anti-aging therapies to assure longevity as well as to ameliorate age-related complications is put high on the agenda. The young humoral milieu has been substantiated to impart youthful characteristics to aged cells or organs. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membrane-limited structures that serve as couriers of proteins and genetic material to regulate intercellular communication. Of note, EVs appeared to be an indispensable component of young blood in prolonging lifespans, and circulating EVs have been indicated to mediate the beneficial effect of a young milieu on aging. Human umbilical cord mesenchymal stem cell-derived EVs (HUCMSC-EVs), isolated from the youngest adult stem cell source, are speculated to reproduce the function of circulating EVs in young blood and partially revitalize numerous organs in old animals. Robust evidence has suggested HUCMSC-EVs as muti-target therapeutic agents in combating aging and alleviating age-related degenerative disorders. Here, we provide a comprehensive overview of the anti-aging effects of HUCMSC-EVs in brain, heart, vasculature, kidney, muscle, bone, and other organs. Furthermore, we critically discuss the current investigation on engineering strategies of HUCMSC-EVs, intending to unveil their full potential in the field of anti-aging research.

Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.

Diabetic cardiomyopathy (DCM) is one of the leading causes of death in patients with diabetes mellitus (DM). This study aimed to identify a reliable method for establishing an animal model of DCM for investigation of new targets and treatments.

Eighty-four 4-week-old male Sprague-Dawley rats were randomly allocated to receive a normal diet or a high-fat diet (HFD) in an approximate ratio of 1:3. At 9 weeks of age, rats in the HFD group received streptozotocin (STZ) 30 mg/kg by intraperitoneal injection and rats in the control group received the same volume of buffer solution. The rodent model of DM was deemed to be successfully established when a random blood glucose measurement was >16.7 mmol/L on three consecutive occasions. If necessary, STZ was readministered.

Three of the 64 rats in the HFD group died after a second STZ injection. DM was induced in 14, 39, and 8 rats after one, two, and three injections, respectively, with cumulative success rates of 21.9 %, 82.8 %, and 95.3 %. Three months later, the rats with DM showed persistent hyperglycemia and insulin resistance and developed histopathological changes indicating cardiac hypertrophy, myocardial fibrosis, and diastolic dysfunction. The metabolic and cardiac histopathological changes were consistent regardless of whether DM was induced by one, two, or three injections of STZ.

An HFD combined with one or more intraperitoneal injections of low-dose STZ is a straightforward and reliable method for inducing DCM in rats. When a single dose of STZ fails to induce DM, repeated injections can be considered.

Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder, and urinary exosomal microRNAs (miRNAs) were utilized as potential disease prediction or diagnostic biomarkers in numerous studies. This study investigated the differential expression of urinary exosomal miRNAs between non-diabetes mellitus (NDM) individuals and those with T2DM. Aim: To elucidate the association between urinary exosomal miRNAs and T2DM. Methods: We recruited patients diagnosed with T2DM and NDM individuals in West China Hospital, Sichuan University, from November 2023 to February 2024. Subsequently, we performed sequencing of urinary exosomal microRNAs in both groups. The obtained sequencing results were further validated using RT-qPCR in both the training set and the validation set. Additionally, we conducted logistic regression analysis and Spearman correlation analysis on miRNAs with significant differential expression, as well as analysis of their biological functions. Results: A total of 118 urine samples were collected, 59 from individuals diagnosed with T2DM and 59 from NDM. There were differentially expressed miR-183-5p (p = 0.034) and miR-125a-5p (p = 0.008) between the two groups. Furthermore, multivariate regression analysis demonstrated that higher miR-125a-5p levels were negatively associated with the risk of T2DM (p = 0.044; OR: 0.046; 95% CI: 0.002, 0.922). Bioinformatics analysis indicated that the target genes of miR-183-5p were predominantly involved in insulin signaling and glucose transport processes, while those target genes of miR-125a-5p primarily mediated autophagy. Conclusions: miR-183-5p and miR-125a-5p might be involved in the pathogenesis of T2DM, while higher urinary exosomal miR-125a-5p was negatively associated with the risk of T2DM.

Mesenchymal stem cells based therapy has been used in clinic for almost 20 years and has shown encouraging effects in treating a wide range of diseases. However, the underlying mechanism is far more complicated than it was previously assumed. Mitochondria transfer is one way that recently found to be employed by mesenchymal stem cells to exert its biological effects. As one way of exchanging mitochondrial components, mitochondria transfer determines both mesenchymal stem cells and recipient cell fates. In this review, we describe the factors that contribute to MSCs-MT. Then, the routes and mechanisms of MSCs-MT are summarized to provide a theoretical basis for MSCs therapy. Besides, the advantages and disadvantages of MSCs-MT in clinical application are analyzed.

Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical-pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating.

Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model.

T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central-or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients.

Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.

Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.

Chronic pancreatitis (CP) is a specific clinical disorder that develops from pancreatic fibrosis and immune cell dysregulation. It has been proposed that bone marrow dendritic cells (BMDCs) exosomes have significant effects on immune regulation. Thus, the current study acquainted the prophylactic and therapeutic effects of exosomes derived from BMDCs on a rat model of CP.

BMDCs were prepared and identified, and then the exosomes were isolated by differential ultracentrifugation. Prophylactic and therapeutic effects of exosomes were investigated on L-arginine induced CP model.

Administration of two tail vein injections of exosomes (200 μg/kg/dose suspended in 0.2 ml PBS) markedly improved the pancreatic function and histology compared to CP group. Moreover, exosomes prominently mitigated the increase in amylase, lipase, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and elevated antioxidant enzymes; catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx).

BMDCs exosomes can be considered as a promising candidate, with a high efficacy and stability compared with its parent cell, for management of CP and similar inflammatory diseases.

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21-adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders.

Pathological scarring results from aberrant cutaneous wound healing due to the overactivation of biological behaviors of human skin fibroblasts, characterized by local inordinate inflammation, excessive extracellular matrix and collagen deposition. Yet, its underlying pathogenesis opinions vary, which could be caused by increased local mechanical tension, enhanced and continuous inflammation, gene mutation, as well as cellular metabolic disorder, etc. Metabolic reprogramming is the process by which the metabolic pattern of cells undergoes a systematic adjustment and transformation to adapt to the changes of the external environment and meet the needs of their growth and differentiation. Therefore, the abnormality of metabolic reprogramming in cells within wounds and scars attaches great importance to scar formation. Mesenchymal stem cells-derived exosomes (MSC-Exo) are the extracellular vesicles that play an important role in tissue repair, cancer treatment as well as immune and metabolic regulation. However, there is not a systematic work to detail the relevant studies. Herein, we gave a comprehensive summary of the existing research on three main metabolisms, including glycometabolism, lipid metabolism and amino acid metabolism, and MSC-Exo regulating metabolic reprogramming in wound healing and scar formation for further research reference.

Small extracellular vesicles (sEVs) are lipid bilayer-enclosed particles secreted by living cells. Here, we present a protocol for the collection and isolation of sEVs derived from human umbilical cord mesenchymal stem cells (hucMSCs). We describe steps for characterizing their morphology and integrity by transmission electron microscopy (TEM) and size distribution using nanoparticle tracking analysis (NTA) and an atomic force microscope (AFM). We then detail procedures for assessing nanoparticle size analysis and molecular markers by western blotting and Flow NanoAnalyzer.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease (ESRD), which places considerable economic pressure on society. Traditional therapies, including glycemic control, blood pressure control, blood lipid control, the use of renin-angiotensin system blockers and novel drugs, such as sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor inhibitors and glucagon-like peptide-1 receptor agonists, have been used in DKD patients. Although the above treatment strategies can delay the progression of DKD, most DKD patients still ultimately progress to ESRD. Therefore, new and multimodal treatment methods need to be explored. In recent years, researchers have continuously developed new treatment methods and targets to delay the progression of DKD, including miRNA therapy, stem cell therapy, gene therapy, gut microbiota-targeted therapy and lifestyle intervention. These new molecular therapy methods constitute opportunities to better understand and treat DKD. In this review, we summarize the progress of molecular therapeutics for DKD, leading to new treatment strategies.

The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness.

The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed.

We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2-related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting.

MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.

Painful diabetic neuropathy (PDN) is a challenging complication of diabetes with patients experiencing a painful and burning sensation in their extremities. Existing treatments provide limited relief without addressing the underlying mechanisms of the disease. PDN involves the gradual degeneration of nerve fibers in the skin. Keratinocytes, the most abundant epidermal cell type, are closely positioned to cutaneous nerve terminals, suggesting the possibility of bi-directional communication. Exosomes are small extracellular vesicles released from many cell types that mediate cell to cell communication. The role of keratinocyte-derived exosomes (KDEs) in influencing signaling between the skin and cutaneous nerve terminals and their contribution to the genesis of PDN has not been explored. In this study, we characterized KDEs in a well-established high-fat diet (HFD) mouse model of PDN using primary adult mouse keratinocyte cultures. We obtained highly enriched KDEs through size exclusion chromatography and then analyzed their molecular cargo using proteomic analysis and small RNA sequencing. We found significant differences in the protein and microRNA content of HFD KDEs compared to KDEs obtained from control mice on a regular diet (RD), including pathways involved in axon guidance and synaptic transmission. Additionally, using an in vivo conditional extracellular vesicle (EV) reporter mouse model, we demonstrated that epidermal-originating GFP-tagged KDEs are retrogradely trafficked into the DRG neuron cell body. Overall, our study presents a potential novel mode of communication between keratinocytes and DRG neurons in the skin, revealing a possible role for KDEs in contributing to the axonal degeneration that underlies neuropathic pain in PDN. Moreover, this study presents potential therapeutic targets in the skin for developing more effective, disease-modifying, and better-tolerated topical interventions for patients suffering from PDN, one of the most common and untreatable peripheral neuropathies.

Diabetic nephropathy (DN) presents a significant therapeutic challenge, compounded by complex pathophysiological mechanisms. Recent studies suggest Exendin-4 (Ex-4) as a potential ameliorative agent for DN, albeit with unclear mechanisms. This research investigates the effects and underlying mechanisms of Ex-4-enriched exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) on DN, focusing on their renoprotective properties and interactions with gut microbiota.

Exosomes from hUCMSCs (hUCMSCs-Exo) were loaded with Ex-4 via electroporation. A streptozotocin (STZ) -induced DN mouse model was employed to assess the therapeutic impact of these engineered exosomes. The study further explored immune cell dynamics, mainly CD4+ regulatory T (Treg) cells, using bioinformatics, flow cytometry, and the influence of gut microbiota through antibiotic treatment and specific bacterial reintroduction.

Treatment with hUCMSCs-Exo@Ex-4 significantly improved key DN markers, including blood glucose and proteinuria, alleviating kidney damage. A notable decrease in natural Treg cell infiltration in DN was observed, while Ex-4-loaded exosomes promoted CD4+ Treg cell induction. The therapeutic benefits of hUCMSCs-Exo@Ex-4 were diminished upon CD4+ Treg cell depletion, underscoring their role in this context. Notably, CD4+ Treg cell induction correlated with the presence of Prevotella species, and disruption of gut microbiota adversely affected these cells and the therapeutic efficacy of the treatment. However, the reintroduction of Prevotella strains counteracted these adverse effects.

This study elucidates a novel therapeutic mechanism of Ex-4-loaded hUCMSCs exosomes in DN, highlighting the induction of CD4+ Treg cells mediated by specific gut microbiota components. These findings underscore the potential of leveraging gut microbiota and immune cell interplay in developing effective DN treatments.

Extracellular vesicles (EVs) have attracted great interest due to their great potential in disease diagnosis and therapy. The separation of EVs from complex biofluids with high purity is essential for the accurate analysis of EVs. Despite various methods, there is still no consensus on the best method for high-quality EV isolation and reliable mass production. Therefore, it is important to offer a standardized method for characterizing the properties (size distribution, particle concentration and purity) of EV preparations from different isolation methods. Herein, we employed a NanoCoulter Counter based on the resistive pulse sensing (RPS) strategy that enabled multi-parameter analysis of single EVs to compare the quality and efficiency of different EV isolation techniques including traditional differential ultracentrifugation, ultrafiltration, size exclusion chromatography, membrane affinity binding and polymer precipitation. The data revealed that the NanoCoulter Counter based on the RPS strategy was reliable and effective for the characterization of EVs. The results suggested that although higher particle concentrations were observed in three commercial isolation kits and ultrafiltration, traditional differential ultracentrifugation showed the highest purity. In conclusion, our results from the NanoCoulter Counter provided reliable evidence for the assessment of different EV isolation methods, which contributed to the development of EV-based disease biomarkers and treatments.

Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acetylation, and glycolysis, have been implicated in IBD. An aberrant ubiquitination in IBD is often associated with dysregulated immune responses and inflammation. Mesenchymal stem cells (MSCs) play a crucial role in regulating ubiquitination modifications through the ubiquitin-proteasome system, a cellular machinery responsible for protein degradation. Specifically, MSCs have been shown to influence the ubiquitination of key signaling molecules involved in inflammatory pathways. This paper reviews the recent research progress in MSC-regulated ubiquitination in IBD, highlighting their therapeutic potential in treating IBD and offering a promising avenue for developing targeted interventions to modulate the immune system and alleviate inflammatory conditions.

Preeclampsia (PE) is a pregnancy-specific complication. Its etiology and pathogenesis remain unclear. Previous studies have shown that neutrophil extracellular traps (NETs) cause placental dysfunction and lead to PE. Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) have been widely used to treat different diseases. We investigated whether hUCMSC-EXOs can protect against NET-induced placental damage.

NETs were detected in the placenta by immunofluorescence. The impact of NETs on cellular function and the effect of hUCMSC-EXOs on NET-induced placental damage were evaluated by 5-ethynyl-20-deoxyuridine (EdU) cell proliferation, lactate dehydrogenase (LDH), reactive oxygen species (ROS), and cell migration, invasion and tube formation assays; flow cytometry; and Western blotting.

The number of placental NETs was increased in PE patients compared with control individuals. NETs impaired the function of endothelial cells and trophoblasts. These effects were partially reversed after N-acetyl-L-cysteine (NAC; ROS inhibitor) or DNase I (NET lysing agent) pretreatment. HUCMSC-EXOs ameliorated NET-induced functional impairment of endothelial cells and trophoblasts in vitro, partially reversed NET-induced inhibition of endothelial cell and trophoblast proliferation, and partially restored trophoblast migration and invasion and endothelial cell tube formation. Exosomes inhibited ROS production in these two cell types, suppressed p38 mitogen-activated protein kinase (p38 MAPK) signaling activation, activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, and modulated the Bax, Bim, Bcl-2 and cleaved caspase-3 levels to inhibit apoptosis.

HUCMSC-EXOs can reverse NET-induced placental endothelial cell and trophoblast damage, possibly constituting a theoretical basis for the treatment of PE with exosomes.

Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease globally. It initiates with simple steatosis (NAFL) and can progress to the more severe condition of non-alcoholic steatohepatitis (NASH). NASH often advances to end-stage liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Notably, the transition from NASH to end-stage liver diseases is irreversible, and the precise mechanisms driving this progression are not yet fully understood. Consequently, there is a critical need for the development of effective therapies to arrest or reverse this progression. This review provides a comprehensive overview of the pathogenesis of NASH, examines the current therapeutic targets and pharmacological treatments, and offers insights for future drug discovery and development strategies for NASH therapy.