Role of hydrogen sulfide-microRNA crosstalk in health and disease.

The mutual regulation between hydrogen sulfide (H2S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H2S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H2S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H2S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H2S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H2S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H2S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases.

Role of hydrogen sulfide in health and disease.

In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-ß-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.

Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

The Emerging Roles of Hydrogen Sulfide in Ferroptosis.

Significance: Ferroptosis, a form of regulated cell death characterized by a large amount of lipid peroxidation-mediated membrane damage, joins the evolution of multisystem diseases, for instance, neurodegenerative diseases, chronic obstructive pulmonary disease, acute respiratory distress syndrome, osteoporosis, osteoarthritis, and so forth. Since being identified as the third gasotransmitter in living organisms, the intricate role of hydrogen sulfide (H2S) in ferroptosis has emerged at the forefront of research. Recent Advances: Novel targets in the relevant metabolic pathways have been found, including transferrin receptor 1, cystine/glutamate antiporter, and others, coupled with the exploration of new signaling pathways, particularly the p53 signaling pathway, the nitric oxide/nuclear factor erythroid 2-related factor 2 signaling pathway, and so on. Many diseases such as emphysema and airway inflammation, myocardial diseases, endothelial dysfunction in aging arteries, and traumatic brain injury have recently been found to be alleviated directly by H2S inhibition of ferroptosis. Safe, effective, and tolerable novel H2S donors have been developed and have shown promising results in phase I clinical trials. Critical Issues: Complicated cross talk between the ferroptosis signaling pathway and oncogenic factors results in the risk of cancer when inhibiting ferroptosis. Notably, targeted delivery of H2S is still a challenging task. Future Directions: Discovering more reliable and stable novel H2S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H2S, determining their safety, efficacy, and tolerance.

Recent advances in the role of hydrogen sulfide in age-related diseases.

In recent years, the impact of age-related diseases on human health has become increasingly severe, and developing effective drugs to deal with these diseases has become an urgent task. Considering the essential regulatory role of hydrogen sulfide (H2S) in these diseases, it is regarded as a promising target for treatment. H2S is a novel gaseous transmitter involved in many critical physiological activities, including anti-oxidation, anti-inflammation, and angiogenesis. H2S also regulates cell activities such as cell proliferation, migration, invasion, apoptosis, and autophagy. These regulatory effects of H2S contribute to relieving and treating age-related diseases. In this review, we mainly focus on the pathogenesis and treatment prospects of H2S in regulating age-related diseases.

Relative efficacy of antibody-drug conjugates and other anti-HER2 treatments on survival in HER2-positive advanced breast cancer: a systematic review and meta-analysis.

BACKGROUND: Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC. METHODS: Relevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration's tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis. RESULTS: Meta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49-0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72-0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable. CONCLUSION: Statistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment.

The potential role of hydrogen sulfide in cancer cell apoptosis.

For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma.

Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Construction of the panoptosis-related gene model and characterization of tumor microenvironment infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common fatal cancer worldwide, patients with HCC have a high mortality rate and poor prognosis. PANoptosis is a novel discovery of programmed cell death associated with cancer development. However, the role of PANoptosis in HCC remains obscure. In this study, we enrolled 274 PANoptosis-related genes (PANRGs) and screened 8 genes to set up a prognostic model. A previous scoring system calculated PANscore was utilized to quantify the individual risk level of each HCC patient, and the reliability of the prognostic model has been validated in an external cohort. Nomogram constructed with PANscore and clinical characteristics were used to optimize individualized treatment for each patient. Single-cell analysis revealed a PANoptosis model associated with tumor immune cell infiltration, particularly natural killer (NK) cells. Further exploration of hub genes and assessment of the prognostic role of these 4 hub genes in HCC by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). In conclusion, we evaluated a PANoptosis-based prognostic model as a potential prognostic biomarker for HCC patients.

Fat tissue, a potential Schwann cell reservoir: isolation and identification of adipose-derived Schwann cells.

Schwann cells can be used to promote peripheral nerve repair. However, it is challenging to obtain abundant autologous Schwann cells without sacrificing nerve integrity. In this study, we isolated Schwann cells from murine inguinal adipose tissue and identified the cell phenotype and function in vivo and in vitro. Through H&E and immunofluorescence staining, we detected tiny nerve fibers and Schwann cells in adipose tissue. We evaluated the phenotype of spindle-shaped cells (Schwann cell-like cells, SCLCs) isolated from adipose tissue using immunofluorescence staining and real-time RT-PCR. The results showed that SCLCs expressed specific Schwann cell markers. Analysis of conditioned SCLC culture media showed that, similar to Schwann cells isolated from sciatic nerves, SCLCs secreted NGF and BDNF. SCLCs were harvested from CAG-EGFP transgenic mice and combined with silicone nerve conduits to repair sciatic nerve defects in wild-type mice. Six months post-surgery, we found EGFP-positive SCLCs forming myelin sheaths in the same way as sciatic nerve-derived Schwann cells. This research indicates the existence of Schwann cells in adipose tissue and identifies the spindle-shaped cells isolated from adipose tissue as Schwann cells using in vitro and in vivo evaluations. Thus, SCLCs might be promising seed cells for peripheral nerve tissue engineering.

Bone marrow-derived cells response in proximal regions of nerves after peripheral nerve injury.

In recent years, bone marrow-derived cells have been found to be crucial for peripheral nerve regeneration. After traumatic peripheral nerve injury, bone marrow-derived macrophages quickly infiltrate into the distal regions of nerves. To explore the changes caused by bone marrow-derived cells within the proximal regions of the nerves, sciatic nerves of chimeric mice carrying bone marrow cells expressing green fluorescent protein were crushed to observe the infiltration of invading bone marrow-derived cells. Seven days after surgery, abundant bone marrow-derived cells had infiltrated into the damaged proximal nerve segments. The numbers of these cells increased to a peak at 2 weeks and then gradually returned to normal levels within 30 weeks. Through immunofluorescence staining, many of these cells were identified as macrophages, and they showed a similar infiltration tendency toward distal nerve segments. However, fewer cells infiltrated proximal segments than distal nerve segments. In conclusion, these findings suggest that bone marrow-derived cells response not only occurs within the distal nerve segments but may also take place within the proximal segments of nerve tissues after nerve injury.

SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction.

Alopecia areata is one of the most common autoimmune diseases resulting from T cell-mediated damage of hair follicles. CD8+ T cells infiltrate hair follicles and are responsible for destruction of hair follicles. However the underlying mechanisms for hair loss remain still obscure. In the present study, we identified that suppressor of cytokine signaling-3 (SOCS3), a classical inhibitor of cytokine signaling, significantly inhibits CD8+T cell maturation, interferon-γ (IFN-γ) production and alopecia areata. SOCS3 is downregulated in the skin of alopecia areata patients and murine autoimmune alopecia model. Furthermore, SOCS3 treatment prevents the development of alopecia areata in the graft model. SOCS3 decreases the CD44high CD62Llow effector memory CD8+ T cells, resulting in the decrease of IFN-γ production. The expression of Fas and major histocompatibility complex-1 (MHC I) is upregulated in skin from C3H/HeJ alopecia areata mice, and this increase is suppressed by SOCS3. The SOCS3 level is negative correlation with the Fas and MHC I level in patients with alopecia areata. These results suggest that SOCS3 treatment may be an effective strategy to treat autoimmune alopecia as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.

Peripheral nerve repair with epimysium conduit.

Autologous tissues such as skeletal muscle have high biocampatibility and can effectively promote nerve regeneration compared to other biological and artificial materials; however, the reasonable and effective application of skeletal muscle requires further study. The purpose of this investigation was to assess the possibility of preparing a hollow nerve conduit, termed the epimysium conduit (EMC), using thin crimps of epimysium with skeletal muscle fibers and evaluate its effectiveness in repairing peripheral nerve defects. We prepared nerve conduits containing lumen with the external oblique muscle of the CAG-EFGP transgenic mice using microsurgical techniques for bridge repair of a 5-mm long sciatic nerve defect in wild-type mice. Systematic histological and functional assessments of the regenerated nerves were performed 8 and 12 weeks after surgery. EMC was found to effectively repair the sciatic nerve defect with significantly greater effectiveness than artificial conduits; however, the repair effect of EMC was lower than that of autologous nerve grafting for some parameters. In addition, our findings showed that some EMC-derived cell components migrated into the region of the regenerated nerves and contributed to reconstruction. Based on these findings, we conclude that a hollow conduit prepared with epimysium and a few skeletal muscle fibers is ideal for repairing peripheral nerve defects, and the cell components in the grafts contribute to nerve regeneration and structural remodeling, which provides an alternative option for the emergency primary repair of peripheral nerve defects in clinical practice.

MRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemia.

Adipose-derived stem cells (ADSCs) exhibit tremendous potential for repair of ischemic diseases. However, studies on the fate, migration, differentiation, and body distribution of the labeled ADSCs are rarely reported. In this study, magnetic iron oxide nanoparticles were designed, synthesized, and coated with meso-2,3-dimercaptosuccinic acid (DMSA) to produce DMSA nanoparticles (DMSA-NPs). The properties, size distribution, and characterization of DMSA-NPs were evaluated. Green fluorescent protein expressing ADSCs (GFP-ADSCs) were obtained and labeled with DMSA-NPs. The viability, cytotoxicity and multi-differentiation capacity of labeled GFP-ADSCs were evaluated in vitro. Labeled and non-labeled GFP-ADSCs were injected into a mouse model of hindlimb ischemia, and 3T magnetic resonance imaging (MRI) was acquired. The synthesized DMSA-NPs efficiently labeled the GFP-ADSCs in vitro and in vivo without affecting cell viability, proliferation, cell cycle, and multi-differentiation capacity. The MRI showed hypointense spots in the labeled GFP-ADSCs that lasted up to 8 weeks. Prussian blue staining and immunofluorescence assay at 4 and 8 weeks indicated that the labeled GFP-ADSCs were in and around the ischemic sites and some differentiated into capillaries. This observation is identical to that seen for transplants of unlabeled cells. Labeled cells were also identified mainly in the liver and spleen, with significantly smaller amounts in the lungs, intestines, heart, and kidney. Developed DMSA-NPs were shown to exhibit a considerable potential for use as nanoprobes for MRI of stem cells, which will enhance our understanding of cell-based therapeutic strategies for ischemic diseases.

Cryopreservation of tissue-engineered epithelial sheets in trehalose.

Tissue-engineered epidermal membranes are useful for clinical wound healing. To facilitate these products in the clinic, optimized storage methods need to be developed. We studied the efficiency of extracellular trehalose at various concentrations for cryopreserving human tissue-engineered epidermal membranes compared with that of dimethyl-sulfoxide (DMSO) used by most organ banks for cryopreserving skin grafts and artificial skin substitutes. Keratinocyte (KC) viability, proliferation and marker expression following cryopreservation in trehalose were examined with similar results to those using DMSO. Trehalose concentration (0.4m) was optimized according to the described cellular activities following cryopreservation. Artificial epidermal substitutes were then cryopreserved in trehalose at the optimized concentration. Cell viability, growth factor secretion and wound healing properties of cryopreserved artificial epidermal substitutes using nude mice were examined and compared with those of DMSO cryopreservation. Cryopreservation with trehalose enhanced human KC viability in suspension and artificial skin substitutes. In addition, trehalose cryopreservation provided fast recovery of EGF and TGF-ß1 secretion by KCs after thawing. When transplanted into nude mice, trehalose-cryopreserved artificial skin repaired skin defects in a similar manner to that of a non-cryopreserved control. Moreover, trehalose-cryopreserved artificial skin resulted in engraftment and wound closure that was significantly enhanced compared with that of DMSO-cryopreserved epidermal membranes. The results indicate that the use of trehalose improves cryopreservation of tissue-engineered epithelial sheets.

Adenoviral transduction of hTGF-beta1 enhances the chondrogenesis of bone marrow derived stromal cells.

TGF-beta1 plays a necessary and important role in the induction of chondrogenic differentiation of bone marrow stromal cells (BMSCs). In this study, porcine BMSCs were infected with a replication-deficient adenovirus expression vector carrying the hTGF-beta1 gene. The transduced BMSCs were cultured as pelleted micromasses in vitro for 21 days, seeded onto disk-shaped PGA scaffolds for 3 days and subsequently implanted into the subcutaneous tissue of mice. BMSCs transduced with AdhTGF-beta1 expressed and secreted more hTGF-beta1 protein in vitro than those of the control group. Histological and immunohistological examination of the pellets revealed robust chondrogenic differentiation. Tissues made from cells transduced with AdhTGF-beta1 exhibited neocartilage formation after 3 weeks in vivo. The neocartilage occupied 42 +/- 5% of the total tissue volume which was significantly greater than that of the control group. Furthermore, there was extensive staining for sulfated proteoglycans and type II collagen in the AdhTGF-beta1 group compared to controls, and quantification of GAG content showed significantly greater amounts of GAG in experimental groups. The results demonstrate that transfer of hTGF-beta1 into BMSCs via adenoviral transduction can induce chondrogenic differentiation in vitro and enhance chondrogenesis in vivo.

Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) are a widely researched adult stem cell population capable of differentiation into various lineages. Because many promising applications of tissue engineering require cell expansion following harvest and involve the treatment of diseases and conditions found in an aging population, the effect of donor age and ex vivo handling must be understood in order to develop clinical techniques and therapeutics based on these cells. Furthermore, there currently exists little understanding as to how these two factors may be influenced by one another. RESULTS: Differences in the adipogenic, chondrogenic, and osteogenic differentiation capacity of murine MSCs harvested from donor animals of different age and number of passages of these cells were observed. Cells from younger donors adhered to tissue culture polystyrene better and proliferated in greater number than those from older animals. Chondrogenic and osteogenic potential decreased with age for each group, and adipogenic differentiation decreased only in cells from the oldest donors. Significant decreases in differentiation potentials due to passage were observed as well for osteogenesis of BMSCs from the youngest donors and chondrogenesis of the cells from the oldest donors. CONCLUSION: Both increasing age and the number of passages have lineage dependent effects on BMSC differentiation potential. Furthermore, there is an obvious interplay between donor age and cell passage that in the future must be accounted for when developing cell-based therapies for clinical use.

A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1.

Bone-marrow-derived mesenchymal stem cells (MSCs) have been shown to possess immunosuppressive properties, e.g., by inhibiting T cell proliferation. Activated T cells can also enhance the immunosuppression ability of MSCs. The precise mechanisms underlying MSC-mediated immunosuppression remain largely undefined, although both cell-cell contact and soluble factors have been implicated; nor is it clear how the immunosuppressive property of MSCs is modulated by T cells. Using MSCs isolated from mouse bone marrow, we show here that interferon gamma (IFNgamma), a well-known proinflammatory cytokine produced by activated T cells, plays an important role in priming the immunosuppressive property of MSCs. Mechanistically, IFNgamma acts directly on MSCs and leads to up-regulation of B7-H1, an inhibitory surface molecule in these stem cells. MSCs primed by activated T cells derived from IFNgamma-/- mouse exhibited dramatically reduced ability to suppress T cell proliferation, a defect that can be rescued by supplying exogenous IFNgamma. Moreover, siRNA-mediated knockdown of B7-H1 in MSCs abolished immunosuppression by these cells. Taken together, our results suggest that IFNgamma plays a critical role in triggering the immunosuppresion by MSCs through up-regulating B7-H1 in these cells, and provide evidence supporting the cell-cell contact mechanism in MSC-mediated immunosuppression.

[Tissue engineered nerve based on plasma treatment and BMSCs].

OBJECTIVE: To evaluate the effect of the plasma treated PLGA nerve conduits seeded BMSCs on repairing SD rat sciatic nerve defects. METHODS: BMSCs were acquired from 30 newborn SD rats. After amplified and passaged for 3 times, PLGA nerve conduits were prepared and some of them were treated with plasma. A 1-cm-length sciatic nerve defect was made in 30 4-week-old SD rats, then they were randomly divided into 3 groups for three different nerve defects reconstruction methods (n = 10). In the experimental group, defect was repaired by plasma treatment and PGLA nerve conduits seeded with BMSCs; in the control group, by normal PLGA nerve conduits seeded with BMSCs; and in the autologous group, by autologous nerve. At 6 weeks after the surgery, the dynamic walking pattern was recorded and the sciatic function index (SFI) was calculated; the electrophysiological test was taken; the gastrocnemius wet weight recovery rate was calculated; and the image analysis of regenerated nerve was made. RESULTS: All rats survived after the surgery and lived to the end of the experiment. At 6 weeks after the surgery, the dynamic walking pattern of the experimental group and autologous group was better than that of the control group. The SFI value of the experimental, control and autologous groups was -51.02 +/- 6.54, -58.73 +/- 7.87 and 48.73 +/- 3.95, respectively, showing statistically significant differences among the experimental group, control group and autologous group (P < 0.05). The results of the motor nerve conduction velocity and wave amplitude showed that there were statistically significant differences between the experimental group and the control group (P < 0.05), and between the control group and the autologous group (P < 0.01); but no significant difference between the experimental group and autologous group (P > 0.05); The gastrocnemius wet weight recovery rate of the experimental, control and autologous groups was 56.13% +/- 4.27%, 43.14% +/- 6.52%, 59.47% +/- 3.85%, respectively; showing statistically significant differences among experimental group, control group and autologous group (P < 0.05). The density, diameter of regenerated nerve fiber as well as neural sheath thickness of the experimental group were all higher than those of the control group (P < 0.05) and lower than those of the autologous nerve group (P < 0.05); there was significant difference between the control group and the autologous group (P < 0.01). CONCLUSION: Plasma treated PLGA nerve conduits seeded with BMSCs can effectively repair sciatic nerve defects and provide a new strategy for the development of tissue engineered nerve to repair the peripheral nerve defects.