mir-605-3p prevents liver premetastatic niche formation by inhibiting angiogenesis via decreasing exosomal nos3 release in gastric cancer.

BACKGROUND: Cancer-induced pre-metastatic niches (PMNs) play a decisive role in promoting metastasis by facilitating angiogenesis in distant sites. Evidence accumulates suggesting that microRNAs (miRNAs) exert significant influence on angiogenesis during PMN formation, yet their specific roles and regulatory mechanisms in gastric cancer (GC) remain underexplored. METHODS: miR-605-3p was identified through miRNA-seq and validated by qRT-PCR. Its correlation with the clinicopathological characteristics and prognosis was analyzed in GC. Functional assays were performed to examine angiogenesis both in vitro and in vivo. The related molecular mechanisms were elucidated using RNA-seq, immunofluorescence, transmission electron microscopy, nanoparticle tracking analysis, enzyme-linked immunosorbent assay, luciferase reporter assays and bioinformatics analysis. RESULTS: miR-605-3p was screened as a candidate miRNA that may regulate angiogenesis in GC. Low expression of miR-605-3p is associated with shorter overall survival and disease-free survival in GC. miR-605-3p-mediated GC-secreted exosomes regulate angiogenesis by regulating exosomal nitric oxide synthase 3 (NOS3) derived from GC cells. Mechanistically, miR-605-3p reduced the secretion of exosomes by inhibiting vesicle-associated membrane protein 3 (VAMP3) expression and affects the transport of multivesicular bodies to the GC cell membrane. At the same time, miR-605-3p reduces NOS3 levels in exosomes by inhibiting the expression of intracellular NOS3. Upon uptake of GC cell-derived exosomal NOS3, human umbilical vein endothelial cells exhibited increased nitric oxide levels, which induced angiogenesis, established liver PMN and ultimately promoted the occurrence of liver metastasis. Furthermore, a high level of plasma exosomal NOS3 was clinically associated with metastasis in GC patients. CONCLUSIONS: miR-605-3p may play a pivotal role in regulating VAMP3-mediated secretion of exosomal NOS3, thereby affecting the formation of GC PMN and thus inhibiting GC metastasis.

A Flavonoid Glycoside Compound from Siraitia grosvenorii with Anti-Inflammatory and Hepatoprotective Effects In Vitro.

Inflammation is a pivotal factor in the development and advancement of conditions like NAFLD and asthma. Diet can affect several phases of inflammation and significantly influence multiple inflammatory disorders. Siraitia grosvenorii, a traditional Chinese edible and medicinal plant, is considered beneficial to health. Flavonoids can suppress inflammatory cytokines, which play a crucial role in regulating inflammation. In the present experiments, kaempferol 3-O-α-L-rhamnoside-7-O-ß-D-xylosyl(1→2)-O-α-L-rhamnoside (SGPF) is a flavonoid glycoside that was first isolated from S. grosvenorii. A series of experimental investigations were carried out to investigate whether the flavonoid component has anti-inflammatory and hepatoprotective effects in this plant. The researchers showed that SGPF has a stronger modulation of protein expression in LPS-induced macrophages (MH-S) and OA-induced HepG2 cells. The drug was dose-dependent on cells, and in the TLR4/NF-κB/MyD88 pathway and Nrf2/HO-1 pathway, SGPF regulated all protein expression. SGPF has a clear anti-inflammatory and hepatoprotective function in inflammatory conditions.

A comprehensive review of Siraitia grosvenorii (Swingle) C. Jeffrey: chemical composition, pharmacology, toxicology, status of resources development, and applications.

Siraitia grosvenorii (Swingle) C. Jeffrey (S. grosvenorii), a perennial indigenous liana from the Cucurbitaceae family, has historically played a significant role in southern China's traditional remedies for various ailments. Its dual classification by the Chinese Ministry of Health for both medicinal and food utility underscores its has the potential of versatile applications. Recent research has shed light on the chemical composition, pharmacological effects, and toxicity of S. grosvenorii. Its active ingredients include triterpenoids, flavonoids, amino acids, volatile oils, polysaccharides, minerals, vitamins, and other microconstituents. Apart from being a natural sweetener, S. grosvenorii has been found to have numerous pharmacological effects, including alleviating cough and phlegm, preventing dental caries, exerting anti-inflammatory and anti-allergic effects, anti-aging and anti-oxidative, hypoglycemic, lipid-lowering, anti-depression, anti-fatigue, anti-schizophrenic, anti-Parkinson, anti-fibrotic, and anti-tumor activities. Despite its versatile potential, there is still a lack of systematic research on S. grosvenorii to date. This paper aims to address this gap by providing an overview of the main active components, pharmacological efficacy, toxicity, current status of development and application, development dilemmas, and strategies for intensive exploitation and utilization of S. grosvenorii. This paper aims to serve as a guide for researchers and practitioners committed to exploiting the biological resources of S. grosvenorii and further exploring its interdisciplinary potential.

HDAC6 Enhances Endoglin Expression through Deacetylation of Transcription Factor SP1, Potentiating BMP9-Induced Angiogenesis.

Histone deacetylase 6 (HDAC6) plays a crucial role in the acetylation of non-histone proteins and is notably implicated in angiogenesis, though its underlying mechanisms were previously not fully understood. This study conducted transcriptomic and proteomic analyses on vascular endothelial cells with HDAC6 knockdown, identifying endoglin (ENG) as a key downstream protein regulated by HDAC6. This protein is vital for maintaining vascular integrity and plays a complex role in angiogenesis, particularly in its interaction with bone morphogenetic protein 9 (BMP9). In experiments using human umbilical vein endothelial cells (HUVECs), the pro-angiogenic effects of BMP9 were observed, which diminished following the knockdown of HDAC6 and ENG. Western blot analysis revealed that BMP9 treatment increased SMAD1/5/9 phosphorylation, a process hindered by HDAC6 knockdown, correlating with reduced ENG expression. Mechanistically, our study indicates that HDAC6 modulates ENG transcription by influencing promoter activity, leading to increased acetylation of transcription factor SP1 and consequently altering its transcriptional activity. Additionally, the study delves into the structural role of HDAC6, particularly its CD2 domain, in regulating SP1 acetylation and subsequently ENG expression. In conclusion, the present study underscores the critical function of HDAC6 in modulating SP1 acetylation and ENG expression, thereby significantly affecting BMP9-mediated angiogenesis. This finding highlights the potential of HDAC6 as a therapeutic target in angiogenesis-related processes.

Association of glutamate receptor gene polymorphisms with attention-deficit hyperactivity disorder susceptibility: a systematic review and meta-analysis.

Background: There is a growing body of evidence indicating a possible association between genetic variations and attention-deficit hyperactivity disorder (ADHD), although the results have been inconsistent. The objective of this study was to evaluate the correlation between the GRIN2A, GRIN2B and GRM7 gene polymorphisms and ADHD. Methods: A comprehensive meta-analysis and subgroup evaluation was conducted using a fixed-effects model to analyze the association between ADHD and GRIN2B (rs2284411), GRIN2A (rs2229193), and GRM7 (rs3792452) in six genetic models (dominant, recessive, overdominant, homozygous, heterozygous, and allele models). Results: The meta-analysis comprised 8 studies. The overall analysis showed that the GRIN2B rs2284411 T allele and T carries were significantly associated with a decreased risk of ADHD (dominant model:TT + CT vs. CC: OR = 0.783; 95% CI: 0.627-0.980; p = 0.032, allele model:T vs. C: OR = 0.795; 95% CI: 0.656-0.964; p = 0.019), especially in the Korean subgroup (dominant model:TT + CT vs. CC: OR = 0.640; 95% CI: 0.442-0.928; p = 0.019, overdominant model: CT vs. TT + CC: OR = 0.641; 95% CI: 0.438-0.938; p = 0.022, allele model:T vs. C: OR = 0.712; 95% CI: 0.521-0.974; p = 0.034 and heterozygous model: CT vs. CC: OR = 0.630; 95% CI: 0.429-0.925; p = 0.018). However, no meaningful associations were found for rs2229193 and rs3792452. Conclusion: The results of the meta-analysis provide strong evidence that the rs2284411 T allele is significantly associated with reduced susceptibility to ADHD, particularly in the Korean population.

Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways.

BACKGROUND: The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PURPOSE: The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. STUDY DESIGN: Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. METHODS: Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. RESULTS: Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1ß, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. CONCLUSIONS: SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.

Genotype-guided new approach for dose optimisation of hydroxychloroquine administration in Chinese patients with SLE.

OBJECTIVES: The study aims to investigate the impact of gene polymorphisms on blood hydroxychloroquine (HCQ) concentrations in patients with SLE and provide guidelines for individualised care. METHODS: 489 Chinese patients with SLE taking HCQ for more than 3 months were collected in this study. The blood HCQ, desethylhydroxychloroquine (DHCQ) and desethylchloroquine concentrations were measured. The optimal blood concentration of HCQ was determined by receiver operating characteristic curve analysis. Single nucleotide polymorphisms of metabolic enzymes involved in HCQ metabolism were genotyped and the associations with treatment effects were investigated. RESULTS: The cut-off value of HCQ was 559.67 ng/mL, with sensitivity and specificity values of 0.51 and 0.89, respectively. The TC and CC genotypes of CYP2C8 (rs7910936) were significantly related to the increase in blood HCQ concentrations, and the CYP2C8 (rs10882521) TT genotype was associated with lower blood HCQ concentrations. The DHCQ:HCQ ratio was highest in patients with the GG genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the AA genotype. Patients with the CYP2C8 (rs7910936) CC genotype were more likely to achieve the optimal blood concentration (p=0.030) in HCQ 200 mg/day group and patients with the CYP2D6*10 (rs1065852) GG genotype were more likely to reach the optimal blood concentration (p=0.049) in 400 mg/day group. CONCLUSIONS: Our results suggest that the optimal blood concentration of HCQ measured approximately 12-18 hours after the last dosage may be between 500 and 600 ng/mL in Chinese patients with SLE. The observed variations in HCQ concentrations between individuals can potentially be attributed to genetic polymorphisms in CYP2D6*10 (rs1065852) and CYP2C8 (rs7910936 and rs10882521). Genotypical testing of patients and regular monitoring of blood levels are recommended for optimising HCQ dosage management in Chinese patients with SLE. TRIAL REGISTRATION NUMBER: ChiCTR2300070628.

Identification of polyunsaturated fatty acids as potential biomarkers of osteoarthritis after sodium hyaluronate and mesenchymal stem cell treatment through metabolomics.

Introduction: Osteoarthritis (OA) is a prevalent joint disorder worldwide. Sodium hyaluronate (SH) and mesenchymal stem cells (MSCs) are promising therapeutic strategies for OA. Previous studies showed they could improve knee function and clinical symptoms of OA. However, the mechanism of the therapeutic effects on the improvement of OA has not been clearly explained. Methods: In our study, we used a technique called 5-(diisopropylamino)amylamine derivatization liquid chromatography coupled with mass spectrometry to find the metabolites in OA synovial fluid under different treatments. Results and Discussion: After looking into the metabolomics, we discovered that SH and MSC treatment led to the downregulation of ω-6 polyunsaturated fatty acids (PUFAs) and the upregulation of ω-3 PUFAs. Significantly, the contents of 5(S)-HETE, PGA2, PGB2, and PGJ2 were lower in the MSC group than in the SH group after quantification using 5-(diisopropylamino)amylamine derivatization-UHPLC-QQQ-MS. This is the first report on the relationship of 11(S)-HETE, PGA2, PGB2, PGF2ß, 11ß-PGF2α, and DK-PGE2 with OA. Moreover, the correlation analysis of metabolites and inflammation factors showed the positive association of ω-6 PUFAs with pro-inflammation cytokines, and of ω-3 PUFAs with anti-inflammation cytokines. Our results indicated the therapeutic effect of SH and MSCs in patients with OA. In addition, this reliable metabolic approach could uncover novel biomarkers to treat OA.

Risk factors for at-risk foot and peripheral artery disease among the population with diabetes: A multicommunity-based cross-sectional study.

AIMS: This study aimed to investigate the prevalence, characteristics, and influence factors of the at-risk foot with diabetes mellitus (DM). METHODS: This study included 3030 DM patients from the at-risk foot screening program of Shanghai in China between March 21 and April 30 in 2021. Data were collected from the questionnaire survey, physical examination, and fasting blood sample. RESULTS: The prevalence of at-risk foot was 27.8% among DM patients. After adjusted, the risk of higher at-risk grade increased with age and urinary albumin creatinine ratio (OR = 1.04, 95%CI = 1.02-1.06; OR = 1.001, 95%CI = 1.000-1.002, respectively), whereas decreased with estimated glomerular filtration rate (eGFR) (OR = 0.991, 95%CI = 0.984-0.998). The incidence of peripheral artery disease (PAD) was 11.1% in all people with DM, and age, pulse rate, and low-density lipoprotein were independent risk factors for PAD. In contrast, high-density lipoprotein, eGFR, and lymphocyte-to-monocyte ratio were independent protective factors for PAD. Glycated hemoglobin HbA1c was not an independent risk factor for increased risk grade or more severe PAD. CONCLUSIONS: The at-risk foot accounted for a high percentage among DM patients. Advanced age and renal dysfunction are independent risk factors for the at-risk foot. Glycemic control does not reduce the risk grade of at-risk foot and the incidence of PAD.

Retrospective analysis and preliminary laboratory validation of treatment efficacy and blood lipid levels in patients with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis is a systemic disease characterized by progressive chronic inflammation resulting in destruction of synovial joints. In addition to joint involvement, abnormal blood lipid indexes have also been found in RA patients. The correlation between various blood lipid indexes and the treatment effects were assessed in patients with rheumatoid arthritis, for the purposes to find a better medication strategy for RA. METHODS: One hundred nineteen rheumatoid arthritis patients were recruited and divided into two groups, 45 patients with significant drug treatment effect and 45 patients with insignificant drug treatment effect through the nearest neighbor matching method in propensity score. The correlation between various blood lipid indexes and drug treatment effect of rheumatoid arthritis patients was analyzed. A mouse model of rheumatoid arthritis was constructed in the laboratory; methotrexate was treated as a positive drug. We observe and record the onset of rheumatoid arthritis in mice, as well as the proportion of immune cells, the expression of inflammatory factors, and the changes in blood lipid profiles was done. RESULTS: The levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), and erythrocyte sedimentation rate (ESR) in rheumatoid arthritis patients were significantly different between the two groups (P < 0.05). There was no significant difference in other indexes between the two groups (P > 0.05). Methotrexate had a good therapeutic effect on CIA model mice, and the levels of TC and HDL-C in the treatment group were higher than those in the model group. CONCLUSION: There is a high correlation between the levels of TC and HDL-C in rheumatoid arthritis patients and the effect of drug treatment. In the clinical treatment of rheumatoid arthritis, we should focus on improving the blood lipid indexes such as TC and HDL-C, and explore more targeted individualized administration, so as to achieve better and faster treatment effect in patients with rheumatoid arthritis. Key Points • In this research, we found that the TC and HDL-C level in RA patients' blood is highly related with the therapeutic effect, and a lower level of TC and HDL-C is better for therapeutic effect of RA.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

Dietary Supplementation of Ancientino Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress.

Ancientino, a complex dietary fiber supplement mimicking the ancient diet, has improved chronic heart failure, kidney function, and constipation. However, its effect on ulcerative colitis is unknown. This study explores the impact of Ancientino on colitis caused by dextran sulfate sodium (DSS) and its mechanisms. Data analyses showed that Ancientino alleviated bodyweight loss, colon shortening and injury, and disease activity index (DAI) score, regulated levels of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-1 beta (IL-1ß), and interleukin 6 (IL-6)), reduced intestinal permeability (d-lactate and endotoxin), fluorescein isothiocyanate-dextran (FITC-dextran), and diamine oxidase (DAO), repaired colonic function (ZO-1 and occludin), and suppressed oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA)) in vivo and in vitro. In short, this study demonstrated that Ancientino alleviates colitis and exerts an anticolitis effect by reducing inflammatory response, suppressing oxidative stress, and repairing intestinal barrier function. Thus, Ancientino may be an effective therapeutic dietary resource for ulcerative colitis.

Poly (ADP-ribose) polymerases 16 triggers pathological cardiac hypertrophy via activating IRE1α-sXBP1-GATA4 pathway.

BACKGROUND: Pressure overload-induced pathological cardiac hypertrophy is an independent predecessor of heart failure (HF), which remains the leading cause of worldwide mortality. However, current evidence on the molecular determinants of pathological cardiac hypertrophy is still inadequacy. This study aims to elucidate the role and mechanisms of Poly (ADP-ribose) polymerases 16 (PARP16) in the pathogenesis of pathological cardiac hypertrophy. METHODS: Gain and loss of function approaches were used to demonstrate the effects of genetic overexpression or deletion of PARP16 on cardiomyocyte hypertrophic growth in vitro. Ablation of PARP16 by transducing the myocardium with serotype 9 adeno-associated virus (AAV9)-encoding PARP16 shRNA were then subjected to transverse aortic construction (TAC) to investigate the effect of PARP16 on pathological cardiac hypertrophy in vivo. Co-immunoprecipitation (IP) and western blot assay were used to detect the mechanisms of PARP16 in regulating cardiac hypertrophic development. RESULTS: PARP16 deficiency rescued cardiac dysfunction and ameliorated TAC-induced cardiac hypertrophy and fibrosis in vivo, as well as phenylephrine (PE)-induced cardiomyocyte hypertrophic responses in vitro. Whereas overexpression of PARP16 exacerbated hypertrophic responses including the augmented cardiomyocyte surface area and upregulation of the fetal gene expressions. Mechanistically, PARP16 interacted with IRE1α and ADP-ribosylated IRE1α and then mediated the hypertrophic responses through activating the IRE1α-sXBP1-GATA4 pathway. CONCLUSIONS: Collectively, our results implicated that PARP16 is a contributor to pathological cardiac hypertrophy at least in part via activating the IRE1α-sXBP1-GATA4 pathway, and may be regarded as a new potential target for exploring effective therapeutic interventions of pathological cardiac hypertrophy and heart failure.

Injectable leonurine nanocrystal-loaded microspheres for long-term hyperlipidemia management.

Hyperlipidemia is a lipid metabolism disorder that requires long-term and daily medication. Leonurine (Leo), an active alkaloid derived from Herba leonuri, can effectively ameliorate lipid profiles in mammals and serve as a candidate antihyperlipidemic agent for clinical applications. In this paper, poly(lactic-co-glycolic acid) (PLGA) microsphere (MP)-based drug delivery platforms were for the first time employed for hyperlipidemia management by encapsulating leonurine nanocrystals (Leo-nano) by a modified solid-in-oil-in-water (S/O/W) double emulsion-solvent emulsion technique. The optimal formulation (Leo-nano@MP) was characterized by a high drug loading and encapsulation efficiency of 19.90 ± 0.82% and 79.62 ± 3.57%, respectively, which followed first-order drug release kinetics over 20 days in vitro. Interestingly, Leo-nano@MP exhibited a unique morphology with a condensed surface yet a porous internal structure, which potentially contributed to the enhanced drug loading and release properties. Furthermore, subcutaneous injection of Leo-nano@MP every two weeks significantly ameliorated the lipid profiles and alleviated liver and kidney injury in HFD-fed rats in comparison with daily administration of free Leo. Besides, no abnormalities in the heart, lung, spleen, and skin tissues at injection sites were observed. In summary, Leo-nano@MP with enhanced therapeutic efficacy, reduced administration frequency, and good biosafety constitutes a promising sustained-release platform for hyperlipidemia management.

Optimization of Strategy for Modified mRNA Inducing Cardiac-Specific Expression in Mice.

Lipid nanoparticle (LNP)-coated-modified RNA(modRNA) has been developed for enhancing the stability of modRNA, but it tends to accumulate in liver. The current study aimed to optimize strategy for increasing cardiac expression efficiency of modRNA. We synthesized Luciferase (Luc)-modRNA, and also developed 122Luc modRNA, a liver silencing Luc modRNA. Intramyocardial injection of naked Luc modRNA induced high bioluminescence signal in heart, but very low in other organs including liver. Luc modRNA-LNP injection showed the signal was increased by 5 folds in the heart and by 15,000 folds in the liver, compared to naked Luc modRNA group. In comparison with Luc modRNA-LNP group, the liver signal was decreased to 0.17%, while cardiac signal showed a slight drop by intramyocardial injection of 122Luc-modRNA-LNP. Our data revealed that intramyocardial injection of naked modRNA could effectively induced cardiac-specific expression. For cardiac delivery of Luc modRNA-LNP, 122modRNA-LNP enhances specificity of cardiac expression by abolishing liver signal.

New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and even permanent disability, seriously affecting patients' quality of life. At present, the complete cure for RA is not achievable, only to relieve the symptoms to reduce the pain of patients. Factors such as environment, genes, and sex can induce RA. Presently, non-steroidal anti-inflammatory drugs, DRMADs, and glucocorticoids are commonly used in treating RA. In recent years, some biological agents have also been applied in clinical practice, but most have side effects. Therefore, finding new mechanisms and targets for treating RA is necessary. This review summarizes some potential targets discovered from the perspective of epigenetics and RA mechanisms.

The Impact of Drugs on Hydrogen Sulfide Homeostasis in Mammals.

Mammalian cells and tissues have the capacity to generate hydrogen sulfide gas (H2S) via catabolic routes involving cysteine metabolism. H2S acts on cell signaling cascades that are necessary in many biochemical and physiological roles important in the heart, brain, liver, kidney, urogenital tract, and cardiovascular and immune systems of mammals. Diminished levels of this molecule are observed in several pathophysiological conditions including heart disease, diabetes, obesity, and immune function. Interestingly, in the last two decades, it has become apparent that some commonly prescribed pharmacological drugs can impact the expression and activities of enzymes responsible for hydrogen sulfide production in cells and tissues. Therefore, the current review provides an overview of the studies that catalogue key drugs and their impact on hydrogen sulfide production in mammals.

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

S-Propargyl-Cysteine Ameliorates Peripheral Nerve Injury through Microvascular Reconstruction.

Microvascular reconstruction is essential for peripheral nerve repair. S-Propargyl-cysteine (SPRC), the endogenous hydrogen sulfide (H2S) donor, has been reported to promote angiogenesis. The aim of this study is to utilize the pro-angiogenic ability of SPRC to support peripheral nerve repair and to explore the potential mechanisms. The effects and mechanisms of SPRC on angiogenesis and peripheral nerve repair were examined under hypoxic condition by establishing a sciatic nerve crushed injury model in mice and rats, and a hypoxia model in human umbilical vascular endothelial cells (HUVECs) in vitro. We found that SPRC accelerated the function recovery of the injured sciatic nerve and alleviated atrophy of the gastrocnemius muscle in mice. It facilitated the viability of Schwann cells (SCs), the outgrowth and myelination of regenerated axons, and angiogenesis in rats. It enhanced the viability, proliferation, adhesion, migration, and tube formation of HUVECs under hypoxic condition. SPRC activated sirtuin1 (SIRT1) expression by promoting the production of endogenous H2S, and SIRT1 negatively regulated Notch signaling in endothelial cells (ECs), thereby promoting angiogenesis. Collectively, our study has provided important evidence that SPRC has an effective role in peripheral nerve repair through microvascular reconstruction, which could be a potentially effective medical therapy for peripheral nerve injury.