Hydrogen Sulfide in Musculoskeletal Diseases: Molecular Mechanisms and Therapeutic Opportunities.

SIGNIFICANCE: Musculoskeletal diseases seriously affect global health, but their importance is greatly underestimated. These diseases often afflict the elderly, leading to disability, paralysis, and other complications. Hydrogen sulfide (H2S) plays an important role in the occurrence and development of musculoskeletal diseases, which may have potential ther-apeutic significance for these diseases. RECENT ADVANCES: Recently, it has been found that many musculoskeletal diseases, such as osteoporosis, periodontitis, muscle atrophy, muscle ischemia-reperfusion injury, mus-cle contraction under high fever, arthritis, and disc herniation, can be alleviated by sup-plementing H2S. H2S may be conducive to the development of multiple myeloma. The mechanism of H2S effect on the musculoskeletal system has been elucidated. A variety of H2S donors and nano-delivery systems provide prospects for H2S-based therapies. CRITICAL ISSUES: Related research remains at the level of cell or animal experiments, and clinical research is lacking. The role of H2S in more musculoskeletal disorders remains largely unknown. The importance of musculoskeletal diseases has not been widely con-cerned. Targeted delivery of H2S remains a challenging task. FUTURE DIRECTION: Develop therapeutic drugs for musculoskeletal diseases based on H2S and test their safety, efficacy, and tolerance. Explore the combination of current musculo-skeletal disease drugs with H2S releasing components to improve efficacy and avoid side effects. Carry out relevant clinical trials to verify the possibility of its widespread use.

The role of cystathionine ß-synthase in cancer.

Cystathionine ß-synthase (CBS) occupies a key position as the initiating and rate-limiting enzyme in the sulfur transfer pathway and plays a vital role in health and disease. CBS is responsible for regulating the metabolism of cysteine, the precursor of glutathione (GSH), an important antioxidant in the body. Additionally, CBS is one of the three enzymes that produce hydrogen sulfide (H2S) in mammals through a variety of mechanisms. The dysregulation of CBS expression in cancer cells affects H2S production through direct or indirect pathways, thereby influencing cancer growth and metastasis by inducing angiogenesis, facilitating proliferation, migration, and invasion, modulating cellular energy metabolism, promoting cell cycle progression, and inhibiting apoptosis. It is noteworthy that CBS expression exhibits complex changes in different cancer models. In this paper, we focus on the CBS synthesis and metabolism, tissue distribution, potential mechanisms influencing tumor growth, and relevant signaling pathways. We also discuss the impact of pharmacological CBS inhibitors and silencing CBS in preclinical cancer models, supporting their potential as targeted cancer therapies.

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.

Emerging roles of hydrogen sulfide in colorectal cancer.

Hydrogen sulfide (H2S), an endogenous gasotransmitter, plays a key role in several critical physiological and pathological processes in vivo, including vasodilation, anti-infection, anti-tumor, anti-inflammation, and angiogenesis. In colorectal cancer (CRC), aberrant overexpression of H2S-producing enzymes has been observed. Due to the important role of H2S in the proliferation, growth, and death of cancer cells, H2S can serve as a potential target for cancer therapy. In this review, we thoroughly analyzed the underlying mechanism of action of H2S in CRC from the following aspects: the synthesis and catabolism of H2S in CRC cells and its effect on cell signal transduction pathways; the inhibition effects of exogenous H2S donors with different concentrations on the growth of CRC cells and the underlying mechanism of H2S in garlic and other natural products. Furthermore, we elucidate the expression characteristics of H2S in CRC and construct a comprehensive H2S-related signaling pathway network, which has important basic and practical significance for promoting the clinical research of H2S-related drugs.

[Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-ß and IL-10 in Hemophilia A Patients with Fâ § Inhibitor].

OBJECTIVE: To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-ß and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. METHODS: 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-ß and IL-10 in serum, and their differences between different groups were compared. RESULTS: Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-ß, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). CONCLUSION: The decrease of Tregs, IL-35, TGF-ß, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

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 gasotransmitters in necroptosis.

Gasotransmitters are endogenous gaseous signaling molecules that can freely pass through cell membranes and transmit signals between cells, playing multiple roles in cell signal transduction. Due to extensive and ongoing research in this field, we have successfully identified many gasotransmitters so far, among which nitric oxide, carbon monoxide, and hydrogen sulfide are best studied. Gasotransmitters are implicated in various diseases related to necroptosis, such as cardiovascular diseases, inflammation, ischemia-reperfusion, infectious diseases, and neurological diseases. However, the mechanisms of their effects on necroptosis are not fully understood. This review focuses on endogenous gasotransmitter synthesis and metabolism and discusses their roles in necroptosis, aiming to offer new insights for the therapeutic approaches to necroptosis-associated diseases.

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.

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.

Exploring the impact of hydrogen sulfide on hematologic malignancies: A review.

Hydrogen sulfide (H2S) is one of the three most crucial gaseous messengers in the body. The discovery of H2S donors, coupled with its endogenous synthesis capability, has sparked hope for the treatment of hematologic malignancies. In the last decade, the investigation into the impact of H2S has expanded, particularly within the fields of cardiovascular function, inflammation, infection, and neuromodulation. Hematologic malignancies refer to a diverse group of cancers originating from abnormal proliferation and differentiation of blood-forming cells, including leukemia, lymphoma, and myeloma. In this review, we delve deeply into the complex interrelation between H2S and hematologic malignancies. In addition, we comprehensively elucidate the intricate molecular mechanisms by which both H2S and its donors intricately modulate the progression of tumor growth. Furthermore, we systematically examine their impact on pivotal aspects, encompassing the proliferation, invasion, and migration capacities of hematologic malignancies. Therefore, this review may contribute novel insights to our understanding of the prospective therapeutic significance of H2S and its donors within the realm of hematologic malignancies.

A strategy combining chemical analysis and network pharmacology to investigate the mechanism of Xiao'er Qingre Zhike Oral solution in cough.

Xiao'er Qingre Zhike Oral Solution (XQZS) is a commonly used TCM formula to treat cough in children in China. Its complicated composition renders its chemical analysis and mechanism elucidation difficult. To evaluate the bioactive components and mechanism of XQZS against cough, we used a combination strategy of chemical analysis and network pharmacology. A UHPLC/Q-Orbitrap-MS method was established for the identification and qualitative analysis of components of XQZS, and a total of 33 components were unambiguously identified. Aiming at identifying the components, network pharmacology revealed 107 potential targets related to cough. Using protein-protein interactions analysis, nine core targets were selected. Several cough-related pathways were enriched using the Kyoto Encyclopedia of Genes and Genomes, including neuroactive ligand-receptor interaction, serotonergic synapse and dopaminergic synapse. The herb-compound-target-pathway network indicated that PTGS2 (COX-2) was the core target of XQZS against cough. To demonstrate the inhibition effects of the major components against the key target, a COX-2 inhibitor screening assay was used. Compounds P2, P4, P23 and P49 exhibited promising inhibition effects on COX-2 at 20 µm, with inhibitory rates of 55.80-69.87%. In conclusion, this study demonstrates that XQZS may alleviate cough via the inhibition of PTGS2 (COX-2) and the regulation of the serotonergic synapse pathway. The chemical analysis and network pharmacology integrated evaluation provided an efficient strategy for discovering the key pharmacological mechanism of XQZS.

Universities' Scientific and Technological Transformation in China: Its Efficiency and Influencing Factors in the Yangtze River Economic Belt.

Universities are important sources of knowledge and key members of the regional innovation system. The key problem in Chinese universities is the low efficiency of the scientific and technological (S&T) transformation, which limits the promotion of regional innovation and economic development. This article proposes the three-stage efficiency analytical framework, which regards it as a complex and interactive process. Avoiding the problem of considering the input and output of university S&T transformation as a "black box" and neglecting the links among different transformation stages. The super efficiency network SBM model is applied to the heterogeneous region of the Yangtze River Economic Belt. Empirical research proves that university S&T transformation has not been effectively improved and the scientific resources invested in universities have not been efficiently utilized in recent years. Generally, Despite the correlation between regional economy and transformation efficiency, the exclusive increase in resources is not enough. Regional openness and the quality of research talents are key factors for the application of technological innovation and technology marketization. Universities should not only pursue the number of research outputs but pay more attention to high-quality knowledge production to overcome difficulties in research achievements transformation.

[Adenovirus-mediated Expression of B-domain-Deleted Human Coagulation Factor â § in ADSC of SD Rats].

OBJECTIVE: To transinfect SD adipose tissue-derived stem cell (ADSC) in vitro with a recombinant adenoviral vector containing human B-domain-deleted FVIII (BDDhFⅧ), so as to lay the foundation for the treatment of hemophilia A by using ADSC combined with BDDhFⅧ gene. METHODS: ADSCs were isolated from the inguinal adipose tissue of SD rats and passed to third passage for identification. Third passage ADSCs were transfected in vitro with recombinant adenovirus vector Ad-BDDhFⅧ-GFP. The experiments were divided into Ad-BDDhFⅧ-GFP-transfected ADSCs group (A), Ad-GFP-transfected ADSC group (B), and untransfected ADSC group (C). CCK-8 method was used to detect the proliferation of transfected cells in three groups, and the expression level of hFⅧ antigen in cell supernatant was detected by ELISA. RT-PCR and Western blot respectively were used to detect the mRNA and protein expression of BDDhFⅧ in the three groups after transfection. RESULTS: The growth curve of third passage cells isolated and cultured showed an inverted "S" shap; the flow cytometry detection showed the positive expression of CD29, CD90, CD44, and the negative expression of CD45 in third passage cells. After the adipogenic and osteogenic induction, the cells could transformed to adipogenic and osteogenic directions. CCK-8 detection showed that the proliferation of cells in 3 groups not was influenced. ELISA showed that the expression of hFⅧAg in group A was significantly higher than that in group B and C (P＜0.05). RT-PCR showed that compared with group A, there was no target band in B and C groups, and BDDhFⅧ gene was not expressed. The results in group A were consistent with the length of amplified fragments, and BDDhFⅧ target gene was expressed. Western blot analysis showed that the expression of hFⅧ protein in group A was significantly higher than that in group B and C. (P＜0.05). CONCLUSION: Recombinant adenovirus Ad-BDDhFⅧ-GFP can effectively transfect rat ADSC in vitro, which lays an experimental foundation for gene therapy of hemophilia A.

[Influence of below-cloud secondary evaporation on stable isotope composition in precipitation in Northwest China.] / è¥¿åŒ—åœ°åŒºé™æ°´ç¨³å®šåŒä½ç´ çš„äº‘ä¸‹äºŒæ¬¡è’¸å‘æ•ˆåº”.

The precipitation isotope data and meteorological data of eight stations provided by GNIP (Global Network for Isotopes in Precipitation) and two stations from the present study, combined with HYSPLIT model and water droplet evaporation model were used to examine the spatial and temporal distribution of precipitation δ18O and d values in Northwest China. The secondary evaporative effect of existence was evaluated and then quantitatively discussed, with the sensitive factors of secondary evaporative effect being considered. The results showed that during the summer monsoon, the δ18O and d values decreased from south to north in Xinjiang, while the δ18O value increased but d values decreased from south to north and from east to west of Shaanxi-Gansu-Ningxia region. During the winter monsoon, the δ18O value decreased from east to west in whole Northwest region, while the d value increased from south to north in Xinjiang, decreased from south to north and increased slightly from east to west in Shanxi-Gansu-Ningxia. The slope and intercept (6.80, -0.07) of the atmospheric precipitation line in the summer monsoon period was significantly lower than that of annual mean (7.27, 3.37) and winter monsoon period (7.46, 6.07), indicating that the secondary evaporation was stronger during the summer monsoon. The evaporation ratio in the summer monsoon was 4.49%, which was higher than 3.65% in the winter monsoon. However, the evaporation ratio of the winter monsoon was higher than the summer monsoon around of Loess Plateau, which might closely relate to the increasing drought of the Loess Plateau in recent years. Finally, the intensity of secondary evaporation decreased with increasing relative humidity, precipitation and vapor pressure but increased with increasing temperature (greater than 0 ℃). The influences of those factors (humidity, precipitation, temperature and vapor pressure) on the secondary evaporation were dependent on the differences of ranges.

Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion.

Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.

[Chromosomal localization of foreign genes in transgenic mice using dual-color fluorescence in situ hybridization].

OBJECTIVE: To establish a highly sensitive and specific dual-color fluorescence in situ hybridization (D-FISH) method used for chromosomal localization of foreign genes in double transgenic mice. METHODS: Two strains of double transgenic mice were used in this experiment, one was integrated with the herpes simplex virus thymidine kinase (HSV-tk) and the enhanced green fluorescence protein (eGFP), the other was with the short hairpin RNA interference(RNAi) and beta(654). Splenic cells cultured in vitro were arrested in metaphase by colchicine and hybridized with digoxigenin-labeled and biotinylated DNA probes, then detected by rhodamine-conjugated avidin and FITC-conjugated anti-digoxigenin. RESULTS: Dual-color fluorescence signals were detected on the same metaphase in both transgenic mice strains. In HSV-tk/eGFP double transgenic mice, strong green fluorescence for HSV-tk and red for eGFP were observed and localized at 2E5-G3 and 8A2-A4 respectively. In beta(654)/RNAi mice, beta(654) was detected as red fluorescence on chromosome 7D3-E2, and RNAi showed random integration on chromosomes. It was detected as green fluorescence on chromosome 12B1 in one mouse, while on 1E2.3-1F and 3A3 in the other. CONCLUSION: Highly sensitive and specific D-FISH method was established using the self-prepared DNA probes, and chromosomal localization of the foreign genes was also performed in combination with G-banding in double transgenic mice. This technology will facilitate the researches in transgenic animals and gene therapy models.