Molecular hydrogen (H2) is a colorless and odorless gas. Studies have shown that H2 inhalation has the therapeutic effects in many animal studies and clinical trials, and its application is recommended in the novel coronavirus pneumonia treatment guidelines in China recently. H2 has a relatively small molecular mass, which helps it quickly spread and penetrate cell membranes to exert a wide range of biological effects. It may play a role in the treatment and prevention of a variety of acute and chronic inflammatory diseases, such as acute pancreatitis, sepsis, respiratory disease, ischemia reperfusion injury diseases, autoimmunity diseases, etc.. H2 is primarily administered via inhalation, drinking H2-rich water, or injection of H2 saline. It may participate in the anti-inflammatory and antioxidant activity (mitochondrial energy metabolism), immune system regulation, and cell death (apoptosis, autophagy, and pyroptosis) through annihilating excess reactive oxygen species production and modulating nuclear transcription factor. However, the underlying mechanism of H2 has not yet been fully revealed. Owing to its safety and potential efficacy, H2 has a promising potential for clinical use against many diseases. This review will demonstrate the role of H2 in antioxidative, anti-inflammatory, and antiapoptotic effects and its underlying mechanism, particularly in coronavirus disease-2019 (COVID-19), providing strategies for the medical application of H2 for various diseases.

Connexins, gap junction proteins, have short half‑lives of only a few hours; therefore, degradation of these proteins can rapidly modulate their function. Autophagy is a type of degradation pathway that has been implicated in several diseases and was reported to be induced following traumatic brain injury (TBI). The aim of the present study was to investigate the involvement of neuronic autophagy in proteolysis of phosphorylated connexin 43 (p‑Cx43) in hippocampal astrocytes following TBI in rats. Western blot analysis and immunofluorescence showed a TBI‑induced increase in levels of astrocytic p‑Cx43 following treatment with 3‑methyladenine, an inhibitor of autophagy, in the hippocampus. Internalized gap junctions were observed in the neuronic cytoplasm using transmission electron microscopy. These results demonstrated that neuronic autophagy may regulate cellular levels of p‑Cx43 in hippocampal astrocytes following TBI. This therefore indicated that the persistence of p‑Cx43 accumulation was due to insufficient degradation capacity of constitutive autophagy.

Endotoxins and other harmful substances may cause an increase in permeability in endothelial cells (ECs) monolayers, as well as ECs shrinkage and death to induce lung damage. Lipopolysaccharide (LPS) can impair endothelial progenitor cells (EPCs) functions, including proliferation, migration, and tube formation. EPCs can migrate to the damaged area, differentiate into ECs, and participate in vascular repair, which improves pulmonary capillary endothelial dysfunction and maintains the integrity of the endothelial barrier. Hydrogen (H2) contributes to the repairment of lung injury and the damage of ECs. We therefore speculate that H2 protects the EPCs against LPS-induced damage, and it’s mechanism will be explored. The bone marrow-derived EPCs from ICR Mice were treated with LPS to establish a damaged model. Then EPCs were incubated with H2, and treated with PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME. MTT assay, transwell assay and tube formation assay were used to detect the proliferation, migration and angiogenesis of EPCs. The expression levels of target proteins were detected by Western blot. Results found that H2 repaired EPCs proliferation, migration and tube formation functions damaged by LPS. LY294002 and L-NAME significantly inhibited the repaired effect of H2 on LPS-induced dysfunctions of EPCs. H2 also restored levels of phosphor-AKT (p-AKT), eNOS and phosphor-eNOS (p-eNOS) suppressed by LPS. LY294002 significantly inhibited the increase of p-AKT and eNOS and p-eNOS expression exposed by H2. L-NAME significantly inhibited the increase of eNOS and p-eNOS expression induced by H2. H2 repairs the dysfunctions of EPCs induced by LPS, which is mediated by PI3K/AKT/eNOS signaling pathway.

Purpose: Dapagliflozin has been used extensively in patients with type 2 diabetes mellitus (T2DM). However, due to the potential diabetic ketoacidosis (DKA) risk of dapagliflozin, its use in type 1 diabetes mellitus (T1DM) is limited. Here, we reported an obese patient with T1DM and inadequate glycemic control. We carefully recommended she use dapagliflozin as an insulin adjuvant to achieve better glycemia control and to assess possible benefits and risks. Methods and Results: The patient was a 27-year-old female who had underlying T1DM for 17 years with a body weight of 75.0 kg, body mass index (BMI) of 28.2 kg/m2, and glycated hemoglobin (HbA1c) 7.7% when admitted. To treat her diabetes, she had used an insulin pump for 15 years (the recent dosage of insulin was 45 IU/d) and oral metformin for 3 years (0.5 g qid). In order to decrease body weight and achieve better glycemic control, dapagliflozin (FORXIGA, AstraZeneca, Indiana) was administered as an insulin adjuvant. The patient presented sever DKA with a euglycemia (euDKA) after two days of the administration of dapagliflozin at a dose of 10 mg/d. euDKA occurred again after the administration of dapagliflozin at a dose of 3.3 mg/d. However, after using a smaller dose of dapagliflozin (1.5 mg/d), this patient achieved better glycemia control, with a significant reduction in daily insulin dosage and gradual weight loss, without significant hypoglycemia or DKA occurring. At the sixth month of the administration of dapagliflozin, the HbA1c was 6.2% for the patient, her daily insulin dosage was 22.5 IU, and her body weight was 60.2 kg. Conclusions: The appropriate dose of dapagliflozin is critical for a patient with T1DM patient therapy in order to find a correct balance between the benefits and risks.

Introduction: It has been proven that hydrogen has obvious anti-inflammatory effects in animal experiments and clinical practice. However, the early dynamic process of the inflammatory response caused by lipopolysaccharide (LPS) and the anti-inflammatory effect of hydrogen has not been definitively reported. Methods: Inflammation in male C57/BL6J mice or RAW264.7 cells was induced with LPS, for which hydrogen was immediately administered until samples were taken. Pathological changes in lung tissue were assessed using hematoxylin and eosin (HE) staining. Levels of inflammatory factors in serum were determined using liquid protein chip. The mRNA levels of chemotactic factors in lung tissues, leukocytes, and peritoneal macrophages were measured by qRT-PCR. The expression levels of IL-1α and HIF-1α were measured by immunocytochemistry. Results: Hydrogen alleviated LPS-induced inflammatory infiltration in the lung tissues of mice. Among the 23 inflammatory factors screened, LPS-induced upregulation of IL-1α etc. was significantly inhibited by hydrogen within 1 hour. The mRNA expression of MCP-1, MIP-1α, G-CSF, and RANTES was inhibited obviously by hydrogen at 0.5 and 1 h in mouse peritoneal macrophages. In addition, hydrogen significantly blocked LPS or H2O2-induced upregulation of HIF-1α, and IL-1α in 0.5 h in RAW264.7 cells. Discussion: The results suggested that hydrogen is potentially inhibitive against inflammation by inhibiting HIF-1α and IL-1α release at early occurrence. The target of the inhibitive LPS-induced-inflammatory action of hydrogen is chemokines in macrophages in the peritoneal cavity. This study provides direct experimental evidence for quickly controlling inflammation with the translational application of a hydrogen-assisted protocol.

Objective To investigate the anti-inflammatory role of H2 in LPS-induced BPD via regulating TNF-α/NF-κB signaling pathway in placenta. Methods We induced a neonatal rat model of BPD by injecting lipopolysaccharide (LPS, 1ug) into the amniotic fluid at embryonic day 16.5(E16.5). Treatment of 30% hydrogen gas for 4 hours/day with continuously 5days. We primarily analyzed the neonatal outcomes and then compared inflammatory levels from Control group (CON), LPS group (LPS) and LPS with H2 inhalation group (LPS + H2). TUNEL and Hematoxylin-Eosin (HE) staining were performed to evaluate inflammatory and apoptotic levels. We further used RNA sequencing and ELISA assay to examine differentially expressed proteins and mRNA levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB) (p65), interleukin (IL)-6, IL-18, IL-1β, C-C motif chemokine ligand 2(CCL2) and C-X-C motif chemokine ligand 1(CXCL1). Bioinformatics analysis (GO and KEEG) of RNA-seq and correlation analysis were applied to clarify the mechanisms of H2 anti-inflammatory effect on LPS-induced BPD. Results We found the H2 inhalation decreased production of inflammatory cytokines/chemokines (IL-6, IL-18, IL-1β, CCL2, CXCL1) in LPS-induced placenta to rescue from the BPD. Upon administration of H2, infiltration degree of LPS-induced placenta was reduced and infiltrating significantly narrowed down. Hydrogen normalized LPS-induced perturbed lung development, reduced lung apoptotic index, death ratio of fetus and neonate. Meanwhile, H2 also upregulated the survival ratio. RNA-seq and Elisa demonstrated that both mRNA and protein levels of TNF-α/NF-κB signaling pathway were activated by LPS, and H2 relieved the pro-inflammatory function of LPS on TNF-α/NF-κB-stimulated placenta. Correlation analysis showed a positive association of TNF-α vs both NF-κB and inflammatory cytokines/chemokines. Conclusion H2 inhalation alleviated LPS-induced BPD by inhibiting excessive pro-inflammatory cytokines and inflammatory chemokines via the TNF-α/NF-κB signaling pathway in placenta and may be a potential therapeutic strategy for BPD.