Metformin Inhibits the Estrogen-mediated Epithelial-Mesenchymal Transition of Ectopic Endometrial Stromal Cells in Endometriosis.

BACKGROUND/AIM: Endometriosis is an estrogen-dependent disease characterized by the ectopic implantation and growth of endometrial tissue outside the uterus. Endometrial stromal cells (ESCs) play a crucial role in the pathogenesis of endometriosis. Epithelial-mesenchymal transition (EMT) has recently been described in endometriosis and was induced by estrogen. Metformin has been shown to inhibit EMT in various diseases, but its role in endometriosis remains unclear. MATERIALS AND METHODS: We collected endometrial tissue samples from patients with endometriosis and healthy controls and isolated primary ESCs. We performed gene expression analysis using the Gene Expression Omnibus (GEO) dataset and validated the results by immunohistochemistry in tissue samples. We also assessed the effects of metformin on the proliferation, migration and invasion of ectopic ESCs (EESCs) by Cell Counting Kit-8 and Transwell migration and invasion assays, respectively. We analyzed the protein expression of EMT-related markers (N-cadherin, vimentin, twist, and snail) and ß-catenin by Western blotting and immunohistochemistry. RESULTS: We found that vimentin was highly expressed in ectopic endometrial tissues compared to normal endometrial tissues. Metformin treatment inhibited the proliferation, migration and invasion of EESCs in a dose-dependent manner. Metformin treatment also downregulated the expression of EMT-related markers and reduced the expression and nuclear translocation of ß-catenin in EESCs. CONCLUSION: Our results suggest that metformin inhibits estrogen-induced EMT and regulates the expression of ß-catenin in EESCs. This study provides new insights into the potential therapeutic role of metformin in endometriosis.

BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling.

OBJECTIVES: The effect of telomerase inhibitor BIBR1532 on endometriotic cells was investigated to explore the inhibitory effect of targeting telomerase on endometriosis. DESIGN: In vitro primary cell culture study. Participants/Materials: Primary endometrial cells derived from eutopic and ectopic endometrium in patients with endometriosis. SETTING: The study was conducted in the university hospital. METHODS: Paired eutopic and ectopic endometrial cells were collected from 6 patients from January 2018 to July 2021. A TRAP assay was performed to detect the telomerase activity of the cells. MTT, cell cycle, apoptosis, migration, and invasion assays were performed to study the inhibitory effect of BIBR1532. Enrichment analysis was performed to identify the key pathways involved in endometriosis progression and telomerase action. Then, Western blotting was used to investigate the expression of related proteins. RESULTS: BIBR1532 treatment significantly inhibited the growth of eutopic and ectopic endometrial cells, with apoptosis and cell cycle signaling involved. Migration and invasion, important characteristics for the establishment of ectopic lesions, were also inhibited by BIBR1532. The MAPK signaling cascade, related to telomerase and endometriosis, was decreased in eutopic and ectopic endometrial stromal cells with the treatment of BIBR1532. LIMITATIONS: The severe side effects of telomerase inhibitors might be the main obstacle to clinical application, so it is necessary to find better drug delivery methods in vivo. CONCLUSIONS: The telomerase inhibitor BIBR1532 affects endometrial cell proliferation, migration, and invasion in endometriosis.

Ovarian Clear Cell Carcinoma: Genomic Characterization, Pathogenesis and Targeted Therapy.

Ovarian clear cell carcinomas (OCCCs) are a subtype of ovarian epithelial tumors that arise from the malignant transformation of endometriosis (EMs). These tumors have distinctive molecular features, high malignant potential, low sensitivity to conventional chemotherapy, and poor prognosis. The process and mechanism of malignant transformation from EMs to OCCCs remains elusive. Elucidation of the molecular pathogenesis and drug resistance mechanism of OCCCs is essential to guide the clinical management and basic research of this disease. This paper provides a comprehensive review of the mechanisms of malignant transformation, genomic characteristics, drug resistance and targeted therapy of OCCCs. The review aims to provide new insights for the clinical management of advanced OCCCs.

Determination of soluble HLA-G serum levels in patients with adenomyosis and uterine fibroids before and after surgery.

Adenomyosis is a benign gynaecological disease caused by the growth of endometrial tissue in the myometrium that affects approximately 30 % of child-bearing-age women. We evaluated the levels of soluble human leukocyte antigen G (sHLA-G) in the serum of patients with adenomyosis before and after treatment. Serum samples of 34 patients with adenomyosis and 31 patients with uterine fibroids were collected before and after the operation and were analysed for sHLA-G levels byELISAassay. The preoperative levels of serum sHLA-G in the adenomyosis group (28.05 ± 2.466 ng/ml) were significantly higher than those in the uterine fibroid group (18.53 ± 1.435 ng/ml) (P < 0.05). Serum sHLA-G levels in the adenomyosis group showed a decreasing trend at different time points after surgery (28.05 ± 14.38 ng/ml, 18.41 ± 8.34 ng/ml, and 14.45 ± 5.77 ng/ml). Adenomyosis patients who underwent total hysterectomy (n = 20) had a more significant decrease in sHLA-G levels in the early postoperative period (2 days post-operative) than those who underwent partial hysterectomy (n = 14). These results suggest that immunologic dysfunctions may be detected in patients with adenomyosis.

Telomere-related genes as potential biomarkers to predict endometriosis and immune response: Development of a machine learning-based risk model.

Introduction: Endometriosis (EM) is an aggressive, pleomorphic, and common gynecological disease. Its clinical presentation includes abnormal menstruation, dysmenorrhea, and infertility, which seriously affect the patient's quality of life. However, the pathogenesis underlying EM and associated regulatory genes are unknown. Methods: Telomere-related genes (TRGs) were uploaded from TelNet. RNA-sequencing (RNA-seq) data of EM patients were obtained from three datasets (GSE5108, GSE23339, and GSE25628) in the GEO database, and a random forest approach was used to identify telomere signature genes and build nomogram prediction models. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the pathways involved in the action of the signature genes. Finally, the CAMP database was used to screen drugs for potential use in EM treatment. Results: Fifteen total genes were screened as EM-telomere differentially expressed genes. Further screening by machine learning obtained six genes as characteristic predictive of EM. Immuno-infiltration analysis of the telomeric genes showed that expressions including macrophages and natural killer cells were significantly higher in cluster A. Further enrichment analysis showed that the differential genes were mainly enriched in biological pathways like cell cycle and extracellular matrix. Finally, the Connective Map database was used to screen 11 potential drugs for EM treatment. Discussion: TRGs play a crucial role in EM development, and are associated with immune infiltration and act on multiple pathways, including the cell cycle. Telomere signature genes can be valuable predictive markers for EM.

Comprehensive analysis of PHGDH for predicting prognosis and immunotherapy response in patients with endometrial carcinoma.

BACKGROUND: PHGDH (Phosphoglycerate Dehydrogenase) is the first branch enzyme in the serine biosynthetic pathway and plays a vital role in several cancers. However, little is known about the clinical significance of PHGDH in endometrial cancer. METHODS: Clinicopathological data of endometrial cancer were downloaded from the Cancer Genome Atlas database (TCGA). First, the expression of PHGDH in pan-cancer was investigated, as well as the expression and prognostic value of PHGDH in endometrial cancer. The effect of PHGDH expression on the prognosis of endometrial cancer was analyzed by Kaplan-Meier plotter and Cox regression. The relationship between PHGDH expression and clinical characteristics of endometrial cancer was investigated by logistic regression. Receiver operating characteristic (ROC) curves and nomograms were developed. Possible cellular mechanisms were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, the Gene Ontology (GO), and gene set enrichment analysis (GSEA). Finally, TIMER and CIBERSORT were used to analyze the relationship between PHGDH expression and immune infiltration. CellMiner™ was used to analyze the drug sensitivity of PHGDH. RESULTS: The results showed that PHGDH expression was significantly higher in endometrial cancer tissues than in normal tissues at mRNA and protein levels. Kaplan-Meier survival curves showed that patients in the high expression group had shorter overall survival (OS) and disease free survival (DFS) than patients in the low PHGDH expression group. Multifactorial COX regression analysis further supported that high PHGDH expression was an independent risk factor associated with prognosis in patients with endometrial cancer. The results showed estrogen response, mTOR, K-RAS, and epithelial mesenchymal transition (EMT) were differentially elevated in the high-expression group of the PHGDH group. CIBERSORT analysis showed that PHGDH expression is related to the infiltration of multiple immune cells. When PHGDH is highly expressed, the number of CD8+T cells decreases. CONCLUSION: PHGDH plays a vital role in the development of endometrial cancer, which is related to tumor immune infiltration, and can be used as an independent diagnostic and prognostic marker for endometrial cancer.

Fournier's Gangrene with Growth of Actinomyces europaeus: A Case Report.

Fournier's gangrene (FG) is a rare infectious disease with rapid disease progression and a high mortality rate. We report a case of a 61-year-old female with type 2 diabetes who developed FG caused by Actinomyces europaeus. A. europaeus is associated with abscesses, decubitus ulcers, and purulent urethritis. Although A. europaeus rarely causes FG as the main causative pathogen, we should still be alert to this pathogenic microorganism. To our knowledge, this is the first case report of FG caused by A. europaeus mono-infection, and it adds to the evidence that A. europaeus has the potential to cause necrotizing fasciitis.

Immune checkpoint inhibitors in cervical cancer: Current status and research progress.

Cervical cancer is the second most common gynecological malignant tumor endangering the health of women worldwide. Despite advances in the therapeutic strategies available to treat cervical cancer, the long-term prognosis of patients with recurrent and metastatic cervical cancer remains unsatisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown encouraging efficacy in the treatment of cervical cancer. ICIs have been approved for use in both first- and second-line cervical cancer therapies. This review summarizes the current knowledge of ICIs and the application of ICIs in clinical trials for the treatment of cervical cancer.

Surgical Staging of Locally Advanced Cervical Cancer: Current Status and Research Progress.

Locally advanced cervical cancer (LACC) has large localized lesions, high recurrence and metastasis rate under standard treatment, and low survival rate. The current guidelines still use concurrent radiotherapy as the gold standard of treatment for locally advanced cervical cancer. Several recent studies have shown that surgical staging has higher accuracy in determining metastasis in the para-aortic lymph nodes, bringing survival benefits to some patients. However, the indications for surgical staging and whether surgical staging can improve prognosis are still controversial. We will review the current status and research progress of surgical staging for locally advanced cervical cancer.

Human leukocyte antigen-G (HLA-G) expression plays an important role in the diagnosis and grading of endometrial cancer.

The research aimed to investigate the expression of human leukocyte antigen G (HLA-G) in cancer tissues and normal endometrium and the expression of HLA-G in the three different grades of Endometrial cancer, to determine if HLA-G expression is related with the diagnosis and grading of endometrial cancer. The expression of HLA-G protein was analysed in the primary tumour in 97 tissue samples obtained from endometrial cancer, in which 30 samples were at pathological Grade 1; 37 samples were at Grade 2; 27 samples were at Grade 3; and the other 5 samples were obtained from normal endometrium. The HLA-G protein level was measured by immunohistochemical method and analysed according to the clinicopathological parameters of patients. A statistically significant difference (p < .05) was observed in HLA-G expression between the cancerous tissue and the normal endometrium (p = .0007), and the histochemistry score (H-score) of the negative control was 0.05 ± 0.03 (mean ± SD). Statistically significant correlations were also observed between samples of pathological Grade 1 and Grade 2 (p = .0126), Grade 2 and Grade 3 (p = .0359), Grade 1 and Grade 3 (p = .0001). Endometrial cancer cells express higher levels of HLA-G probably to escape immune surveillance, and HLA-G expression level is related with the pathological grade of endometrial cancer. Therefore, HLA-G detecting and quantifying could possibly help diagnosing, grading and treatment of endometrial cancer.Impact statementWhat is already known on this subject? The expression of a member of the non-classical HLA antigens, HLA-G, is one of the main ways for tumour immune escape and progression. The significance of HLA-G in tumour biology has been intensively investigated (Carosella et al. 2015), and now it is widely acknowledged that HLA-G expression in tumours is highly linked with immune suppressive microenvironments, advanced tumour stage, poor therapeutic responses and prognosis (Lin and Yan, 2018). However, to our knowledge, no research has been conducted on the correlation between HLA-G expression and pathological grades of endometrial cancer.What do the results of this study add? Our study demonstrated that the expression of HLA-G plays an important role in the pathological grading of endometrial cancer.What are the implications of these findings for clinical practice and/or further research? Measuring the level of HLA-G expression to help pathological grading of endometrial cancer is important in determining the treatment of patients with endometrial cancer and studying the underlying mechanisms of the development of endometrial cancer, while proving or finding new targeted therapies inhibiting or modifying these processes still requires further investigation.

Giant hysteromyoma after vaginoplasty in a woman with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: case report and review of the literature.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder characterized by congenital absence of both the uterus and vagina. Some patients require surgery to create a neovagina, however, the preservation of a nonfunctional rudimentary uterus after surgery may lead to long-term complications. Herein, a rare case of a giant hysteromyoma after vaginoplasty, in a 31-year-old Chinese female patient who was diagnosed with MRKH syndrome, is reported. The patient, who had undergone vaginal reconstruction 4 years previously, presented with abdominal distension for the previous 2 weeks. Transabdominal ultrasonography showed a firm mass of approximately 10 × 10 cm in the lower abdomen. The patient subsequently underwent an exploratory laparotomy, and a leiomyoma from her rudimentary uterus was removed. Beside this case, seven cases, published between 2004 and 2020, were identified during a literature search. Findings of the present and previously published cases suggest that gynaecologists should pay particular attention to the risks of pelvic complications in female patients with MRKH syndrome who have previously undergone surgery, and select appropriate therapeutic methods.

Cisplatin remodels the tumor immune microenvironment via the transcription factor EB in ovarian cancer.

The mortality rate of ovarian cancer (OC) remains the highest among all gynecological malignancies. Platinum-based chemotherapies are effective in treating most OC cases. However, chemoresistance is still a major challenge for successful OC treatments. Emerging evidence has highlighted that the modulation of the tumor immune microenvironment is involved in chemoresistance, but the mechanism remains unclear. This study aimed to investigate whether resistance to cisplatin (CDDP), the standard treatment for OC, is due to the remodeling of the tumor immune microenvironment by the transcription factor EB (TFEB). We hypothesized that TFEB is not essential for tumor survival but is associated with CDDP resistance. We collected 20 tissue samples of OC patients who had not undergone chemotherapy or radiotherapy prior to surgery. We cultured OC cell lines and performed cell transfection and assays as well as analytical, fluorescence microscopy, and immunohistochemical techniques to explore a novel function of TFEB in remodeling the tumor immune microenvironment in OC. We found a positive correlation between TFEB and programmed cell death-ligand 1 (PD-L1), PD-L2, and HLA-A expression in OC cells and tissues. We also found that CDDP treatment induced TFEB nuclear translocation, thus increasing PD-L1 and PD-L2 expression to foster an immunosuppressive tumor microenvironment, which mediates tumor immune evasion and drug resistance. Interestingly, TFEB also regulated HLA-A expression, which increases the tumor immunogenicity of OC. Finally, in a syngenic murine model of OC, we observed the therapeutic benefit of CDDP plus programmed cell death-1 (PD-1) inhibitor, which enhanced the cytolytic activity of CD8+ T cells and inhibited tumor growth. Our study illustrates the important role of TFEB in regulating the tumor immune microenvironment in OC.

Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress.

Previous studies have shown that resveratrol, a bioactive substance found in many plants, can reduce early brain injury after subarachnoid hemorrhage, but how it acts is still unclear. This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern. Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2, 6, 24 and 46 hours after injury. At 48 hours after injury, their neurological function was assessed using a modified Garcia score. Brain edema was measured by the wet-dry method. Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry. CHOP, glucose-regulated protein 78, nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription polymerase chain reaction. Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay. Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78, CHOP and glial fibrillary acidic protein. Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex. The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats, and reduced neuronal apoptosis in the prefrontal cortex. Resveratrol reduced the levels of reactive oxygen species and malondialdehyde, and increased the expression of nuclear factor-erythroid 2-related factor 2, heme oxygenase-1 mRNA and protein in the prefrontal cortex. Resveratrol decreased glucose-regulated protein 78, CHOP mRNA and protein expression and tumor necrosis factor-alpha level. It also activated astrocytes. The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage, endoplasmic reticulum stress and neuroinflammation. The study was approved by the Animals Ethics Committee of Shandong University, China on February 22, 2016 (approval No. LL-201602022).

Inhibition of Necroptosis Rescues SAH-Induced Synaptic Impairments in Hippocampus via CREB-BDNF Pathway.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to incurable outcomes. Increasing evidence has proved that early brain injury (EBI) contributes mostly to unfavorable outcomes after SAH. A previously unknown mechanism of regulated cell death known as necroptosis has recently been reported. Necrostatin-1 (nec-1), a specific and potent inhibitor of necroptosis, can attenuate brain impairments after SAH. However, the effect of nec-1 on the hippocampus and its neuroprotective impact on synapses after SAH is not well understood. Our present study was designed to investigate the potential effects of nec-1 administration on synapses and its relevant signal pathway in EBI after SAH. Nec-1 was administrated in a rat model via intracerebroventricular injection after SAH. Neurobehavior scores and brain edema were detected at 24 h after SAH occurred. The expression of the receptor-interacting proteins 1 and 3 (RIP1and3) was examined as a marker of necroptosis. We used hematoxylin and eosin staining, Nissl staining, silver staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to observe the morphological changes in hippocampus. The protective effect of nec-1 on synapses was evaluated using western blotting and electron microscopy and Western blotting was used to detect the cAMP responsive element binding (CREB) protein and brain-derived neurotrophic factor (BDNF), and we used transmission electron microscopy and TUNEL to detect the protective effects of nec-1 when a specific inhibitor of CREB, known as 666-15, was used. Our results showed that in the SAH group, RIP1, and RIP3 significantly increased in the hippocampus. Additionally, injection of nec-1 alleviated brain edema and improved neurobehavior scores, compared with those in the SAH group. The damage to neurons was attenuated, and synaptic structure also improved in the Sham+nec-1 group. Furthermore, nec-1 treatment significantly enhanced the levels of phospho-CREB and BDNF compared with those in the SAH group. The protective effect of nec-1 could hindered by 666-15. Thus, nec-1 mitigated SAH-induced synaptic impairments in the hippocampus through the inhibition of necroptosis in connection with the CREB-BDNF pathway. This study may provide a new strategy for SAH patients in clinical practice.

Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress.

Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-ß-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI.

Resveratrol reversed chronic restraint stress-induced impaired cognitive function in rats.

Chronic stress occurs in everyday life, and often results in memory impairments and depressive symptoms. Resveratrol is a natural polyphenol that possesses numerous biological properties, including potent antidepressant­like effects. The present study aimed to examine the effects of resveratrol treatment on chronic restraint stress (CRS)­induced cognitive impairment and to explore the underlying molecular mechanisms. Male Wistar rats were exposed to CRS for 21 days in order to induce depressive­like behavior. The results demonstrated that CRS (6 h/day, 21 days) was able to induce cognitive deficits in rats, as evidenced by Morris water maze and novel object recognition tests. In addition, CRS exposure significantly decreased the mRNA and protein expression levels of hippocampal brain­derived neurotrophic factor (BDNF) in the rats. Conversely, chronic treatment with resveratrol (80 mg/kg, i.p.; 21 days) significantly prevented the behavioral and biochemical alterations induced by CRS. The effects of resveratrol were nearly identical to those observed with fluoxetine treatment. In conclusion, the present study demonstrated that resveratrol may be a potential therapeutic agent for the treatment of chronic stress­induced cognitive impairments, and its underlying molecular mechanism may be associated with the increased levels of hippocampal BDNF.

Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H2S Pathway Following Subarachnoid Hemorrhage in Rats.

l-Cysteine is a semi-essential amino acid and substrate for cystathionine-ß-synthase (CBS) in the central nervous system. We previously reported that NaHS, an H2S donor, significantly alleviated brain damage after subarachnoid hemorrhage (SAH) in rats. However, the potential therapeutic value of l-cysteine and the molecular mechanism supporting these beneficial effects have not been determined. This study was designed to investigate whether l-cysteine could attenuate early brain injury following SAH and improve synaptic function by releasing endogenous H2S. Male Wistar rats were subjected to SAH induced by cisterna magna blood injection, and l-cysteine was intracerebroventricularly administered 30 min after SAH induction. Treatment with l-cysteine stimulated CBS activity in the prefrontal cortex (PFC) and H2S production. Moreover, l-cysteine treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the PFC; these effects were associated with a decrease in the Bax/Bcl-2 ratio and the suppression of caspase-3 activation 48 h after SAH. Furthermore, l-cysteine treatment activated the CREB-brain-derived neurotrophic factor (BDNF) pathway and intensified synaptic density by regulating synapse proteins 48 h after SAH. Importantly, all the beneficial effects of l-cysteine in SAH were abrogated by amino-oxyacetic acid, a CBS inhibitor. Based on these findings, l-cysteine may play a neuroprotective role in SAH by inhibiting cell apoptosis, upregulating CREB-BDNF expression, and promoting synaptic structure via the CBS/H2S pathway.

Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice.

Hydrogen as a new medical gas exerts organ-protective effects through regulating oxidative stress, inflammation and apoptosis. Multiple lines of evidence reveal the protective effects of hydrogen in various models of brain injury. However, the exact mechanism underlying this protective effect of hydrogen against hypoxic-ischemic brain damage (HIBD) is not fully understood. The present study was designed to investigate whether hydrogen-rich saline (HS) attenuates HIBD in neonatal mice and whether the observed protection is associated with reduced endoplasmic reticulum (ER) stress and regulated autophagy. The results showed that HS treatment significantly improved brain edema and decreased infarct volume. Furthermore, HS significantly attenuated HIBD-induced ER stress responses, including the decreased expression of glucose-regulated protein 78, C/EBP homologous protein, and down-regulated transcription factor. Additionally, we demonstrated that HS induced autophagy, including increased LC3B and Beclin-1 expression and decreased phosphorylation of mTOR and Stat3, as well as phosphorylation of ERK. Taken together, HS exerts neuroprotection against HIBD in neonatal mouse, mediated in part by reducing ER stress and increasing autophagy machinery.

Resveratrol reverses chronic restraint stress-induced depression-like behaviour: Involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats.

Chronic stress occurs in everyday life and induces depression-like behaviors, associated with proteins alterations and apoptosis in brain. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic restraint stress (CRS) - induced depression-like behaviors and explores underlying mechanisms. Male Wistar rats were subjected to CRS protocol for a period of 3 weeks to induce depressive-like behavior. The results showed that resveratrol (80mg/kg/i.p) administrated for 3 weeks significantly reversed the CRS-induced behavioral abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CRS exposure significantly decreased BDNF levels and phosphorylation of extracellular signal-regulated kinase (pERK) in hippocampus and prefrontal cortex (PFC), accompanied by decreased Bcl-2 mRNA expression and increased Bax mRNA expression, while resveratrol treatment normalized these levels. All of these effects of resveratrol were essentially identical to that observed with fluoxetine. In conclusion, our studies showed that resveratrol exerted antidepressant-like effects in CRS rats, mediated in part by the apoptotic machinery and up-regulating BDNF and pERK levels in the brain region.

Resveratrol exerts antidepressant properties in the chronic unpredictable mild stress model through the regulation of oxidative stress and mTOR pathway in the rat hippocampus and prefrontal cortex.

Depression is one of the most common neuropsychiatric disorders and has been associated with oxidative stress and brain protein alterations. Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities including potent antidepressant-like effects. The present study attempts to explore the mechanisms underlying the antidepressant-like action of resveratrol by measuring oxidative stress parameters and phosphorylation of AKT/mTOR pathway in the rat hippocampus and prefrontal cortex (PFC) exposed to the chronic unpredictable mild stress (CUMS). Male Wistar rats were subjected to CUMS protocol for a period of 4 weeks to induce depressive-like behavior. The results showed that resveratrol treatment (80 mg/kg/i.p. 4 weeks) significantly reversed the CUMS-induced behavioral abnormalities (reduced sucrose preference, increased immobility time and decreased locomotor activity) and biochemical changes (increased lipid peroxidation and decreased superoxide dismutase). Additionally, CUMS exposure significantly decreased phosphorylation of Akt and mTOR in the hippocampus and PFC, while resveratrol treatment normalized these parameters. In conclusion, our study showed that resveratrol exerted antidepressant-like effects in CUMS rats, which was mediated in part by its antioxidant action, up-regulation of phosphor-Akt and mTOR levels in the hippocampus and PFC.