The Sirtuin 5 Inhibitor MC3482 Ameliorates Microglia­induced Neuroinflammation Following Ischaemic Stroke by Upregulating the Succinylation Level of Annexin-A1.

In our previous study, we concluded that sirtuin 5 (SIRT5) was highly expressed in microglia following ischaemic stroke, which induced excessive neuroinflammation and neuronal injury. Therefore, SIRT5-targeting interventions should reduce neuroinflammation and protect against ischaemic brain injury. Here, we showed that treatment with a specific SIRT5 inhibitor, MC3482, alleviated microglia-induced neuroinflammation and improved long-term neurological function in a mouse model of stroke. The mice were administrated with either vehicle or 2 mg/kg MC3482 daily for 7 days via lateral ventricular injection following the onset of middle cerebral artery occlusion. The outcome was assessed by a panel of tests, including a neurological outcome score, declarative memory, sensorimotor tests, anxiety-like behavior and a series of inflammatory factors. We observed a significant reduction of infarct size and inflammatory factors, and the improvement of long-term neurological function in the early stages during ischaemic stroke when the mice were treated with MC3482. Mechanistically, the administration of MC3482 suppressed the desuccinylation of annexin-A1, thereby promoting its membrane recruitment and extracellular secretion, which in turn alleviated neuroinflammation during ischaemic stroke. Based on our findings, MC3482 offers promise as an anti-ischaemic stroke treatment that targets directly the disease's underlying factors.

Development of interpretable machine learning models for prediction of acute kidney injury after noncardiac surgery: a retrospective cohort study.

BACKGROUND: Early identification of patients at high-risk of postoperative acute kidney injury (AKI) can facilitate the development of preventive approaches. This study aimed to develop prediction models for postoperative AKI in noncardiac surgery using machine learning algorithms. The authors also evaluated the predictive performance of models that included only preoperative variables or only important predictors. MATERIALS AND METHODS: Adult patients undergoing noncardiac surgery were retrospectively included in the study (76 457 patients in the discovery cohort and 11 910 patients in the validation cohort). AKI was determined using the KDIGO criteria. The prediction model was developed using 87 variables (56 preoperative variables and 31 intraoperative variables). A variety of machine learning algorithms were employed to develop the model, including logistic regression, random forest, extreme gradient boosting, and gradient boosting decision trees. The performance of different models was compared using the area under the receiver operating characteristic curve (AUROC). Shapley Additive Explanations (SHAP) analysis was employed for model interpretation. RESULTS: The patients in the discovery cohort had a median age of 52 years (IQR: 42-61 years), and 1179 patients (1.5%) developed AKI after surgery. The gradient boosting decision trees algorithm showed the best predictive performance using all available variables, or only preoperative variables. The AUROCs were 0.849 (95% CI: 0.835-0.863) and 0.828 (95% CI: 0.813-0.843), respectively. The SHAP analysis showed that age, surgical duration, preoperative serum creatinine, and gamma-glutamyltransferase, as well as American Society of Anesthesiologists physical status III were the most important five features. When gradually reducing the features, the AUROCs decreased from 0.852 (including the top 40 features) to 0.839 (including the top 10 features). In the validation cohort, the authors observed a similar pattern regarding the models' predictive performance. CONCLUSIONS: The machine learning models the authors developed had satisfactory predictive performance for identifying high-risk postoperative AKI patients. Furthermore, the authors found that model performance was only slightly affected when only preoperative variables or only the most important predictive features were included.

Chronic restraint stress induces abnormal behaviors in pain sensitivity and cognitive function in mice: the role of Keap1/Nrf2 pathway.

Stress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.

Vialinin A alleviates oxidative stress and neuronal injuries after ischaemic stroke by accelerating Keap1 degradation through inhibiting USP4-mediated deubiquitination.

BACKGROUND: Oxidative stress is known as a hallmark of cerebral ischaemia‒reperfusion injury and it exacerbates the pathologic progression of ischaemic brain damage. Vialinin A, derived from a Chinese edible mushroom, possesses multiple pharmacological activities in cancer, Kawasaki disease, asthma and pathological scarring. Notably, vialinin A is an inhibitor of ubiquitin-specific peptidase 4 (USP4) that shows anti-inflammatory and antioxidative properties. However, the precise effect of vialinin A in ischaemic stroke, as well as its underlying mechanisms, remains largely unexplored. PURPOSE: The present research focuses on the impacts of vialinin A on oxidative stress and explores the underlying mechanisms involved while also examining its potentiality as a therapeutic candidate for ischaemic stroke. METHODS: Mouse ischaemic stroke was conducted by MCAO surgery. Vialinin A was administered via lateral ventricular injection at a dose of 2 mg/kg after reperfusion. Subsequent experiments were meticulously conducted at the appropriate time points. Stroke outcomes were evaluated by TTC staining, neurological score, Nissl staining and behavioural analysis. Co-IP assays were operated to examine the protein-protein interactions. Immunoblot analysis, qRT-PCR, and luciferase reporter assays were conducted to further investigate its underlying mechanisms. RESULTS: In this study, we initially showed that administration of vialinin A alleviated cerebral ischaemia‒reperfusion injury-induced neurological deficits and neuronal apoptosis. Furthermore, vialinin A, which is an antioxidant, reduced oxidative stress injury, promoted the activation of the Keap1-Nrf2-ARE signaling pathway and increased the protein degradation of Keap1. The substantial neuroprotective effects of vialinin A against ischaemic stroke were compromised by the overexpression of USP4. Mechanistically, vialinin A inhibited the deubiquitinating enzymatic activity of USP4, leading to enhanced ubiquitination of Keap1 and subsequently promoting its degradation. This cascade caused the activation of Nrf2-dependent antioxidant response, culminating in a reduction of neuronal apoptosis and the amelioration of neurological dysfunction following ischaemic stroke. CONCLUSIONS: This study demonstrates that inhibition of USP4 to activate Keap1-Nrf2-ARE signaling pathway may represent a mechanism by which vialinin A conferred protection against cerebral ischaemia‒reperfusion injury and sheds light on its promising prospects as a therapeutic intervention for ischaemic stroke.

A cell-penetrating peptide exerts therapeutic effects against ischemic stroke by mediating the lysosomal degradation of sirtuin 5.

Stroke is a major public health concern worldwide. The lack of effective therapies heightens the need for new therapeutic agents. Previous study identified sirtuin 5 (SIRT5) as a positive regulator of microglia-induced excessive neuroinflammation following ischemic stroke. Interventions targeting SIRT5 should therefore alleviate neuroinflammation and protect against ischemic stroke. Here, we synthesized a membrane-permeable peptide specifically bound to SIRT5 through a chaperone-mediated autophagy targeting motif (Tat-SIRT5-CTM) and examined its therapeutic effect in vitro and in vivo. First, in primary microglia, Tat-SIRT5-CTM suppressed the binding of SIRT5 with annexin-A1 (ANXA1), leading to SIRT5 degradation and thus inhibition of SIRT5-mediated desuccinylation of ANXA1, followed by increased membrane accumulation and secretion of ANXA1. These changes, in turn, alleviated microglia-induced neuroinflammation. Moreover, following intravenous injection, Tat-SIRT5-CTM could efficiently pass through the blood‒brain barrier. Importantly, systemic administration of Tat-SIRT5-CTM reduced the brain infarct area and neuronal loss, mitigated neurological deficit scores, and improved long-term neurological functions in a mouse model of ischemic stroke. Furthermore, no toxicity was observed when high doses Tat-SIRT5-CTM were injected into nonischemic mice. Collectively, our study reveals the promising efficacy of the peptide-directed lysosomal degradation of SIRT5 and suggests it as an effective therapeutic approach for the treatment of ischemic stroke.

Exploring Astrocyte-Mediated Mechanisms in Sleep Disorders and Comorbidity.

Astrocytes, the most abundant cells in the brain, are integral to sleep regulation. In the context of a healthy neural environment, these glial cells exert a profound influence on the sleep-wake cycle, modulating both rapid eye movement (REM) and non-REM sleep phases. However, emerging literature underscores perturbations in astrocytic function as potential etiological factors in sleep disorders, either as protopathy or comorbidity. As known, sleep disorders significantly increase the risk of neurodegenerative, cardiovascular, metabolic, or psychiatric diseases. Meanwhile, sleep disorders are commonly screened as comorbidities in various neurodegenerative diseases, epilepsy, and others. Building on existing research that examines the role of astrocytes in sleep disorders, this review aims to elucidate the potential mechanisms by which astrocytes influence sleep regulation and contribute to sleep disorders in the varied settings of brain diseases. The review emphasizes the significance of astrocyte-mediated mechanisms in sleep disorders and their associated comorbidities, highlighting the need for further research.

Role of astrocytes in sleep deprivation: accomplices, resisters, or bystanders?

Sleep plays an essential role in all studied animals with a nervous system. However, sleep deprivation leads to various pathological changes and neurobehavioral problems. Astrocytes are the most abundant cells in the brain and are involved in various important functions, including neurotransmitter and ion homeostasis, synaptic and neuronal modulation, and blood-brain barrier maintenance; furthermore, they are associated with numerous neurodegenerative diseases, pain, and mood disorders. Moreover, astrocytes are increasingly being recognized as vital contributors to the regulation of sleep-wake cycles, both locally and in specific neural circuits. In this review, we begin by describing the role of astrocytes in regulating sleep and circadian rhythms, focusing on: (i) neuronal activity; (ii) metabolism; (iii) the glymphatic system; (iv) neuroinflammation; and (v) astrocyte-microglia cross-talk. Moreover, we review the role of astrocytes in sleep deprivation comorbidities and sleep deprivation-related brain disorders. Finally, we discuss potential interventions targeting astrocytes to prevent or treat sleep deprivation-related brain disorders. Pursuing these questions would pave the way for a deeper understanding of the cellular and neural mechanisms underlying sleep deprivation-comorbid brain disorders.

SENP3-mediated deSUMOylation of c-Jun facilitates microglia-induced neuroinflammation after cerebral ischemia and reperfusion injury.

Recent evidences have implicated that SENP3 is a deSUMOylase which possesses neuronal damage effects in cerebral ischemia. However, its role in microglia remains poorly understood. Here, we found that SENP3 was upregulated in the peri-infarct areas of mice following ischemic stroke. Furthermore, knockdown of SENP3 significantly inhibits the expression of proinflammatory cytokines and chemokines in microglial cells. Mechanistically, SENP3 can bind and then mediated the deSUMOylation of c-Jun, which activated its transcriptional activity, ultimately followed by the activation of MAPK/AP-1 signaling pathway. In addition, microglia-specific SENP3 knockdown alleviated ischemia-induced neuronal damage, and markedly diminished infract volume, ameliorated sensorimotor and cognitive function in animals subjected to ischemic stroke. These results indicated SENP3 functions as a novel regulator of microglia-induced neuroinflammation by activating the MAPK/AP-1 signaling pathway via mediating the deSUMOylation of c-Jun. Interventions of SENP3 expression or its interaction with c-Jun would be a new and promising therapeutic strategy for ischemic stroke.

TRIM67 alleviates cerebral ischemia‒reperfusion injury by protecting neurons and inhibiting neuroinflammation via targeting IκBα for K63-linked polyubiquitination.

BACKGROUND: Excessive and unresolved neuroinflammation plays an important role in the pathophysiology of many neurological disorders, such as ischemic stroke, yet there are no effective treatments. Tripartite motif-containing 67 (TRIM67) plays a crucial role in the control of inflammatory disease and pathogen infection-induced inflammation; however, the role of TRIM67 in cerebral ischemia‒reperfusion injury remains poorly understood. RESULTS: In the present study, we demonstrated that the expression level of TRIM67 was significantly reduced in middle cerebral artery occlusion and reperfusion (MCAO/R) mice and primary cultured microglia subjected to oxygen-glucose deprivation and reperfusion. Furthermore, a significant reduction in infarct size and neurological deficits was observed in mice after TRIM67 upregulation. Interestingly, TRIM67 upregulation alleviated neuroinflammation and cell death after cerebral ischemia‒reperfusion injury in MCAO/R mice. A mechanistic study showed that TRIM67 bound to IκBα, reduced K48-linked ubiquitination and increased K63-linked ubiquitination, thereby inhibiting its degradation and promoting the stability of IκBα, ultimately inhibiting NF-κB activity after cerebral ischemia. CONCLUSION: Taken together, this study demonstrated a previously unidentified mechanism whereby TRIM67 regulates neuroinflammation and neuronal apoptosis and strongly indicates that upregulation of TRIM67 may provide therapeutic benefits for ischemic stroke.

Contribution of preoperative gut microbiota in postoperative neurocognitive dysfunction in elderly patients undergoing orthopedic surgery.

Objective: To investigate the role of gut microbiota and metabolites in POCD in elderly orthopedic patients, and screen the preoperative diagnostic indicators of gut microbiota in elderly POCD. Method: 40 elderly patients undergoing orthopedic surgery were enrolled and divided into Control group and POCD group following neuropsychological assessments. Gut microbiota was determined by 16S rRNA MiSeq sequencing, and metabolomics of GC-MS and LC-MS was used to screen the differential metabolites. We then analyzed the pathways enriched by metabolites. Result: There was no difference in alpha or beta diversity between Control group and POCD group. There were significant differences in 39 ASV and 20 genera bacterium in the relative abundance. Significant diagnostic efficiency analyzed by the ROC curves were found in 6 genera bacterium. Differential metabolites in the two groups including acetic acid, arachidic acid, pyrophosphate etc. were screened out and enriched to certain metabolic pathways which impacted the cognition function profoundly. Conclusion: Gut microbiota disorders exist preoperatively in the elderly POCD patients, by which there could be a chance to predict the susceptible population. Clinical Trial Registration: [http://www.chictr.org.cn/edit.aspx?pid=133843&htm=4], identifier [ChiCTR2100051162].

Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery.

Postoperative cognitive dysfunction (POCD) is a severe neurological complication after anesthesia and surgery. However, there is still a lack of effective clinical pharmacotherapy due to its unclear pathogenesis. Caffeic acid phenethyl ester (CAPE), which is obtained from honeybee propolis and medicinal plants, shows powerful antioxidant, anti-inflammatory, and immunomodulating properties. In this study, we aimed to evaluate whether CAPE mitigated cognitive impairment following anesthesia and surgery and its potential underlying mechanisms in aged mice. Here, isoflurane anesthesia and tibial fracture surgery were used as the POCD model, and H2O2-induced BV2 cells were established as the microglial oxidative stress model. We revealed that CAPE pretreatment suppressed oxidative stress and promoted the switch of microglia from the M1 to the M2 type in the hippocampus, thereby ameliorating cognitive impairment caused by anesthesia and surgery. Further investigation indicated that CAPE pretreatment upregulated hippocampal Sirt6/Nrf2 expression after anesthesia and surgery. Moreover, mechanistic studies in BV2 cells demonstrated that the potent effects of CAPE pretreatment on reducing ROS generation and promoting protective polarization were attenuated by a specific Sirt6 inhibitor, OSS_128167. In summary, our findings opened a promising avenue for POCD prevention through CAPE pretreatment that enhanced the Sirt6/Nrf2 pathway to suppress oxidative stress as well as favor microglia protective polarization.

Sirtuin 5 aggravates microglia-induced neuroinflammation following ischaemic stroke by modulating the desuccinylation of Annexin-A1.

BACKGROUND: Microglia-induced excessive neuroinflammation plays a crucial role in the pathophysiology of multiple neurological diseases, such as ischaemic stroke. Controlling inflammatory responses is considered a promising therapeutic approach. Sirtuin 5 (SIRT5) mediates lysine desuccinylation, which is involved in various critical biological processes, but its role in ischaemic stroke remains poorly understood. This research systematically explored the function and potential mechanism of SIRT5 in microglia-induced neuroinflammation in ischaemic stroke. METHODS: Mice subjected to middle cerebral artery occlusion were established as the animal model, and primary cultured microglia treated with oxygen-glucose deprivation and reperfusion were established as the cell model of ischaemic stroke. SIRT5 short hairpin RNA, adenovirus and adeno-associated virus techniques were employed to modulate SIRT5 expression in microglia both in vitro and in vivo. Coimmunoprecipitation, western blot and quantitative real-time PCR assays were performed to reveal the molecular mechanism. RESULTS: In the current study, we showed that SIRT5 expression in microglia was increased in the early phase of ischaemic stroke. SIRT5 interacts with and desuccinylates Annexin A1 (ANXA1) at K166, which in turn decreases its SUMOylation level. Notably, the desuccinylation of ANXA1 blocks its membrane recruitment and extracellular secretion, resulting in the hyperactivation of microglia and excessive expression of proinflammatory cytokines and chemokines, ultimately leading to neuronal cell damage after ischaemic stroke. Further investigation showed that microglia-specific forced overexpression of SIRT5 worsened ischaemic brain injury, whereas downregulation of SIRT5 exhibited neuroprotective and cognitive-preserving effects against ischaemic brain injury, as proven by the decreased infarct area, reduced neurological deficit scores, and improved cognitive function. CONCLUSIONS: Collectively, these data identify SIRT5 as a novel regulator of microglia-induced neuroinflammation and neuronal damage after cerebral ischaemia. Interventions targeting SIRT5 expression may represent a potential therapeutic target for ischaemic stroke.

SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia-reperfusion injury.

BACKGROUND: Previous data have reported that Sentrin/SUMO-specific protease 6 (SENP6) is involved in ischaemic brain injury and induces neuronal apoptosis after cerebral ischaemia, but the role of SENP6 in microglia-induced neuroinflammation and its underlying mechanism remain poorly understood. This research systematically explored the function and potential mechanism of SENP6 in microglia-induced neuroinflammation after ischaemic stroke. RESULTS: We first identified an increased protein level of SENP6 in microglia after cerebral ischaemia. Then, we demonstrated that SENP6 promoted detrimental microglial phenotype polarization. Specifically, SENP6-mediated de-SUMOylation of ANXA1 targeted the IκB kinase (IKK) complex and selectively inhibited the autophagic degradation of IKKα in an NBR1-dependent manner, activating the NF-κB pathway and enhancing proinflammatory cytokine expression. In addition, downregulation of SENP6 in microglia effectively reduced cocultured neuronal damage induced by ischaemic stroke. More importantly, we employed an AAV-based technique to specifically knockdown SENP6 in microglia/macrophages, and in vivo experiments showed that SENP6 inhibition in microglia/macrophages notably lessened brain ischaemic infarct size, decreased neurological deficit scores, and ameliorated motor and cognitive function in mice subjected to cerebral ischaemia surgery. CONCLUSION: We demonstrated a previously unidentified mechanism by which SENP6-mediated ANXA1 de-SUMOylation regulates microglial polarization and our results strongly indicated that in microglia, inhibition of SENP6 may be a crucial beneficial therapeutic strategy for ischaemic stroke.

Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies.

Type 2 diabetes (T2D) and its target organ injuries cause distressing impacts on personal health and put an enormous burden on the healthcare system, and increasing attention has been paid to T2D-associated cognitive dysfunction (TDACD). TDACD is characterized by cognitive dysfunction, delayed executive ability, and impeded information-processing speed. Brain imaging data suggest that extensive brain regions are affected in patients with T2D. Based on current findings, a wide spectrum of non-specific neurodegenerative mechanisms that partially overlap with the mechanisms of neurodegenerative diseases is hypothesized to be associated with TDACD. However, it remains unclear whether TDACD is a consequence of T2D or a complication that co-occurs with T2D. Theoretically, anti-diabetes methods are promising neuromodulatory approaches to reduce brain injury in patients with T2D. In this review, we summarize potential mechanisms underlying TDACD and promising neurotropic effects of anti-diabetes methods and some neuroprotective natural compounds. Constructing screening or diagnostic tools and developing targeted treatment and preventive strategies would be expected to reduce the burden of TDACD.

TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury.

Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Tripartite motif-containing 45 (TRIM45) is a ubiquitin E3 ligase involved in various critical biological processes. However, the role of TRIM45 in cerebral ischemia remains unknown. Here, we found that the TRIM45 protein was highly expressed in the peri-infarct areas of mice subjected to cerebral ischemia and reperfusion injury induced by middle cerebral artery occlusion. This study systemically evaluated the putative role of TRIM45 in the regulation of neuroinflammation during ischemic injury and the potential underlying mechanisms. We found that TRIM45 knockdown significantly decreased proinflammatory cytokine and chemokine production in primary cultured microglia challenged with oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Mechanistically, we demonstrated that TRIM45 constitutively interacted with TAB2 and consequently facilitated the Lys-63-linked polyubiquitination of TAB2, leading to the formation of the TAB1-TAK1-TAB2 complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. In an in vitro coculture Transwell system, downregulation of TRIM45 expression also inhibited the OGD/R-induced activation of microglia and alleviated neuronal apoptosis. More importantly, microglia-specific knockdown of TRIM45 in mice significantly reduced the infarct size, mitigated neurological deficit scores, and improved cognitive function after ischemic stroke. Taken together, our study reveals that the TRIM45-TAB2 axis is a crucial checkpoint that controls NF-κB signaling in microglia during cerebral ischemia and reperfusion injury. Therefore, targeting TRIM45 may be an attractive therapeutic strategy.

Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites.

Long-term stress causes hyperalgesia; and there are gender differences in the mechanism of pain in male and female individuals. The role of gut microbiota in pain has also been verified. However, whether gut microbiota plays a role in hyperalgesia caused by chronic restraint stress (CRS) with gender differences has not been explored. This study investigated the role of gut microbiota in CRS-induced hyperalgesia gender-specifically through 16 S ribosomal RNA (16 S rRNA) gene sequencing and untargeted metabolomic analysis using liquid chromatography-mass spectrometry (LC-MS). The study found that both male and female mice experienced hyperalgesia after CRS and antibiotic treatment. 16 S rRNA gene sequencing reveals gender differences in the fecal microbiota induced by CRS. The pain threshold decreased after transplanting the fecal microbiota from the male and female CRS group to the corresponding pseudo-germ-free mice. In addition, this study detected gender differences in the host gut microbiota and serum metabolism induced by fecal microbiota transplantation (FMT). Specifically, the different serum metabolites between the pseudo-germ-free mice receiving FMT from the CRS group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice. In summary, the gut microbiota participates in stress-induced hyperalgesia (SIH) with gender differences by influencing the host's gut microbiota composition and serum metabolism. Therefore, our findings provided insights into developing novel gut microbiota-associated drugs for the management of gender-specific SIH.

Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia?

In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic community has also recognized the existence of the microbiota-gut-brain axis. Chronic pain has always been an urgent difficulty for human beings, which often causes anxiety, depression, and other mental symptoms, seriously affecting people's quality of life. Hyperalgesia is one of the main adverse reactions of chronic pain. The mechanism of gut microbiota in hyperalgesia has been extensively studied, providing a new target for pain treatment. Enterochromaffin cells, as the chief sentinel for sensing gut microbiota and its metabolites, can play an important role in the interaction between the gut microbiota and hyperalgesia through paracrine or neural pathways. Therefore, this systematic review describes the role of gut microbiota in the pathological mechanism of hyperalgesia, learns about the role of enterochromaffin cell receptors and secretions in hyperalgesia, and provides a new strategy for pain treatment by targeting enterochromaffin cells through restoring disturbed gut microbiota or supplementing probiotics.

Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms.

Brain diseases, including neurodegenerative, cerebrovascular and neuropsychiatric diseases, have posed a deleterious threat to human health and brought a great burden to society and the healthcare system. With the development of medical technology, vagus nerve stimulation (VNS) has been approved by the Food and Drug Administration (FDA) as an alternative treatment for refractory epilepsy, refractory depression, cluster headaches, and migraines. Furthermore, current evidence showed promising results towards the treatment of more brain diseases, such as Parkinson's disease (PD), autistic spectrum disorder (ASD), traumatic brain injury (TBI), and stroke. Nonetheless, the biological mechanisms underlying the beneficial effects of VNS in brain diseases remain only partially elucidated. This review aims to delve into the relevant preclinical and clinical studies and update the progress of VNS applications and its potential mechanisms underlying the biological effects in brain diseases.

Digestive system involvement of infections with SARS-CoV-2 and other coronaviruses: Clinical manifestations and potential mechanisms.

Although coronavirus (CoV) infection is often characterized by respiratory symptoms, the virus can also result in extrapulmonary symptoms, especially the symptoms related to the digestive system. The outbreak of coronavirus disease 2019 (COVID-19) is currently the world's most pressing public health threat and has a significant impact on civil societies and the global economy. The occurrence of digestive symptoms in patients with COVID-19 is closely related to the development and prognosis of the disease. Moreover, thus far, there are no specific antiviral drug or vaccine approved for the treatment or prevention of COVID-19. Therefore, we elaborate on the effects of CoVs on the digestive system and the potential underlying mechanisms.

Gut microbiota transplantation from db/db mice induces diabetes-like phenotypes and alterations in Hippo signaling in pseudo germ-free mice.

Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is of increasing concern. Gut microbiota might have a critical role in the pathogenesis of T2DM. Additionally, Hippo signaling has been associated strongly with the progression of T2DM and the aging process. We adopted db/db male mice as a T2DM model, and the gut microbiota of db/db and m/m mice were transplanted successfully into pseudo germ-free mice. Furthermore, Hippo signaling, including mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP), and phosphorylation of YAP (p-YAP) in peripheral tissues were significantly altered and highly correlated with blood glucose in db/db mice. Interestingly, the host after gut microbiota transplantation from db/db mice showed decreased MST1 and LATS1 levels, and p-YAP/YAP ratio in the heart, liver, and kidney compared to those from m/m mice. Negative correlations between fasting blood glucose and Hippo signaling levels in selected peripheral tissues also were identified. These findings suggest that alterations in Hippo signaling in selected peripheral tissues may contribute to the development of T2DM, and that therapeutic interventions improving Hippo signaling by gut microbiota transplantation might be beneficial for the treatment of T2DM and other age-related metabolic diseases.