Optogenetic activation of the lateral habenulaD1R-ventral tegmental area circuit induces depression-like behavior in mice.

A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R-VTA axons. Conversely, optogenetic inhibition of the LHbD1R-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.

Myelopathy associated with mixed connective tissue disease: clinical manifestation, diagnosis, treatment, and prognosis.

Mixed connective tissue disease (MCTD) is a chronic autoimmune disease, which has a broad range of clinical manifestations shared by systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis. MCTD is featured with high serum titers of anti-ribonucleoprotein antibodies and multiple system involvement. Its spinal cord involvement mainly manifests as transverse myelopathy (TM) and longitudinal extensive transverse myelopathy (LETM). Myelopathy in MCTD is extremely rare, and is usually characterized by serious neurological complications, such as paralysis or muscular paresis, sensory impairment, and smooth muscle dysfunction. Progressive clinical manifestations combined with laboratory examinations and magnetic resonance imaging examinations play important roles in the diagnosis of this disease. In order to prevent permanent neurological damage to the spinal cord, plasmapheresis and intravenous immunoglobulin can be performed in patients at the early disease stage. Early high-dose corticosteroids combined with cyclophosphamide, followed by low doses of immunosuppressors, can improve the long-term prognosis of patients. There are only nine global cases reported on MCTD associated with myelopathy at present. The death rate and disability rate of myelopathy in MCTD are extremely high. In this review, the pathomechanisms, clinical manifestations, auxiliary examination, diagnosis, differential diagnosis, treatment, and prognosis of myelopathy in MCTD were systematically elucidated.

Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia.

BACKGROUND: Stroke is the second leading cause of death worldwide and the most common cause of adult-acquired disability in many nations. Thus, attenuating the damage after ischemic injury and improving patient prognosis are of great importance. We have indicated that ischemic preconditioning (IP) can effectively reduce the damage of ischemia reperfusion and that inhibition of gap junctions may further reduce this damage. Although we confirmed that the function of gap junctions is closely associated with glutamate, we did not investigate the mechanism. In the present study, we aimed to clarify whether the blockade of cellular communication at gap junctions leads to significant reductions in the levels of glutamate released by astrocytes following cerebral ischemia. METHODS: To explore this hypothesis, we utilized the specific blocking agent carbenoxolone (CBX) to inhibit the opening and internalization of connexin 43 channels in an in vitro model of oxygen-glucose deprivation/re-oxygenation (OGD/R), following IP. RESULTS: OGD/R resulted in extensive astrocytic glutamate release following upregulation of hemichannel activity, thus increasing reactive oxygen species (ROS) generation and subsequent cell death. However, we observed significant increases in neuronal survival in neuron-astrocyte co-cultures that were subjected to IP prior to OGD/R. Moreover, the addition of CBX enhanced the protective effects of IP during the re-oxygenation period following OGD, by means of blocking the release of glutamate, increasing the level of the excitatory amino acid transporter 1, and downregulating glutamine expression. CONCLUSIONS: Our results suggest that combined use of IP and CBX represents a novel therapeutic strategy to attenuate damage from cerebral ischemia with minimal adverse side effects.

Roles of astrocytic connexin-43, hemichannels, and gap junctions in oxygen-glucose deprivation/reperfusion injury induced neuroinflammation and the possible regulatory mechanisms of salvianolic acid B and carbenoxolone.

BACKGROUND: Glia-mediated neuroinflammation is related to brain injury exacerbation after cerebral ischemia/reperfusion (I/R) injury. Astrocytic hemichannels or gap junctions, which were mainly formed by connexin-43, have been implicated in I/R damage. However, the exact roles of astrocytic hemichannels and gap junction in neuroinflammatory responses induced by I/R injury remain unknown. METHODS: Primary cultured astrocytes were subjected to OGD/R injury, an in vitro model of I/R injury. Salvianolic acid B (SalB) or carbenoxolone (CBX) were applied for those astrocytes. Besides, Cx43 mimetic peptides Gap19 or Gap26 were also applied during OGD/R injury; Cx43 protein levels were determined by western blot and cytoimmunofluorescene staining, hemichannel activities by Ethidium bromide uptake and ATP concentration detection, and gap junction intercellular communication (GJIC) permeability by parachute assay. Further, astrocyte-conditioned medium (ACM) was collected and incubated with microglia. Meanwhile, ATP or apyrase were applied to explore the role of ATP during OGD/R injury. Microglial activation, M1/M2 phenotypes, and M1/M2-related cytokines were detected. Also, microglia-conditioned medium (MEM) was collected and incubated with astrocytes to further investigate its influence on astrocytic hemichannel activity and GJIC permeability. Lastly, effects of ACM and MCM on neuronal viability were detected by flow cytometry. RESULTS: We found that OGD/R induced abnormally opened hemichannels with increased ATP release and EtBr uptake but reduced GJIC permeability. WB tests showed decreased astrocytic plasma membrane's Cx43, while showing an increase in cytoplasma. Treating OGD/R-injured microglia with ATP or OGD/R-ACM induced further microglial activation and secondary pro-inflammatory cytokine release, with the M1 phenotype predominating. Conversely, astrocytes incubated with OGD/R-MCM exhibited increased hemichannel opening but reduced GJIC coupling. Both SalB and CBX inhibited abnormal astrocytic hemichannel opening and ATP release and switched the activated microglial phenotype from M1 to M2, thus providing effective neuroprotection. Application of Gap19 or Gap26 showed similar results with CBX. We also found that OGD/R injury caused both plasma membrane p-Cx43(Ser265) and p-Src(Tyr416) significantly upregulated; application of SalB may be inhibiting Src kinase and attenuating Cx43 internalization. Meanwhile, CBX treatment induced obviously downregulation of p-Cx43(Ser368) and p-PKC(Ser729) protein levels in plasma membrane. CONCLUSIONS: We propose a vicious cycle exists between astrocytic hemichannel and microglial activation after OGD/R injury, which would aggravate neuroinflammatory responses and neuronal damage. Astrocytic Cx43, hemichannels, and GJIC play critical roles in OGD/R injury-induced neuroinflammatory responses; treatment differentially targeting astrocytic Cx43, hemichannels, and GJIC may provide novel avenues for therapeutics during cerebral I/R injury.

Rational Design and Synthesis of Unsaturated Se-Containing Osmacycles with σ-Aromaticity.

Isolation of the simplest 4π three-membered heterocycles (1H-azirine, oxirene, thiirene, and selenirene) remains a big challenge due to their π-antiaromaticity and significant ring strain. Here we demonstrate that the incorporation of a transition-metal fragment could stabilize the antiaromatic selenirene and pentalene frameworks simultaneously by density functional theory (DFT) calculations. Experimental verification leads to the Se-containing metallapolycycles, osmapentaloselenirenes, with remarkable thermal stability. The osmaselenirene unit in the metallapolycycle is determined to be the first example of σ-aromaticity dominating in an unsaturated Se-containing ring. Our results not only highlight a remarkable stabilization by the transition-metal but also widen the scope of σ-aromaticity in unsaturated rings, which is traditionally reserved for the domain of π-aromaticity.

σ Aromaticity Dominates in the Unsaturated Three-Membered Ring of Cyclopropametallapentalenes from Groups†7-9: A DFT Study.

Aromaticity, an old but still fantastic topic, has long attracted considerable interest of chemists. Generally, π aromaticity is described by π-electron delocalization in closed circuits of unsaturated compounds whereas σ-electron delocalization in saturated rings leads to σ aromaticity. Interestingly, our recent study shows that σ aromaticity can be dominating in an unsaturated three-membered ring (3MR) of cyclopropaosmapentalene. An interesting question is raised: Can the σ aromaticity, which is dominant in the unsaturated 3MR, be extended to other cyclopropametallapentalenes? If so, how could the metal centers, ligands, and substituents affect the σ aromaticity? Here, we report a thorough theoretical study on these issues. The nucleus-independent chemical shift calculations and the anisotropy of the current-induced density plots reveal the dominant σ aromaticity in these unsaturated 3MRs. In addition, our calculations show that substituents on the 3MRs have significant effects on the σ aromaticity, whereas the ligand effect is particularly small.

The Relationship of Astrocytes and Microglia with Different Stages of Ischemic Stroke.

Ischemic stroke is the predominant cause of severe morbidity and mortality worldwide. Post-stroke neuroinflammation has recently received increasing attention with the aim of providing a new effective treatment strategy for ischemic stroke. Microglia and astrocytes are major components of the innate immune system of the central nervous system. They can be involved in all phases of ischemic stroke, from the early stage, contributing to the first wave of neuronal cell death, to the late stage involving phagocytosis and repair. In the early stage of ischemic stroke, a vicious cycle exists between the activation of microglia and astrocytes (through astrocytic connexin 43 hemichannels), aggravating neuroinflammatory injury post-stroke. However, in the late stage of ischemic stroke, repeatedly activated microglia can induce the formation of glial scars by triggering reactive astrogliosis in the peri-infarct regions, which may limit the movement of activated microglia in reverse and restrict the diffusion of inflammation to healthy brain tissues, alleviating the neuroinflammatory injury poststroke. In this review, we elucidated the various roles of astrocytes and microglia and summarized their relationship with neuroinflammation. We also examined how astrocytes and microglia influence each other at different stages of ischemic stroke. Several potential therapeutic approaches targeting astrocytes and microglia in ischemic stroke have been reviewed. Understanding the details of astrocytemicroglia interaction processes will contribute to a better understanding of the mechanisms underlying ischemic stroke, contributing to the identification of new therapeutic interventions.

A review of stress-induced hyperglycaemia in the context of acute ischaemic stroke: Definition, underlying mechanisms, and the status of insulin therapy.

The transient elevation of blood glucose produced following acute ischaemic stroke (AIS) has been described as stress-induced hyperglycaemia (SIH). SIH is common even in patients with AIS who have no previous diagnosis of diabetes mellitus. Elevated blood glucose levels during admission and hospitalization are strongly associated with enlarged infarct size and adverse prognosis in AIS patients. However, insulin-intensive glucose control therapy defined by admission blood glucose for SIH has not achieved the desired results, and new treatment ideas are urgently required. First, we explore the various definitions of SIH in the context of AIS and their predictive value in adverse outcomes. Then, we briefly discuss the mechanisms by which SIH arises, describing the dual effects of elevated glucose levels on the central nervous system. Finally, although preclinical studies support lowering blood glucose levels using insulin, the clinical outcomes of intensive glucose control are not promising. We discuss the reasons for this phenomenon.

Effects of remote ischemic postconditioning on the pro-inflammatory neutrophils of peripheral blood in acute cerebral infarction.

BACKGROUND: Neutrophils play crucial roles in the inflammatory response after acute cerebral infarction (ACI). Previous studies revealed neutrophils are non-homogeneous and can be divided into at least two subtypes, pro-inflammatory and anti-inflammatory, correlated with patients' prognosis. OBJECTIVE: We aimed to explore the correlation between disease severity and peripheral blood neutrophils in patients with ACI and determine whether remote ischemic postconditioning (RIPostC) exerts neuroprotective effects by regulating neutrophils. METHODS: Patients (n = 38) with acute anterior circulation cerebral infarction were assigned to conventional treatment (n = 24; included aspirin, statins, neuro nutrition drugs, and circulation improvement drugs) or RIPostC (n = 14; 7-day ischemia adaptation [complete ischemia of both upper extremities for 5 minutes followed by remission for 5 minutes, 5 repeated cycles, twice a day, started from the morning of the second day of admission] based on conventional treatment) groups, based on their preference. General clinical data and peripheral blood samples were taken three times, in the morning before and 3 and 7 days after treatment. Fifteen adults with non-acute cerebral infarction matched for sex, age, and risk factors were recruited as controls; peripheral blood samples were only collected on the recruitment day. We used flow cytometry to detect the percentage of neutrophils and Real-Time PCR to detect the gene expression of interleukin (IL)-1ß in the peripheral blood samples. RESULTS: The percentage of neutrophils, pro-inflammatory neutrophils (IL-1ß high expression in flow cytometry), and IL-1ß mRNA expression increased after ACI (P = 0.01, P = 0.001, P < 0.001). The National Institutes of Health Stroke Scale (NIHSS) score of patients with ACI within one day of onset was positively correlated with the percentage of pro-inflammatory neutrophils (R = 0.618, P = 0.043). Pro-inflammatory neutrophils in the RIPostC group decreased compared with those in the conventional treatment group, with the most significant difference observed on Day 7 (P = 0.01). However, the percentage of neutrophils was not statistically different. IL-1ß mRNA expression decreased, with the most significant difference on Day 3 (P = 0.004). The NIHSS and Modified Rankin Scale scores for RIPostC decreased more significantly than for conventional treatment (P = 0.002, P = 0.019). CONCLUSION: More severe cerebral infarction was associated with a higher percentage of pro-inflammatory neutrophils. The neuroprotective effect of RIPostC may partly be exerted through gene regulation to reduce pro-inflammatory neutrophils.

Neutrophil Heterogeneity and its Roles in the Inflammatory Network after Ischemic Stroke.

As the first peripheral immune cells to enter the brain after ischemic stroke, neutrophils are important participants in stroke-related neuroinflammation. Neutrophils are quickly mobilized from the periphery in response to a stroke episode and cross the blood-brain barrier to reach the ischemic brain parenchyma. This process involves the mobilization and activation of neutrophils from peripheral immune organs (including the bone marrow and spleen), their chemotaxis in the peripheral blood, and their infiltration into the brain parenchyma (including disruption of the blood-brain barrier, inflammatory effects on brain tissue, and interactions with other immune cell types). In the past, it was believed that neutrophils aggravated brain injuries through the massive release of proteases, reactive oxygen species, pro-inflammatory factors, and extracellular structures known as neutrophil extracellular traps (NETs). With the failure of early clinical trials targeting neutrophils and uncovering their underlying heterogeneity, our view of their role in ischemic stroke has become more complex and multifaceted. As neutrophils can be divided into N1 and N2 phenotypes in tumors, neutrophils have also been found to have similar phenotypes after ischemic stroke, and play different roles in the development and prognosis of ischemic stroke. N1 neutrophils are dominant during the acute phase of stroke (within three days) and are responsible for the damage to neural structures via the aforementioned mechanisms. However, the proportion of N2 neutrophils gradually increases in later phases, and this has a beneficial effect through the release of anti-inflammatory factors and other neuroprotective mediators. Moreover, the N1 and N2 phenotypes are highly plastic and can be transformed into each other under certain conditions. The pronounced differences in their function and their high degree of plasticity make these neutrophil subpopulations promising targets for the treatment of ischemic stroke.

Development and validation of a tumor immune cell infiltration-related gene signature for recurrence prediction by weighted gene co-expression network analysis in prostate cancer.

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes. Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines. Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.

A biocompatible and fully erodible conducting polymer enables implanted rechargeable Zn batteries.

Implanted rechargeable batteries that can provide energy over a sufficient lifetime and ultimately degrade into non-toxic byproducts are highly desirable. However, their advancement is significantly impeded by the limited toolbox of electrode materials with a known biodegradation profile and high cycling stability. Here we report biocompatible, erodible poly(3,4-ethylenedioxythiophene) (PEDOT) grafted with hydrolyzable carboxylic acid pendants. This molecular arrangement combines the pseudocapacitive charge storage from the conjugated backbones and dissolution via hydrolyzable side chains. It demonstrates complete erosion under aqueous conditions in a pH-dependent manner with a predetermined lifetime. The compact rechargeable Zn battery with a gel electrolyte offers a specific capacity of 31.8 mA h g-1 (57% of theoretical capacity) and outstanding cycling stability (78% capacity retention over 4000 cycles at 0.5 A g-1). Subcutaneous implantation of this Zn battery into Sprague-Dawley (SD) rats demonstrates complete biodegradation in vivo and biocompatibility. This molecular engineering strategy presents a viable avenue for developing implantable conducting polymers with a predetermined degradation profile and high energy storage capability.

Metabolic changes with the occurrence of atherosclerotic plaques and the effects of statins.

Atherosclerosis is a common cardiovascular disease caused by the abnormal expression of multiple factors and genes influenced by both environmental and genetic factors. The primary manifestation of atherosclerosis is plaque formation, which occurs when inflammatory cells consume excess lipids, affecting their retention and modification within the arterial intima. This triggers endothelial cell (EC) activation, immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, foam cell formation, lipid streaks, and fibrous plaque development. These processes can lead to vascular wall sclerosis, lumen stenosis, and thrombosis. Immune cells, ECs, and VSMCs in atherosclerotic plaques undergo significant metabolic changes and inflammatory responses. The interaction of cytokines and chemokines secreted by these cells leads to the onset, progression, and regression of atherosclerosis. The regulation of cell- or cytokine-based immune responses is a novel therapeutic approach for atherosclerosis. Statins are currently the primary pharmacological agents utilised for managing unstable plaques owing to their ability to enhance endothelial function, regulate VSMC proliferation and apoptosis by reducing cholesterol levels, and mitigate the expression and activity of inflammatory cytokines. In this review, we provide an overview of the metabolic changes associated with atherosclerosis, describe the effects of inflammatory responses on atherosclerotic plaques, and discuss the mechanisms through which statins contribute to plaque stabilisation. Additionally, we examine the role of statins in combination with other drugs in the management of atherosclerosis.

The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke.

Ischemic stroke, caused by a lack of blood supply in brain tissues, is the third leading cause of human death and disability worldwide, and usually results in sensory and motor dysfunction, cognitive impairment, and in severe cases, even death. Autophagy is a highly conserved lysosome-dependent process in which eukaryotic cells removal misfolded proteins and damaged organelles in cytoplasm, which is critical for energy metabolism, organelle renewal, and maintenance of intracellular homeostasis. Increasing evidence suggests that autophagy plays important roles in pathophysiological mechanisms under ischemic conditions. However, there are still controversies about whether autophagy plays a neuroprotective or damaging role after ischemia. G-protein-coupled receptors (GPCRs), one of the largest protein receptor superfamilies in mammals, play crucial roles in various physiological and pathological processes. Statistics show that GPCRs are the targets of about one-fifth of drugs known in the world, predicting potential values as targets for drug research. Studies have demonstrated that nutritional deprivation can directly or indirectly activate GPCRs, mediating a series of downstream biological processes, including autophagy. It can be concluded that there are interactions between autophagy and GPCRs signaling pathway, which provides research evidence for regulating GPCRs-mediated autophagy. This review aims to systematically discuss the underlying mechanism and dual roles of autophagy in cerebral ischemia, and describe the GPCRs-mediated autophagy, hoping to probe promising therapeutic targets for ischemic stroke through in-depth exploration of the GPCRs-mediated autophagy signaling pathway.

A Prognostic Survival Model of Pancreatic Adenocarcinoma Based on Metabolism-Related Gene Expression.

Accurately predicting the survival prospects of patients suffering from pancreatic adenocarcinoma (PAAD) is challenging. In this study, we analyzed RNA matrices of 182 subjects with PAAD based on public datasets obtained from The Cancer Genome Atlas (TCGA) as training datasets and those of 63 subjects obtained from the Gene Expression Omnibus (GEO) database as the validation dataset. Genes regulating the metabolism of PAAD cells correlated with survival were identified. Furthermore, LASSO Cox regression analyses were conducted to identify six genes (XDH, MBOAT2, PTGES, AK4, PAICS, and CKB) to create a metabolic risk score. The proposed scoring framework attained the robust predictive performance, with 2-year survival areas under the curve (AUCs) of 0.61 in the training cohort and 0.66 in the validation cohort. Compared with the subjects in the low-risk cohort, subjects in the high-risk training cohort presented a worse survival outcome. The metabolic risk score increased the accuracy of survival prediction in patients suffering from PAAD.

Subacute combined degeneration of the spinal cord concurrent with acute pulmonary embolism: a case report.

A 58-year-old male vegetarian presented with progressive numbness and weakness in the lower extremities. Laboratory examinations showed reduced vitamin B12 level with megaloblastic anaemia. Spinal magnetic resonance imaging (MRI) revealed hyperintensity within the posterior and lateral columns on T2-weighted imaging. The diagnosis of subacute combined degeneration (SCD) of the spinal cord was established. Unexpectedly, the patient developed transitory syncope on the second day after hospitalization. The diagnostic computed tomography pulmonary angiography (CTPA) confirmed multiple small pulmonary emboli. An isolated significantly elevated level of homocysteine (117.1 µmol/l) was documented when screening for hypercoagulable markers. Except for a long-term vegetarian diet, no other risk factors for hyperhomocysteinaemia (such as a family history of homocysteinuria) was found. The severity of the hyperhomocysteinaemia found in this current patient was unusual for patients with an insufficient intake of vitamin B12. In SCD patients, elevated homocysteine may increase the risk of thrombosis, which may exacerbate existing problems. Knowing the risk factors should help physicians choose appropriate diagnostic and therapeutic strategies.

Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury.

Ischemic stroke contributes to more than 80% of all strokes and has the four characteristics of high prevalence, high disability, high mortality, and high recurrence. Stroke is a preventable and controllable disease. In addition to controlling the primary disease, effective prevention and control measures need to be given to the occurrence and development of stroke. With the development and progress of modern treatment methods for ischemic stroke, the mortality and disability rate have decreased significantly. At present, the main treatment methods for ischemic stroke include thrombolysis, thrombus removal at the ultra-early stage, and treatment of improving collateral circulation in the acute phase. However, the ultra-early and early blood reperfusion involves reperfusion injury, which will cause secondary nerve damage, which is called cerebral ischemia/reperfusion injury (CIRI). Studies have found that autophagy is involved in the entire process of CIRI and can reduce the damage of CIRI. The mammalian target of Rapamycin (mTORC1) is the primary signal pathway regulating autophagy. And the mTORC1 inhibitor, Rapamycin, has been proved to exert neuroprotective effects in the ultra-early and early cerebral ischemia-reperfusion. Therefore, screening and designing mTORC1 inhibitors is very important to control reperfusion injury and reduce neuronal death and apoptosis. In this research, plenty of computer-assisted was applied to virtually screen and select potential mTORC1's inhibitors. We used Libdock to screen the structure and performed toxicity predictions, ADME (absorption, distribution, metabolism, excretion) to predict small molecules' pharmacological and toxicological properties. To assess the binding mechanism and affinity between the mTORC1 dimer and the ligand, molecular docking was performed. Then, the pharmacophore of small molecules in the docking conformation with the protein was supplemented by Schrodinger. Additionally, molecular dynamics simulations were conducted to assess if the ligand-receptor complex was stable in a natural environment. Furthermore, an experiment was performed to verify the inhibitory effect of compound 1 and compound 2 on mTOR protein. All in all, the study provides a hand of candidate drugs as well as pharmacological properties, which can play an essential role in mTORC1 inhibitors.

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges.

Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.

The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions.

Ischemic stroke is a multi-factorial cerebrovascular disease with high worldwide morbidity and mortality. In the past few years, multiple studies have revealed the underlying mechanism of ischemia/reperfusion injury, including calcium overload, amino acid toxicity, oxidative stress, and inflammation. Connexin 43 (Cx43), the predominant connexin protein in astrocytes, has been recently proven to display non-substitutable roles in the pathology of ischemic stroke development and progression through forming gap junctions and hemichannels. Under normal conditions, astrocytic Cx43 could be found in hemichannels or in the coupling with other hemichannels on astrocytes, neurons, or oligodendrocytes to form the neuro-glial syncytium, which is involved in metabolites exchange between communicated cells, thus maintaining the homeostasis of the CNS environment. In ischemic stroke, the phosphorylation of Cx43 might cause the degradation of gap junctions and the opening of hemichannels, contributing to the release of inflammatory mediators. However, the remaining gap junctions could facilitate the exchange of protective and harmful metabolites between healthy and injured cells, protecting the injured cells to some extent or damaging the healthy cells depending on the balance of the exchange of protective and harmful metabolites. In this study, we review the changes in astrocytic Cx43 expression and distribution as well as the influence of these changes on the function of astrocytes and other cells in the CNS, providing new insight into the pathology of ischemic stroke injury; we also discuss the potential of astrocytic Cx43 as a target for the treatment of ischemic stroke.

The efficacy and safety of salvianolic acids on acute cerebral infarction treatment: A protocol for systematic review and meta analysis.

BACKGROUND: Salvianolic acids (SA) has been widely used for the treatment of acute cerebral infarction (ACI) combined with basic western medicine therapy in China. This study was aimed to evaluate the efficacy and safety of SA on ACI treatment and its influence on neurological functions, activity of daily living, and cognitive functions. METHODS: We retrieved related articles from PubMed, the Cochrane Center Controlled Trials Register, EMBASE, Medline, Ovid, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Database without date and language restrictions. Finally, 58 randomized controlled trials were included from 239 retrieved records. Two researchers extracted the basic information and data from included articles and assessed the quality and analysis of data by using Review Manager 5.3. RESULTS: The administration of SA significantly increased the total clinical effective rate of ACI treatment (P < .001) and improved the National Institute of Health Stroke Scale scores, modified Rankin Scale scores, and Barthel Index scores after treatment and 3 months after ACI (P < .05). The activities of daily living scores in the SA group were significantly increased after treatment (P < .001), whereas they were remarkably decreased 3 months after ACI (P < .001) compared with that in the control group. Besides, SA profoundly promoted the recovery of Montreal Cognitive Assessment scores (P < .001). However, the use of SA increased the risk of adverse events occurrence (P = .007). CONCLUSION: SA combined with basic western medicine treatment could promote neurological functions, daily living activities, and cognitive functions recovery of ACI patients. Although SA increased the risk of adverse events occurrence, these adverse events were easily controlled or disappeared spontaneously.