Mechanism of metformin regulation in central nervous system: Progression and future perspectives.

Metformin as a first-line drug for type 2 diabetes mellitus(T2DM) treatment is widely studied. Metformin can reduce liver glucose output and improve insulin resistance. Recent evidence from in vivo and in vitro has confirmed that metformin can transport across the blood-brain barrier(BBB) and activate specific neurons and neuroglia to exert neurological actions, however, the specific effect of metformin regulation on CNS is still obscure. In this review, we summarized current evidence from preclinical evidence focusing on the regulatory role of metformin in CNS and found that metformin can exert potential neuroprotective, neurotrophic, and neurogenesis-stimulated actions; besides, metformin also exerts antiinflammatory effect by inhibiting microglial activates and regulating microglial polarization. These findings indicate there might be extensive pharmacological efficacy and therapeutic insights of metformin in neurological diseases' clinical application.

Transcription factors are potential therapeutic targets in epilepsy.

Academics generally believe that imbalance between excitation and inhibition of the nervous system is the root cause of epilepsy. However, the aetiology of epilepsy is complex, and its pathogenesis remains unclear. Many studies have shown that epilepsy is closely related to genetic factors. Additionally, the involvement of a variety of tumour-related transcription factors in the pathogenesis of epilepsy has been confirmed, which also confirms the heredity of epilepsy. In this review, we summarize the existing research on a variety of transcription factors and epilepsy and present relevant evidence related to transcription factors that may be targets in epilepsy. This information is of great significance for revealing the in-depth molecular and cellular mechanisms of epilepsy.

Hydrogen sulfide: A new therapeutic target in vascular diseases.

Hydrogen sulfide (H2S) is one of most important gas transmitters. H2S modulates many physiological and pathological processes such as inflammation, oxidative stress and cell apoptosis that play a critical role in vascular function. Recently, solid evidence show that H2S is closely associated to various vascular diseases. However, specific function of H2S remains unclear. Therefore, in this review we systemically summarized the role of H2S in vascular diseases, including hypertension, atherosclerosis, inflammation and angiogenesis. In addition, this review also outlined a novel therapeutic perspective comprising crosstalk between H2S and smooth muscle cell function. Therefore, this review may provide new insight inH2S application clinically.

Brain-immune interaction mechanisms: Implications for cognitive dysfunction in psychiatric disorders.

OBJECTIVES: Cognitive dysfunction has been identified as a major symptom of a series of psychiatric disorders. Multidisciplinary studies have shown that cognitive dysfunction is monitored by a two-way interaction between the neural and immune systems. However, the specific mechanisms of cognitive dysfunction in immune response and brain immune remain unclear. MATERIALS AND METHODS: In this review, we summarized the relevant research to uncover our comprehension of the brain-immune interaction mechanisms underlying cognitive decline. RESULTS: The pathophysiological mechanisms of brain-immune interactions in psychiatric-based cognitive dysfunction involve several specific immune molecules and their associated signaling pathways, impairments in neural and synaptic plasticity, and the potential neuro-immunological mechanism of stress. CONCLUSIONS: Therefore, this review may provide a better theoretical basis for integrative therapeutic considerations for psychiatric disorders associated with cognitive dysfunction.

Berberine: A Promising Treatment for Neurodegenerative Diseases.

Berberine, as a natural alkaloid compound, is characterized by a diversity of pharmacological effects. In recent years, many researches focused on the role of berberine in central nervous system diseases. Among them, the effect of berberine on neurodegenerative diseases has received widespread attention, for example Alzheimer's disease, Parkinson's disease, Huntington's disease, and so on. Recent evidence suggests that berberine inhibits the production of neuroinflammation, oxidative, and endoplasmic reticulum stress. These effects can further reduce neuron damage and apoptosis. Although the current research has made some progress, its specific mechanism still needs to be further explored. This review provides an overview of berberine in neurodegenerative diseases and its related mechanisms, and also provides new ideas for future research on berberine.

Current Evidence and Future Directions of Berberine Intervention in Depression.

A major type of serious mood disorder, depression is currently a widespread and easily overlooked psychological illness. With the low side effects of natural products in the treatment of diseases becoming the pursuit of new antidepressants, natural Chinese medicine products have been paid more and more attention for their unique efficacy in improving depression. In a view from the current study, the positive antidepressant effects of berberine are encouraging. There is a lot of work that needs to be done to accurately elucidate the efficacy and mechanism of berberine in depression. In this review, the relevant literature reports on the treatment of depression and anxiety by berberine are updated, and the potential pharmacological mechanism of berberine in relieving depression has also been discussed.

Stress induced microglial activation contributes to depression.

Major depressive disorder (MDD) is a debilitating neuropsychological disorder, which has caused serious health and socio-economic burdens worldwide. A growing body of evidence indicates that inflated neuroinflammation and aberrant microglial activity are associated with depressive-like symptoms. In the central nervous system (CNS), microglia constantly survey the internal environment, playing crucial roles in injury response and pathogen defense. From developmental stage through the whole adult life, microglia dynamically sculpt neural circuits by modulation of synaptic plasticity or engulfment of redundant synapses. Dysregulated microglia may impact these fundamental biophysiological processes and contribute to the pathogenesis of depressive disorder. In this review, we discuss candidate mechanisms by which stress induces microglia to deviate from its fine-tuned homeostasis in clinical and preclinical studies. These triggering factors include the neuroendocrine system, the noradrenergic system, gut-brain axis, and unbalanced pro- v.s. anti-inflammatory milieu composed of diversified cytokines and neurotransmitters. We argue that functional changes in microglia can strongly influence neuronal network activity due to dysregulated secretion of cytokines and elevated release of neurotoxic metabolites, therefore contributing to the pathological outcomes in stress. Understanding the role that microglia play in the etiology of depression may provide a tantalizing therapeutic target and help with the development of novel intervention strategies against this devastating mental health problem.

Highly Efficient Modular Construction of Functional Drug Delivery Platform Based on Amphiphilic Biodegradable Polymers via Click Chemistry.

Amphiphilic copolymers with pendant functional groups in polyester segments are widely used in nanomedicine. These enriched functionalities are designed to form covalent conjugates with payloads or provide additional stabilization effects for encapsulated drugs. A general method is successfully developed for the efficient preparation of functional biodegradable PEG-polyester copolymers via click chemistry. Firstly, in the presence of mPEG as initiator, Sn(Oct)2-catalyzed ring-opening polymerization of the α-alkynyl functionalized lactone with D,L-lactide or ε-caprolactone afforded linear mPEG-polyesters bearing multiple pendant alkynyl groups. Kinetic studies indicated the formation of random copolymers. Through copper-catalyzed azide-alkyne cycloaddition reaction, various small azido molecules with different functionalities to polyester segments are efficiently grafted. The molecular weights, polydispersities and grafting efficiencies of azido molecules of these copolymers were investigated by NMR and GPC. Secondly, it is demonstrated that the resulting amphiphilic functional copolymers with low CMC values could self-assemble to form nanoparticles in aqueous media. In addition, the in vitro degradation study and cytotoxicity assays indicated the excellent biodegradability and low cytotoxicity of these copolymers. This work provides a general approach toward the preparation of functional PEG-polyester copolymers in a quite efficient way, which may further facilitate the application of functional PEG-polyesters as drug delivery materials.

Filamentous Bacteriophage-A Powerful Carrier for Glioma Therapy.

Glioma is a life-threatening malignant tumor. Resistance to traditional treatments and tumor recurrence present major challenges in treating and managing this disease, consequently, new therapeutic strategies must be developed. Crossing the blood-brain barrier (BBB) is another challenge for most drug vectors and therapy medications. Filamentous bacteriophage can enter the brain across the BBB. Compared to traditional drug vectors, phage-based drugs offer thermodynamic stability, biocompatibility, homogeneity, high carrying capacity, self-assembly, scalability, and low toxicity. Tumor-targeting peptides from phage library and phages displaying targeting peptides are ideal drug delivery agents. This review summarized recent studies on phage-based glioma therapy and shed light on the developing therapeutics phage in the personalized treatment of glioma.

Gut microbiota and neuropsychiatric disorders: Implications for neuroendocrine-immune regulation.

Recently, increasing evidence has shown gut microbiota dysbiosis might be implicated in the physiological mechanisms of neuropsychiatric disorders. Altered microbial community composition, diversity and distribution traits have been reported in neuropsychiatric disorders. However, the exact pathways by which the intestinal microbiota contribute to neuropsychiatric disorders remain largely unknown. Given that the onset and progression of neuropsychiatric disorders are characterized with complicated alterations of neuroendocrine and immunology, both of which can be continually affected by gut microbiota via "microbiome-gut-brain axis". Thus, we assess the complicated crosstalk between neuroendocrine and immunological regulation might underlie the mechanisms of gut microbiota associated with neuropsychiatric disorders. In this review, we summarized clinical and preclinical evidence on the role of the gut microbiota in neuropsychiatry disorders, especially in mood disorders and neurodevelopmental disorders. This review may elaborate the potential mechanisms of gut microbiota implicating in neuroendocrine-immune regulation and provide a comprehensive understanding of physiological mechanisms for neuropsychiatric disorders.

GABAergic System Dysfunction in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.

Gender Differences in Depression: Evidence From Genetics.

Compared with men, female accounts for a larger proportion of patients with depression. Behavioral genetics researches find gender differences in genetic underpinnings of depression. We found that gender differences exist in heritability and the gene associated with depression after reviewing relevant research. Both genes and gene-environment interactions contribute to the risk of depression in a gender-specific manner. We detailed the relationships between serotonin transporter gene-linked promoter region (5-HTTLPR) and depression. However, the results of these studies are very different. We explored the reasons for the contradictory conclusions and provided some suggestions for future research on the gender differences in genetic underpinnings of depression.

Optogenetics: What it has uncovered in potential pathways of depression.

Optogenetics is a biological technique, which involves controlling the biological functions of target cells using light. In recent years, optogenetics has become one of the most advanced experimental techniques in neuroscience. It provides precise control on target cells in addition to rapidly and specifically altering the neuronal activity both in vivo and ex vivo. The emergence of optogenetic technology enabled researchers to study the pathogenesis of diseases at the level of neurons and explore new ideas for the treatment of brain diseases. Depression is a highly prevalent and disabling mental disorder, which seriously impacts people's work and life. Currently, our understanding of the occurrence, development, and treatment of depression has made great progress, but the exact pathogenesis of depression is still unclear. In this article, we summarize the applications of optogenetics in improving our understanding of depression and provide new insight for uncovering the potential pathways of depression.

Leptin in depression: a potential therapeutic target.

Leptin, produced and secreted by white adipose tissue, plays a critical role in regulating body weight, food intake, and energy metabolism. Recently, several studies have identified an underlying role for leptin in regulation of mood and cognition via regulation of synaptic changes in the brain that have been associated with antidepressant-like actions. Brain neural plasticity occurs in response to a range of intrinsic and extrinsic stimuli, including those that may mediate the effects of antidepressants. Neural plasticity theories of depression are thought to explain multiple aspects of depression and the effects of antidepressants. It is also well documented that leptin has effects on neural plasticity. This review summarizes the recent literature on the role of leptin in neural plasticity in order to elaborate the possible mechanism of leptin's antidepressant-like effects. Recent findings provide new insights into the underlying mechanisms of neural plasticity in depression. Leptin may influence these mechanisms and consequently constitute a possible target for novel therapeutic approaches to the treatment of depression.

The mechanism of acute fasting-induced antidepressant-like effects in mice.

Acute fasting induced antidepressant-like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant-like effects of acute fasting on c-Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant-like effects of 9 fasting were inhibited by a 5-HT2A/2C receptor agonist (±)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5-HT2A receptor antagonist ketanserin. Immunohistochemical study has shown that c-Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting-induced c-Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant-like effects of acute fasting may be exerted via 5-HT2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant-like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.

Long-Term Plasticity in Amygdala Circuits: Implication of CB1-Dependent LTD in Stress.

The amygdala mediates many forms of emotional learning, during which the central nucleus of amygdala (CeA) functions as a major output of the amygdala by converging inputs from the basolateral nucleus (BLA) and other amygdalar subregions. However, the contribution of BLA-CeA synaptic transmission and plasticity of this transmission after exposure to emotional stimuli remains to be completely understood. Using paired recording, we simultaneously recorded BLA and CeA neurons, and observed that BLA-CeA transmission was glutamatergic. In this transmission, high-frequency stimulation induced NMDA receptor (NMDAR)-dependent LTP, low-frequency stimulation induced NMDAR-dependent LTD, whereas modest-frequency stimulation induced cannabinoid receptor1 (CB1)-dependent LTD. After acute stress, CB1-dependent LTD of this transmission was selectively abolished. This effect of stress was mimicked by intra-CeA administration of CB1-selective agonists and prevented by CB1-selective antagonists. Furthermore, intra-CeA administration of CB1 antagonists prevented stress-induced reduction of explorative behaviors. These results indicate that CB1 signaling-mediated plasticity in local circuits of the amygdala plays a critical role in emotional responses.

Preclinical evidence of ghrelin as a therapeutic target in epilepsy.

Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, plays a major role in inhibiting seizures. However, the underlying mechanism of ghrelin's anticonvulsant action is still unclear. Nowadays, there are considerable evidences showing that ghrelin is implicated in various neurophysiological processes, including learning and memory, neuroprotection, neurogenesis, and inflammatory effects. In this review, we will summarize the effects of ghrelin on epilepsy. It may provide a comprehensive picture of the role of ghrelin in epilepsy.

Berberine produces antidepressant-like effects in ovariectomized mice.

Berberine has been reports to have antidepressant-like effects. However, it is seldom known whether berberine produces antidepressant-like effects in ovariectomized mice, which exhibit depressive-like responses. To examine the antidepressant-like effects of berberine in ovariectomized mice, behavioral tests were conducted, including the forced swimming test and the open field test. To elucidate the mechanisms, levels of BDNF, phosphorylated CREB and phosphorylated eEF2 were analyzed by western blotting, and c-Fos induction was examined by immunohistochemistry. In the forced swimming test, berberine decreased the immobility time in a dose-dependent manner, reversing the depressive-like effect observed in ovariectomized mice, and this effect was blocked by the 5-HT2 antagonist ketanserin. In addition, western blotting indicated that BDNF and peEF2 in the hippocampus, but not pCREB/CREB in the frontal cortex, were affected by berberine treatment. Furthermore, immunohistochemistry demonstrated that the reduction in c-Fos induced by ovariectomy were greater after berberine treatment. Ketanserin also antagonized the effect of berberine on the c-Fos expression. Our findings suggest that berberine exerts antidepressant-like effects in ovariectomized mice, and 5-HT2 receptor activation may be partially related to the antidepressant-like effects of the berberine by BDNF-CREB and eEF2 pathways.

The effects of herbal medicine on epilepsy.

Traditional herbal medicine plays a significant role in the treatment of epilepsy. Though herbal medicine is widely used in antiepileptic treatment, there is a lack of robust evidence for efficacy and toxicity of most herbs. Besides, the herbal medicine should be subject to evidence-based scrutiny. In this context, we present a review to introduce the effects of herbal medicine on epilepsy. However, hundreds of herbal medicines have been investigated in the available studies. Some commonly used herbal medicines for epilepsy have been listed in our study. The overwhelming majority of these data are based on animal experiments. The lack of clinical data places constraints on the clinical recommendation of herbal medicine. Our study may conduct further studies and provide some insight on the development of anti-epileptic drugs.

The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex.

Neural plasticity, a fundamental mechanism of neuronal adaptation, is disrupted in depression. The changes in neural plasticity induced by stress and other negative stimuli play a significant role in the onset and development of depression. Antidepressant treatments have also been found to exert their antidepressant effects through regulatory effects on neural plasticity. However, the detailed mechanisms of neural plasticity in depression still remain unclear. Therefore, in this review, we summarize the recent literature to elaborate the possible mechanistic role of neural plasticity in depression. Taken together, these findings may pave the way for future progress in neural plasticity studies.