A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression.

PURPOSE: To systematically assess the evidence of efficacy and safety of the use of ketamine and esketamine for patients with treatment-resistant depression (TRD) with suicidal ideation (SI). METHODS: We independently searched for clinical trials from inception to January 2023 using electronic databases, e.g., PubMed and EMBASE. A systematic review and meta-analysis were performed to assess SI scores of depression rating scales, which were regarded as the outcomes. RESULTS: A total of five independent double-blind, placebo controlled randomized clinical trials (RCTs) are eligible for inclusion. Four of the studies used ketamine as an intervention and one used esketamine as an intervention. Three hundred ninety-one patients with TRD were included (the intervention group with ketamine or esketamine is 246, and the control group is 145). No statistically significant interaction between the subscales of suicide ideation (SMD = - 0.66, 95% CI (- 1.61, 0.29); Z = 1.36, P = 0.17) and antidepressant effects (SMD = - 0.99, 95% CI (- 2.33, 0.34); Z = 1.46, P = 0.15) based on the results of ketamine and esketamine, compared with placebo groups. CONCLUSION: This meta-analysis suggested that esketamine and ketamine have failed to reduce suicidal ideation in patients with TRD. Further studies are desirable to confirm the effects of ketamine and esketamine in TRD patients.

Astroglial Connexin 43-Mediated Gap Junctions and Hemichannels: Potential Antidepressant Mechanisms and the Link to Neuroinflammation.

Major depression disorder (MDD) is a neuropsychiatric disorder associated with a high suicide rate and a higher disability rate than any other disease. Evidence suggests that the pathological mechanism of MDD is related to astrocyte dysfunction. Depression is mainly associated with the expression of connexin 43 (Cx43) and the function of Cx43-mediated gap junctions and hemichannels in astrocytes. Moreover, neuroinflammation has been a hotspot in research on the pathology of depression, and Cx43-mediated functions are thought to be involved in neuroinflammation-related depression. However, the specific mechanism of Cx43-mediated functions in neuroinflammation-related depression pathology remains unclear. Therefore, this review summarizes and discusses Cx43 expression, the role of gap junction intercellular communication, and its relationship with neuroinflammation in depression. This review also focuses on the effects of antidepressant drugs (e.g., monoamine antidepressants, psychotropic drugs, and N-methyl-D-aspartate receptor antagonists) on Cx43-mediated function and provides evidence for Cx43 as a novel target for the treatment of MDD. The pathogenesis of MDD is related to astrocyte dysfunction, with reduced Cx43 expression, GJ dysfunction, decreased GJIC and reduced BDNF expression in the depressed brain. The effect of Cx43 on neuroinflammation-related depression involving inflammatory cytokines, glutamate excitotoxicity, and HPA axis dysregulation. Antidepressant drugs targeting Cx43 can effectively relieve depressive symptoms.

Possible Involvement of Perineuronal Nets in Anti-Depressant Effects of Electroacupuncture in Chronic-Stress-Induced Depression in Rats.

Acupuncture can alleviate depression-like behaviors. However, the neural mechanisms behind the anti-depressive effect remain unknown. Perineuronal net (PNN) abnormalities have been reported in multiple psychiatric disorders. This study investigated the modulation and neural mechanism of PNNs in the anti-depressant process of electroacupuncture (EA) at Baihui (GV20) and Yintang (GV29) points. A rat depression model was induced by chronic unpredicted mild stress (CUMS). The results revealed that CUMS, applied for four weeks, specifically reduces PNNs around parvalbumin (PV). In addition, EA and fluoxetine treatments reverse the decrease in PNNs+ cell density and the ratio of PV and PNN double-positive cells to PV+ neurons in the medial prefrontal cortex (mPFC) after CUMS. Furthermore, EA treatment can reverse the decrease in the protein expression of PNN components (aggrecan and brevican) in the mPFC caused by stress. After EA treatment, the decreased expression of GAD67, GLuA1, and PSD95 in the mPFC induced by CUMS for four weeks was also reversed. PNN degradation in mPFC brain areas potentially interferes with the anti-depressant benefits of EA in rats with depression induced by CUMS. EA treatment did not increase PNNs+ cell density and the ratio of PV and PNN double-positive cells to PV+ neurons after PNNs degradation in the mPFC brain region of rats. This finding indicated that the mechanism of acupuncture's anti-depressant effect may be based on reversing the CUMS-induced decline in PNN expression, the functional impairment of γ-aminobutyric acid (GABA) neurons, and the regulation of excitatory synaptic proteins expression.

Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis.

Background: Psychiatric disorders have seriously affected human life, one of the risk genes related to psychosis is the methylenetetrahydrofolatereductase (MTHFR) gene. This gene has a potential role in psychiatric disorders. Therefore, a meta-analysis is conducted to investigate the correlations between two prevalent MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T, A1298C, severe psychological disorders (schizophrenia, major depression, bipolar disorder). Methods: A total of 81 published studies were screened and selected by a search of electronic databases up to April 2022. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR polymorphism and psychiatric disorders susceptibility by using random effect models. Results: We found that MTHFR C677T polymorphism is significantly related to schizophrenia and major depression in the overall population. MTHFR C677T has been linked to an increased risk of bipolar disorder in the recessive model (TT vs. CT + CC). Ethnic subgroup analysis shows that schizophrenia and major depression significantly correlate with MTHFR C677T and A1298C in Asian populations but not Caucasians. Besides, schizophrenia is correlated substantially with MTHFR C677T in the African population. However, the MTHFR A1298C polymorphism is only marginally linked to major depression. Conclusion: Findings of the current study revealed that MTHFR may contribute to the common pathogenesis of psychiatric diseases and that its variants may be essential in controlling the expression of psychosis-related genes. This study could help the researchers and health specialists in the early diagnosis and treatment of psychiatric disorders.

Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the "nine immortal grasses". Dendrobium chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted. AIM OF THE STUDY: The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC. MATERIALS AND METHODS: Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The "component-target-pathway" networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot. RESULTS: The "component-target-pathway" network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3ß, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway. CONCLUSION: This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.

Electroacupuncture in treatment of Parkinson disease: A protocol for meta-analysis and systematic review.

BACKGROUND: Parkinson disease (PD) is a worldwide spread neurodegenerative disorder. Dopamine replacement therapy is currently the mainstream treatment, which can alleviate the symptoms but induces motor complications. Electroacupuncture (EA) is beneficial for PD as an alternative medicine. However, few reliable clinical trials or objective systematic reviews are available to give a verdict on the effectiveness of EA in the treatment of PD. Thus, we evaluate the evidence for EA in PD patients by conducting this meta-analysis. METHODS: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, Chinese Scientific and Technology Journal database, WanFang Digital Periodicals, and Chinese Biomedical Literature Database (SinoMed) will be systematically searched for evidence by 2 authors individually. The analysis will be conducted by RevMan 5.3 software according to Cochrane Handbook. RESULTS: The efficacy and safety of EA for PD will be comprehensively assessed from the outcomes, including the effectiveness rate, scores of Unified Parkinson Disease Rating Scale, and Webster scale, superoxide dismutase, lipid peroxides, and dopamine content. CONCLUSION: This systematic review will provide evidence for whether EA can treatment PD. REGISTRATION INFORMATION: PROSPERO CRD42019120956.

Bu-Yin-Qian-Zheng Formula Ameliorates MPP+-Induced Mitochondrial Dysfunction in Parkinson's Disease via Parkin.

As a typical traditional Chinese medicine, Bu-Yin-Qian-Zheng Formula (BYQZF) has been shown to have neuroprotective effects in patients with Parkinson's disease (PD), particularly by ameliorating mitochondrial dysfunction and regulating expression of the parkin protein. However, the underlying mechanisms by which BYQZF affects mitochondrial function through parkin are unclear. Accordingly, in this study, we evaluated the mechanisms by which BYQZF ameliorates mitochondrial dysfunction through parkin in PD. We constructed a parkin-knockdown cell model and performed fluorescence microscopy to observe transfected SH-SY5Y cells. Quantitative real-time reverse transcription polymerase chain reaction and western blotting were conducted to detect the mRNA and protein expression levels of parkin. Additionally, we evaluated the cell survival rates, ATP levels, mitochondrial membrane potential (ΔΨm), mitochondrial morphology, parkin protein expression, PINK1 protein expression, and mitochondrial fusion and fission protein expression after treatment with MPP+ and BYQZF. Our results showed that cell survival rates, ATP levels, ΔΨm, mitochondrial morphology, parkin protein levels, PINK1 protein levels, and mitochondrial fusion protein levels were reduced after MPP+ treatment. In contrast, mitochondrial fission protein levels were increased after MPP+ treatment. Moreover, after transient transfection with a negative control plasmid, the above indices were significantly increased by BYQZF. However, there were no obvious differences in these indices after transient transfection with a parkin-knockdown plasmid. Our findings suggest that BYQZF has protective effects on mitochondrial function in MPP+-induced SH-SY5Y cells via parkin-dependent regulation of mitochondrial dynamics.

Da-Bu-Yin-Wan and Qian-Zheng-San Ameliorate Mitochondrial Dynamics in the Parkinson's Disease Cell Model Induced by MPP.

To investigate the effect of Da-Bu-Yin-Wan and Qian-Zheng-San (DBYW and QZS) on mitochondrial mass in Parkinson's disease (PD) cell model induced by 1-Methyl-4-phenylpyridinium Ion (MPP+). The SH-SY5Y cell was selected and treated with MPP+. The PD model was intervened with DBYW and QZS. CCK-8 method was used to detect the survival rate of cells in each group. Mitochondria was labeled by mitoTracker®Red CMXRos probe and observed by laser scanning confocal microscope, and ImageJ software was used to process images and measure mitochondrial form factors; Tetramethylrhodamine methyl ester was used to detect mitochondrial membrane potential (ΔΨm); Luciferase method was used to detect cellular ATP levels; Western-Blot technique was applied to detect the expression levels of Parkin protein, and the expression levels of Mfn1, Mfn2, OPA1, Drp1, and Fis1. We found that DBYW and QZS treatment significantly increased the cell survival rate, form factor (F-factor), mitochondrial activity and ΔΨm after MPP+ treatment, while the increase of ATP levels was not significant. In addition, the results of western blot analysis showed that the MPP+ induced increase in the expression of Drp1 and Fis1, as well as decrease in Parkin, Mfn1, Mfn2, and OPA1 were all partially revised by DBYW and QZS. In summary, our data strongly suggested that DBYW and QZS treatment can exert protective effects against PD related neuronal injury through regulation the homeostasis between mitochondrial fission and fusion.

Protective effects of DJ-1 medicated Akt phosphorylation on mitochondrial function are promoted by Da-Bu-Yin-Wan in 1-methyl-4-phenylpyridinium-treated human neuroblastoma SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Da-Bu-Yin-Wan (DBYW), a historically traditional Chinese medicine formula, was originally defined over 600 years ago. In recent decades, DBYW was clinically employed to treat Parkinson's disease (PD). AIM OF THE STUDY: To explore the underlying mechanism of DBYW on mitochondrial function, we investigated the effect of DBYW on mitochondrial function from the perspectives of DJ-1 and Akt signaling. MATERIALS AND METHODS: Human derived neuroblastoma SH-SY5Y cells were transiently transfected with the plasmid pcDNA3-Flag-DJ-1 aimed to overexpress the DJ-1 protein. Transfected cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), a PD-related mitochondrial complex I inhibitor, in the absence and presence of DBYW. The cell viability was assessed by Cell Counting Kit-8 assay. The protein expressions of DJ-1 and Akt signaling were examined by western blotting. The mitochondrial mass was evaluated by confocal fluorescence microscopy. The mitochondrial complex I activity and cellular ATP content were measured by commercial kits. RESULTS: Transfection with pcDNA3-Flag-DJ-1 decreased the MPP(+)-induced toxicity and overexpressed the DJ-1. In DJ-1 overexpressed cells, the mitochondrial mass was raised, mitochondrial complex I activity was improved, and cellular ATP content was increased. In addition, overexpression of DJ-1 augmented the Akt phosphorylation on threonine 308 and serine 473. Moreover, DBYW promoted the above effects in DJ-1 expressed cells. CONCLUSIONS: These data suggest that DJ-1 protects the mitochondrial function by medicating Akt phosphorylation in MPP(+)-treated SH-SY5Y cells. Moreover, DBYW enhances the protective effect of DJ-1 medicated Akt phosphorylation on mitochondrial function.

Da-bu-yin-wan and qian-zheng-san to neuroprotect the mouse model of Parkinson's disease.

Da-Bu-Yin-Wan (DBYW) and Qian-Zheng-San (QZS), two classic traditional Chinese medicinal formulas, were clinically employed to treat Parkinson's disease (PD). Our previous studies demonstrated neuroprotective effects of them on mitochondrial function in PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The purpose of this research was to investigate their possible mechanisms in the light of mitochondrial ATP-sensitive potassium (mitoKATP) channels. The neuroprotective effect of DBYW and QZS on dopamine (DA) neurons in substantia nigra (SN) in the MPTP-induced PD mice was investigated by behavioral test (pole test) and immunohistochemistry. Adenosine triphosphate (ATP) level in the midbrain tissue was detected by firefly luciferase method. MitoKATP channel subunits SUR1 and Kir6.2 mRNA and protein expressions were tested by real-time PCR (RT-PCR) and Western blot. It was observed that DBYW and/or QZS served to ameliorate MPTP-induced behavioral impairment and prevent the loss of substantia nigra dopamine neurons, as well as increase ATP level in the midbrain tissue and downregulate SUR1 expression at mRNA and protein levels with no marked influence on Kir6.2. We concluded that DBYW and QZS exhibit neuroprotective effects probably through the regulation of ATP level and mitoKATP channel subunit expressions.