The Role of HSP90 Molecular Chaperones in Depression: Potential Mechanisms.

Major depressive disorder (MDD) is characterized by high rates of disability and death and has become a public health problem that threatens human life and health worldwide. HPA axis disorder and neuroinflammation are two common biological abnormalities in MDD patients. Hsp90 is an important molecular chaperone that is widely distributed in the organism. Hsp90 binds to the co-chaperone and goes through a molecular chaperone cycle to complete its regulation of the client protein. Numerous studies have demonstrated that Hsp90 regulates how the HPA axis reacts to stress and how GR, the HPA axis' responsive substrate, matures. In addition, Hsp90 exhibits pro-inflammatory effects that are closely related to neuroinflammation in MDD. Currently, Hsp90 inhibitors have made some progress in the treatment of a variety of human diseases, but they still need to be improved. Further insight into the role of Hsp90 in MDD provides new ideas for the development of new antidepressant drugs targeting Hsp90.

The bidirectional relationship of depression and disturbances in B cell homeostasis: Double trouble.

Major depressive disorder (MDD) is a recurrent, persistent, and debilitating neuropsychiatric syndrome with an increasing morbidity and mortality, representing the leading cause of disability worldwide. The dysregulation of immune systems (including innate and adaptive immune systems) has been identified as one of the key contributing factors in the progression of MDD. As the main force of the humoral immunity, B cells have an essential role in the defense against infections, antitumor immunity and autoimmune diseases. Several recent studies have suggested an intriguing connection between disturbances in B cell homeostasis and the pathogenesis of MDD, however, the B-cell-dependent mechanism of MDD remains largely unexplored compared to other immune cells. In this review, we provide an overview of how B cell abnormality regulates the progression of MMD and the potential consequence of the disruption of B cell homeostasis in patients with MDD. Abnormalities of B-cell homeostasis not only promote susceptibility to MDD, but also lead to an increased risk of developing infection, malignancy and autoimmune diseases in patients with MDD. A better understanding of the contribution of B cells underlying MDD would provide opportunities for identification of more targeted treatment approaches and might provide an overall therapeutic benefit to improve the long-term outcomes of patients with MDD.

Quercetin Ameliorates Cognitive Impairment in Depression by Targeting HSP90 to Inhibit NLRP3 Inflammasome Activation.

Cognitive dysfunction was a common symptom of major depressive disorder (MDD). In previous studies, psychological stress leads to activation and proliferation of microglial cells in different brain regions. Quercetin, a bioflavonoid derived from vegetables and fruits, exerts anti-inflammatory effects in various diseases. To demonstrate the role of quercetin in the hippocampal inflammatory response in depress mice. The chronic unpredictable stress (CUS) depressive mice model built is used to explore the protective effects of quercetin on depression. Neurobehavioral test, protein expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and heat shock protein 90 (HSP90), and cytokines (IL-6, IL-1ß, MCP-1, and TNF-α) were assessed. Quercetin ameliorated depressive-like behavior and cognitive impairment, and quercetin attenuates neuroinflammation and by targeting HSP90 to inhibit NLRP3 inflammasome activation. Quercetin inhibited the increase of HSP90 levels in the hippocampus and reverses inflammation-induced cognitive impairment. Besides, quercetin inhibited the increased level of cytokines (IL-6, IL-1ß, MCP-1, and TNF-α) in the hippocampus of the depressive model mouse and the increased level of cytokines (IL-6, IL-1ß, and MCP-1) in microglia. The current study indicated that quercetin mitigated depressive-like behavior and by targeting HSP90 to inhibit NLRP3 inflammasome activation in microglia and depressive mice model, meanwhile ameliorated cognitive impairment in depression. Quercetin has huge potential for the novel pharmacological efficacy of antidepressant therapy.

The N6-methyladenosine modification in pathologic angiogenesis.

The vascular system is a vital circulatory network in the human body that plays a critical role in almost all physiological processes. The production of blood vessels in the body is a significant area of interest for researchers seeking to improve their understanding of vascular function and maintain normal vascular operation. However, an excessive or insufficient vascular regeneration process may lead to the development of various ailments such as cancer, eye diseases, and ischemic diseases. Recent preclinical and clinical studies have revealed new molecular targets and principles that may enhance the therapeutic effect of anti-angiogenic strategies. A thorough comprehension of the mechanism responsible for the abnormal vascular growth in disease processes can enable researchers to better target and effectively suppress or treat the disease. N6-methyladenosine (m6A), a common RNA methylation modification method, has emerged as a crucial regulator of various diseases by modulating vascular development. In this review, we will cover how m6A regulates various vascular-related diseases, such as cancer, ocular diseases, neurological diseases, ischemic diseases, emphasizing the mechanism of m6A methylation regulators on angiogenesis during pathological process.

[Health Assessment of the Stream Ecosystem in Beijing, China].

With economic development, the health of river ecosystems is becoming severely threatened because of the increasing effects of human activities on river ecosystems. Here, 101 sites along regional river systems in Beijing rivers were investigated from autumn 2020 to summer 2021. A total of 34 metrics, including aquatic organisms, hydrology, water quality, and habitat, were calculated to be the candidate indicators. Principal component and correlation analyses were used to select the core metrics from the candidate indicators, and the weight of each core metric was estimated using the entropy method. The integrated index of stream ecological health was constructed to assess the health condition of the Beijing rivers. The results of the PCA and correlation analyses revealed that eleven metrics were selected as the core metrics to construct the integrated index of stream ecological health, including water temperature, flow velocity, BOD5, NH4+-N, Cu, the density of phytoplankton and zooplankton, the Shannon-Wiener diversity index of macroinvertebrates and fish, the BMWP index, and the qualitative habitat evaluation index. According to the health assessment results, 4.95% of the sampling sites were healthy, 23.76% were subhealthy, and 71.29% were in a fair or below healthy state. The river health status showed strong spatial heterogeneity, and the river health statuses in the northern and western regions were relatively good, whereas the river health status in the central and southeastern regions were relatively poor. The results of four aspects stream ecosystem assessment showed that the overall water quality of the rivers was "subhealthy" and the aquatic organisms and habitat were "general poor," but the hydrology was "poor." The evaluation results of five water systems demonstrated that the Chaobai River had the best health status, followed by that of the Yongding River, Daqing River, and Jiyun River, and the Beiyun River had the worst health status. Maintaining river ecological baseflow, ensuring river system connectivity, and improving and restoring the river habitat environment are the key aspects of river ecological restoration and protection in Beijing in the future.

Swimming exercise ameliorates depressive-like behavior by anti-inflammation activity, rebalancing gut Escherichia coli and Lactobacilli.

Major depressive disorder (MDD) is a common mental disease with high morbidity, recurrence and mortality and is a serious global health problem.Aerobic exercise produces beneficial effects on depression and associated comorbidities.Swimming exercise with high motor complexity may be particularly beneficial for patients with depression.We hypothesized that swimming exercise improves various types of depression-like behaviors and these effects are related to improved immune and inflammatory response by regulating microbiota-gut-brain axis.We established the Lipopolysaccharides (LPS)/Chronic unpredictable stress (CUS) mice model of depression. The forced swimming test (FST) and tail suspension test (TST) were used as predictive animal models of antidepressant-like activity.Swimming exercise significantly decreased the duration of immobility in FST and TST.We found that swimming exercise could significantly decrease the levels of pro-inflammatory cytokines in the central nervous system (CNS). Shifts in the composition of the gut microbiota were significant in depression model induced by LPS/CUS, notably as decreases in lactobacilli and increases in escherichia coli (E. coli), which were reversed byswimming exercise. Current study indicated that swimming exercise has huge potential for antidepressant therapy, and gut microbiotaplays an important role inregulating inflammation. We are pleased that current can study reveal a potentially promising method with less adverse reaction for combating depression and open up an important new area for future research.

FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy.

As is the case with neurodegenerative diseases, abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke. However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis. FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke.

Blood-Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder.

Major depression represents a complex and prevalent psychological disease that is characterized by persistent depressed mood, impaired cognitive function and complicated pathophysiological and neuroendocrine alterations. Despite the multifactorial etiology of depression, one of the most recent factors to be identified as playing a critical role in the development of depression is blood-brain barrier (BBB) disruption. The occurrence of BBB integrity disruption contributes to the disturbance of brain homeostasis and leads to complications of neurological diseases, such as stroke, chronic neurodegenerative disorders, neuroinflammatory disorders. Recently, BBB associated tight junction disruption has been shown to implicate in the pathophysiology of depression and contribute to increased susceptibility to depression. However, the underlying mechanisms and importance of BBB damage in depression remains largely unknown. This review highlights how BBB disruption regulates the depression process and the possible molecular mechanisms involved in development of depression-induced BBB dysfunction. Moreover, insight on promising therapeutic targets for treatment of depression with associated BBB dysfunctions are also discussed.

Protein Aggregation in the Pathogenesis of Ischemic Stroke.

Despite the distinction between ischemic stroke and neurodegenerative disorders, they share numerous pathophysiologies particularly those mediated by inflammation and oxidative stress. Although protein aggregation is considered to be a hallmark of neurodegenerative diseases, the formation of protein aggregates can be also induced within a short time after cerebral ischemia, aggravating cerebral ischemic injury. Protein aggregation uncovers a previously unappreciated molecular overlap between neurodegenerative diseases and ischemic stroke. Unfortunately, compared with neurodegenerative disease, mechanism of protein aggregation after cerebral ischemia and how this can be averted remain unclear. This review highlights current understanding on protein aggregation and its intrinsic role in ischemic stroke.

Correction to: Role of PUMA in the methamphetamine-induced migration of microglia.

In the original publication of this article, wrong western blot images were inadvertently included in Fig. 2 and Fig. 3. The corrected figures are shown below. The authors declare that these amendments do not change the results or conclusions of their paper, and apologize for this oversight.

CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination.

Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression.

Role of PUMA in the methamphetamine-induced migration of microglia.

In this study, we demonstrated that PUMA was involved in the microglial migration induced by methamphetamine. PUMA expression was examined by western blotting and immunofluorescence staining. BV2 and HAPI cells were pretreated with a sigma-1R antagonist and extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), c-Jun N-terminal protein kinase (JNK), and phosphatidylinositol-3 kinase (PI3K)/Akt inhibitors, and PUMA expression was detected by western blotting. The cell migration in BV2 and HAPI cells transfected with a lentivirus encoding red fluorescent protein (LV-RFP) was also examined using a wound-healing assay and nested matrix model and cell migration assay respectively. The molecular mechanisms of PUMA in microglial migration were validated using a siRNA approach. The exposure of BV2 and HAPI cells to methamphetamine increased the expression of PUMA, reactive oxygen species (ROS), the MAPK and PI3K/Akt pathways and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3) pathways. PUMA knockdown in microglia transfected with PUMA siRNA attenuated the increased cell migration induced by methamphetamine, thereby implicating PUMA in the migration of BV2 and HAPI cells. This study demonstrated that methamphetamine-induced microglial migration involved PUMA up-regulation. Targeting PUMA could provide insights into the development of a potential therapeutic approach for the alleviation of microglia migration induced by methamphetamine.

Involvement of NLRP3 inflammasome in methamphetamine-induced microglial activation through miR-143/PUMA axis.

Nod-like Receptor Protein 3 (NLRP3) inflammasome activation is known to lead to microglia-mediated neuroinflammation. Methamphetamine is known to induce microglial activation. However, whether NLRP3 inflammasome activation contributes to the microglial activation induced by methamphetamine remains elusive. P53-up-regulated modulator of apoptosis (PUMA) is a known apoptosis inducer; however, their role in microglial activation remains poorly understood. Methamphetamine treatment induced NLRP3 inflammasome activation as well microglial activation in animal model. Intriguingly, downregulation of PUMA significantly inhibited the activation of microglia. Methamphetamine treatment increased the expression of PUMA at protein level but not mRNA level. Further study indicated that PUMA expression was regulated at post-transcriptional level by miR-143, which was decreased in methamphetamine-treated cells via the negative transcription factor nuclear factor-kappa B1 (NF-κB1). Using gain- and loss-of-function approaches, we identified a unique role of miR-143/PUMA in mediating microglial activation via regulation of NLRP3 inflammasome activation. These findings provide new insight regarding the specific contributions of the miR-143/PUMA pathway to NLRP3 inflammasome activation in the context of drug abuse.

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization.

Our previous study demonstrated that the sigma-1 receptor is involved in methamphetamine-induced microglial apoptosis and death; however, whether the sigma-1 receptor is involved in microglial activation as well as the molecular mechanisms underlying this process remains poorly understood. The aim of this study is to demonstrate the involvement of the sigma-1 receptor in methamphetamine-mediated microglial activation. The expression of σ-1R, iNOS, arginase and SOCS was examined by Western blot; activation of cell signaling pathways was detected by Western blot analysis. The role of σ-1R in microglial activation was further validated in C57BL/6 N WT and sigma-1 receptor knockout mice (male, 6-8 weeks) injected intraperitoneally with saline or methamphetamine (30 mg/kg) by Western blot combined with immunostaining specific for Iba-1. Treatment of cells with methamphetamine (150 µM) induced the expression of M1 markers (iNOS) with concomitant decreased the expression of M2 markers (Arginase) via its cognate sigma-1 receptor followed by ROS generation. Sequential activation of the downstream MAPK, Akt and STAT3 pathways resulted in microglial polarization. Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation.

[Analysis of epidemic situation of malaria in Yunnan Province from 2011 to 2013].

OBJECTIVE: To understand the epidemic situation and characteristics of malaria in Yunnan Province, so as to provide the reference for malaria elimination. METHODS: The data of malaria reported in the information system were collected and analyzed in Yunnan Province from 2011 to 2013. RESULTS: From 2011 to 2013, totally 2 256 malaria cases were found in Yunnan Province, with a morbidity of 0.162 8 per million and three of them were death cases. The local cases mainly distributed along the boundary and accounted for 29.48%, while the imported cases mainly came from Myanmar and accounted for 70.52%. The number of endemic counties with local malaria cases decreased from 37 to 10 during the three years. The number of imported cases reached the peak in May and the local cases in June. The patients were mainly aged from 20 to 49 years old (accounted for 70.58%), and 85.24% of the cases were peasants and laborers. Totally 86.66% of cases were laboratory confirmed cases, and 13.14% were clinically diagnosed. The proportions of cases reported by hospitals, health service centers and CDCs were 33.02%, 37.06% and 29.92%, respectively. CONCLUSIONS: The prevalence of malaria in Yunnan Province decreased from 2011 to 2013. The work of malaria cases double-checked by province-level CDCs is effective. However, the awareness and accurately diagnostic capability of clinical doctors still should be strengthened.

Metabonomic analysis of the joint toxic action of long-term low-level exposure to a mixture of four organophosphate pesticides in rat plasma.

In previously published articles, we evaluated the toxicity of four organophosphate (OP) pesticides (dichlorvos, dimethoate, acephate, and phorate) in rats using metabonomic technology at their corresponding no observed adverse effect levels (NOAELs). The results show that a single pesticide did not elicit a toxic response. The joint toxic action of four pesticides (at their corresponding NOAELs) was evaluated by metabolomic analysis of rat plasma under experimental conditions similar to those of the four single OP pesticides. The pesticides were administered daily to rats through drinking water for 24 weeks. The mixture of four pesticides showed a joint toxic action at the NOAELs of each pesticide. The 19 metabolites were statistically significantly changed in all the treated groups compared with those in the control group (p < 0.05 or p < 0.01). Exposure to OP pesticides resulted in increased lysoPC (15 : 0/0 : 0), lysoPC (16 : 0/0 : 0), lysoPC (O-18 : 0/0 : 0), lysoPC (P-19 : 1(12Z)/0 : 0), lysoPC (18 : 1(9Z)/0 : 0), lysoPC (18 : 0/0 : 0), lysoPC (20 : 4(5Z, 8Z, 11Z, 14Z)/0 : 0), lysoPE (16 : 0/0 : 0), lysoPC (17 : 0/0 : 0), 4-pyridoxic acid, glutamic acid, glycocholic acid, and arachidonic acid, as well as decreased C16 sphinganine, C17 sphinganine, phytosphingosine, indoleacrylic acid, tryptophan, and iodotyrosine in rat plasma. The results indicate that the mixture of OP pesticides induced oxidative stress, liver and renal dysfunction, disturbed the metabolism of lipids and amino acids, and interfered with the function of the thyroid gland. The present plasma results provided complementarities with our previous metabolomic analysis of the rat urine profile exposed to a mixture of four OP pesticides, and also contributed to the understanding of the mechanism of joint toxic action.

Application of ultraperformance liquid chromatography/mass spectrometry-based metabonomic techniques to analyze the joint toxic action of long-term low-level exposure to a mixture of organophosphate pesticides on rat urine profile.

In previously published articles, we evaluated the toxicity of four organophosphate (OP) pesticides (dichlorvos, dimethoate, acephate, and phorate) to rats using metabonomic technology at their corresponding no observed adverse effect level (NOAEL). Results show that a single pesticide elicits no toxic response. This study aimed to determine whether chronic exposure to a mixture of the above four pesticides (at their corresponding NOAEL) can lead to joint toxic action in rats using the same technology. Pesticides were administered daily to rats through drinking water for 24 weeks. The above mixture of the four pesticides showed joint toxic action at the NOAEL of each pesticide. The metabonomic profiles of rats urine were analyzed by ultraperformance liquid chromatography/mass spectrometry. The 16 metabolites statistically significantly changed in all treated groups compared with the control group. Dimethylphosphate and dimethyldithiophosphate exclusively detected in all treated groups can be used as early, sensitive biomarkers for exposure to a mixture of the OP pesticides. Moreover, exposure to the OP pesticides resulted in increased 7-methylguanine, ribothymidine, cholic acid, 4-pyridoxic acid, kynurenine, and indoxyl sulfate levels, as well as decreased hippuric acid, creatinine, uric acid, gentisic acid, C18-dihydrosphingosine, phytosphingosine, suberic acid, and citric acid. The results indicated that a mixture of OP pesticides induced DNA damage and oxidative stress, disturbed the metabolism of lipids, and interfered with the tricarboxylic acid cycle. Ensuring food safety requires not only the toxicology test data of each pesticide for the calculation of the acceptable daily intake but also the joint toxic action.