Effect of sponge city facilities on the exposure characteristics and ecological risks of antibiotics in urban inland lakes: A case study at Fuzhou, China.

Antibiotics are increasingly found in urban lakes, posing significant ecological risks to lake ecosystems. The impact of sponge city facilities on urban flood control is significant; however, their influence on the exposure characteristics and risks associated with antibiotics in urban inland lakes remains unclear. This study investigated the exposure characteristics and evaluated the ecological risks of 15 antibiotics across seven lakes of Fuzhou (as the target of sponge city) in different seasons, in comparison to non-sponge cities. The results revealed that 12 antibiotics were consistently detectable across all lakes, with concentrations ranging from non-detectable (ND) to 20.61 ng/L, with sulfamethoxazole (SMX) emerging as the predominant contaminant. Most antibiotics exhibited higher concentrations in the dry season, attributed to environmental conditions, biological mechanisms, and their physicochemical properties. SMX, tetracycline (TTC), oxytetracycline (OTC), and ciprofloxacin (CIP) posed moderate to high ecological risks, with risk quotient (RQ) values of 0.46, 0.14, 0.17, and 0.61, respectively, while the remaining antibiotics presented lower ecological risks in both seasons. Notably, the RQ values for TTC, OTC, and CIP were elevated during the dry season, whereas SMX displayed a higher RQ value in the wet season, indicating an increased ecological risk during the dry months. In comparison to non-sponge cities, sponge cities exhibited significantly lower concentrations of nearly all antibiotics, particularly during the wet season (p ≤ 0.05). Moreover, over 85% of the antibiotics in non-sponge cities were classified as high risk, contrasted with only 55% in sponge cities, underscoring the heightened ecological risks associated with non-sponge urban designs. This study provides critical insights for controlling antibiotic pollution in the lakes of Fuzhou and serves as a valuable reference for maintaining aquatic ecosystem health through the implementation of sponge city infrastructure.

Association between magnesium depletion score and stroke in US adults with chronic kidney disease: A population-based study.

BACKGROUND: Magnesium ion metabolism disorder is pervasive in the chronic kidney disease population, which is affected by many factors. Magnesium ion plays an important role in maintaining vascular functional integrity.. The Magnesium Depletion Score (MDS), serving as a novel metric for the assessment of magnesium deficiency, has not been thoroughly investigated for its association with stroke in patients with chronic kidney disease (CKD). Therefore, this study aims to explore the relationship between the MDS index and stroke in CKD patients. METHODS: We conducted a cross-sectional population-based study using data from the National Health and Nutrition Examination Survey 2009-2016 to explore the impact of MDS on the stroke outcome of CKD patients. The primary outcome was the risk of stroke in CKD patients. Sample-weighted multivariate logistic regression was used in our analysis. RESULTS: In this study of 3536 CKD patients from the database, we found an 8.6 % prevalence of stroke with higher stroke risk in older individuals and males. Lower dietary magnesium intake and higher MDS scores were significantly associated with stroke risk. Multivariate logistic regression analysis revealed a dose-dependent relationship between MDS scores and stroke likelihood, independent of demographic and clinical factors. Subgroup analysis confirmed these findings, particularly in those with hypertension, diabetes, and obesity, without significant interactions (all p > 0.05). CONCLUSION: Magnesium depletion is independently associated with a heightened stroke risk in chronic kidney disease patients.

Injective hydrogel loaded with liposomes-encapsulated MY-1 promotes wound healing and increases tensile strength by accelerating fibroblast migration via the PI3K/AKT-Rac1 signaling pathway.

Failed skin wound healing, through delayed wound healing or wound dehiscence, is a global public health issue that imposes significant burdens on individuals and society. Although the application of growth factor is an effective method to improve the pace and quality of wound healing, the clinically approved factors are limited. Parathyroid hormone (PTH) demonstrates promising results in wound healing by promoting collagen deposition and cell migration, but its application is limited by potentially inhibitory effects when administered continuously and locally. Through partially replacing and repeating the amino acid domains of PTH(1-34), we previously designed a novel PTH analog, PTH(3-34)(29-34) or MY-1, and found that it avoided the inhibitory effects of PTH while retaining its positive functions. To evaluate its role in wound healing, MY-1 was encapsulated in liposomes and incorporated into the methacryloyl gelatin (GelMA) hydrogel, through which an injectable nanocomposite hydrogel (GelMA-MY@Lipo, or GML) was developed. In vitro studies revealed that the GML had similar properties in terms of the appearance, microstructure, functional groups, swelling, and degradation capacities as the GelMA hydrogel. In vitro drug release testing showed a relatively more sustainable release of MY-1, which was still detectable in vivo 9 days post-application. When the GML was topically applied to the wound areas of rat models, wound closure as well as tensile strength were improved. Further studies showed that the effects of GML on wound repair and tensile strength were closely related to the promotion of fibroblast migration to the wound area through the controlled release of MY-1. Mechanically, MY-1 enhanced fibroblast migration by activating PI3K/AKT signaling and its downstream molecule, Rac1, by which it increased fibroblast aggregation in the early stage and resulting in denser collagen deposition at a later time. Overall, these findings demonstrated that the nanocomposite hydrogel system promoted skin wound healing and increased tensile strength, thus offering new potential in the treatment of wound healing.

Role of ginsenoside Rb1 in attenuating depression-like symptoms through astrocytic and microglial complement C3 pathway.

Ginsenoside Rb1, known as gypenoside III, exerts antidepressant-like effects in previous studies. It has also been indicated that ginsenoside Rb1 regulated neuroinflammation via inhibiting NF-κB signaling. According to the evidence that astrocytes can regulate microglia and neuroinflammation by secreting complement C3, the present study aimed to demonstrate the molecular mechanisms underlying ginsenoside Rb1-induced antidepressant-like effects from the astrocytic and microglial complement C3 pathway. The complement C3 mediated mechanism of ginsenoside Rb1 was investigated in mice exposed to chronic restraint stress (CRS). The results showed that ginsenoside Rb1 reversed the depressive-like behaviors in CRS. Treatment with ginsenoside Rb1 reduced both the number of astrocytes and microglia. In addition, ginsenoside Rb1 suppressed TLR4/NF-κB/C3 signaling in the astrocytes of the hippocampus. Furthermore, ginsenoside Rb1 attenuated the contents of synaptic protein including synaptophysin and PSD95 in microglia, suggesting the inhibition of microglia-mediated synaptic elimination caused by CRS. Importantly, ginsenoside Rb1 also maintained the dendritic spines in mice. In conclusion, our results demonstrate that ginsenoside Rb1 produces the antidepressant-like effects by inhibiting astrocyte TLR4/NF-κB/C3 signaling to covert microglia from a pro-inflammatory phenotype (amoeboid) towards an anti-inflammatory phenotype (ramified), which inhibit the synaptic pruning in the hippocampus.

Changing Patterns of Injury Mortality Among the Elderly Population in Urban and Rural Areas - China, 1987-2021.

What is already known about this topic?: Injury is a significant public health issue, particularly among the elderly population. However, the extent of this problem varies significantly based on age, gender, and geographic location. What is added by this report?: This study aims to examine the changing patterns of injury mortality rates in China over a 35-year period and assess the age-period-cohort effects on mortality trends. What are the implications for public health practice?: This study examines the evolving patterns of injury mortality in the elderly population and identifies potential high-risk groups. The findings offer valuable insights for informing injury prevention policies.

[Correlation between frailty and erectile dysfunction in elderly males].

OBJECTIVE: To investigate the correlation of frailty with ED in Chinese elderly men. METHODS: This community-based study was conducted with a sample of 258 Chinese men aged 60 to 83 years old in Fuyang City, Anhui Province. All the participants completed a standard questionnaire on demographics, lifestyle, underlying diseases and medical and sexual histories. They also scored on the Chinese version of Tilburg Frailty Indicator (TFI) and International Index of Erectile Function-5 (IIEF-5). RESULTS: The incidence rates of ED and frailty in the elderly men were 85.27% and 75.58%, respectively. The ED patients, compared with the non-ED males, had a significantly older age (ï¼»71.25 ± 5.83ï¼½ vs ï¼»66.92 ± 5.44ï¼½ yr, P < 0.01) and higher body mass index (ï¼»24.37 ± 3.31ï¼½ vs ï¼»23.35 ± 2.97ï¼½ kg/m 2, P < 0.05), incidence of diabetes mellitus (38.0% vs 19.2%, P < 0.05) and TFI scores (8.61 ± 4.29 vs 5.95 ± 4.36, P < 0.05), but lower education and frequency of irregular intercourse (less than once a week) (all P<0.05). Multivariate analysis indicated that diabetes (OR：3.292，95% CI：1.236－8.768), irregular intercourse (OR：2.425，95% CI：1.114－5.279), and scores of frailty (OR：4.502，95% CI：1.905－10.640) were regarded as independent risk factors for ED (all P < 0.05). CONCLUSION: There is a strong correlation between ED and frailty in elderly men. Sexual health care for elderly ED patients should be more focused on the multidimensional assessment and treatment of senile frailty.

Yamogenin Exhibits Antidepressant-like Effects via Inhibition of ER Stress and Microglial Activation in LPS-Induced Mice.

Depression is a multifaceted psychiatric disorder that affects a significant number of individuals worldwide, and its pathophysiology encompasses a variety of mechanisms, including the induction of endoplasmic reticulum (ER) stress, which has been correlated with depressive-like behaviors in animal models. Yamogenin, a bioactive compound derived from traditional Chinese medicine Dioscorea species, possesses diverse pharmacological properties. This investigation aimed to explore the antidepressant-like effects of yamogenin and the underlying mechanisms involved. By utilizing a murine model of lipopolysaccharide (LPS)-induced depressive-like behavior, we demonstrated that yamogenin enhanced sucrose preference and reduced immobility time in the forced swimming test. These effects were observed alongside the attenuation of ER stress through modulation of the PERK/eIF2α/ATF4/CHOP signaling pathway in the prefrontal cortex. Moreover, yamogenin augmented the expression of the antiapoptotic protein Bcl-2 while diminishing the expression of the proapoptotic protein caspase-3. Additionally, yamogenin exhibited inhibitory effects on microglial activation but did not elicit the promotion of brain-derived neurotrophic factor (BDNF) signaling. Collectively, our findings propose that yamogenin exerts antidepressant-like effects in LPS-induced mice by inhibiting ER stress and microglial activation. This study contributes novel insights into the potential utilization of yamogenin as a natural antidepressant agent.

Human Parathyroid Hormone Analog (3-34/29-34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial-mesenchymal transition via PTHR1-PI3K/AKT activation.

BACKGROUND: Re-epithelialization is important in the process of wound healing. Various methods have been identified to expedite the process, but their clinical application remains limited. While parathyroid hormone (PTH) has shown promising results in wound healing due to its role in promoting collagen deposition and cell migration, application is limited by its potentially inhibitive effects when being continuously and locally administrated. Herein, we developed a novel PTH analog, Human parathyroid hormone (hPTH) (3-34/29-34) (henceforth MY-1), by partially replacing and repeating the amino acid sequences of hPTH (1-34), and evaluated its effect on skin wound re-epithelialization. METHODS: CCK-8, colony formation unit assay, and Ki67 immunofluorescent staining were performed to evaluate the effect of MY-1 on HaCaT cell proliferation. Then, wound scratch assay, Transwell assay and lamellipodia staining were carried out to evaluate the effect of MY-1 on cell migration. Moreover, the epithelial-mesenchymal transition (EMT) markers were measured using qPCR and western blot analysis. For in-vivo drug delivery, gelatin methacryloyl (GelMA) hydrogel was employed to load the MY-1, with the physicochemical characteristics evaluated prior to its application in wound models. Then, MY-1's role in wound healing was determined via acute skin wound models. Finally, the mechanism that MY-1 activated was also detected on HaCaT cells and in-vivo wound models. RESULTS: In-vitro, MY-1 accelerated the migration and EMT of HaCaT cells, while having little effect on cell proliferation. GelMA and MY-1-incorporated GelMA hydrogels showed similar physicochemical characteristics and were used in the in-vivo studies, where the results revealed that MY-1 led to a stronger re-epithelialization by inducing basal keratinocyte migration and EMT. Further studies on in-vivo wound models and in-vitro HaCaT cells revealed that MY-1 regulated cell migration and EMT through activating PI3K/AKT signaling. The parathyroid hormone type 1 receptor (PTHR1), the main receptor of PTH, was found to be the upstream of PI3K/AKT signaling, through interfering PTHR1 expression with a small interference RNA following detection of the PI3K/AKT activation. CONCLUSION: Collectively, our study demonstrated that MY-1 accelerates skin wound re-epithelialization by inducing keratinocyte migration and EMT via PTHR1-PI3K/AKT axis activation. Video Abstract.

Inhibition of NLRP3 attenuates sodium dextran sulfate-induced inflammatory bowel disease through gut microbiota regulation.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota. METHODS: Here, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS). RESULTS: Firstly, NLRP3 and IL-1ß levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1ß signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri. CONCLUSIONS: This study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.

Gut microbiota mediated inflammation, neuroendocrine and neurotrophic functions involved in the antidepressant-like effects of diosgenin in chronic restraint stress.

BACKGROUND: Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms. METHODS: The antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated. RESULTS: The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function. LIMITATIONS: Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites. CONCLUSIONS: The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.

CY-09 Alleviates the Depression-like Behaviors via Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation in Lipopolysaccharide-Induced Mice.

Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.

Effects of ischemia-hypoperfusion on neuro-vascular units in dual transgenic mice with Alzheimer's disease.

INTRODUCTION: The study aimed to investigate the effects of ischemia on neuro-vascular units in transgenic mice, and to investigate the role of ischemia-hypoperfusion in the model of dual transgenic mice with dementia. MATERIAL AND METHODS: In this study, the ischemic model was generated by operating a bilateral common carotid artery micro-embolism. Mice were divided into four groups, including group 1: C57BL sham surgery group (control), group 2: C57BL ischemic group, group 3: amyloid precursor protein/presenilin-1 (APP/PS1) group, and group 4: APP/PS1 ischemic group. Each group comprised 20 mice. Spatial behavior and memory ability of mice were detected by Morris water maze and jumping platform test. Mouse hippocampus was observed by HE staining and Congo red staining. Ultrastructure of each group of neuro-cyclic units was observed by electron microscopy. Various biochemical indicators were detected by ELISA. Western blot detected the amount of protein expression. qRT-PCR identified mRNA expression. RESULTS: The results indicated that learning and memory functions of C57 ischemic mice were lower than those of control group. Positive expression area of APP in APP/PS1 ischemic group was higher than in APP/PS1 group. In APP/PS1 group and APP/PS1 ischemic group, the content of Ab was significantly higher than in C57 ischemic group. Electron microscopic observation revealed that there were more mitochondrial vacuoles in hippocampal neurons of APP/PS1 mice, and the structure was relatively intact. Mitochondrial vacuoles in hippocampus increased significantly, and vascular wall proliferated in APP/PS1 ischemic group. Compared with C57 control group, the content of vascular endothelial growth factor (VEGF) increased significantly in C57 ischemic group. CONCLUSIONS: Ischemia deteriorates the learning and memory function of transgenic mice, aggravates the damage of neuro-vascular units, and impairs the blood-brain barrier transport of Ab, leading to an increase in the concentration of Ab cerebrospinal fluid, and further deterioration of neuro-vascular units. At the same time, ischemia is an effective stimulating factor in the release of VEGF.

IL-1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression.

BACKGROUND: Major depressive disorder is characterized by not only monoamine neurotransmitters deficiencies but also persistent neuroinflammation. The complement system is an attractive therapeutic target for various inflammation-related diseases due to its early activation in inflammatory processes. RESULTS: In the present study, the dynamic alteration of complement C3 and its receptor C3aR during the occurrence of depression and the mechanism of astrocyte-microglia IL-1R/C3/C3aR on synaptic pruning were investigated. The proteomic analysis firstly showed that chronic stress caused an elevation of C3. GO analysis indicated that complement system-mediated synaptic pruning signaling was involved in depression. The dynamic observation indicated that C3/C3aR was activated in the early onset and throughout the course of depression induced by lipopolysaccharide (LPS) and chronic stress. In contrast, C3aR blockade inhibited the hyperactivation of microglial APT2/DHHC7 palmitoylation cycle, which mediated the translocation of STAT3 and the expression of proinflammatory cytokines. Meanwhile, C3aR blockade also attenuated the synaptic pruning and enhanced the synaptogenesis in the prefrontal cortex of mice. Moreover, the blockade of IL-1R/NF-κB signaling pathway reduced the release of C3 from astrocyte. CONCLUSIONS: The current study demonstrates that astrocyte-microglia IL-1R/C3/C3aR activation causes the abnormal synaptic pruning in depression, and suggests that the activation of complement C3/C3aR may be particularly helpful in predicting the onset stage of depression.

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice.

Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

Correlations between Personality Traits, Patient-Reported Outcome, and Chronic Prostatitis Symptoms in Men with Different Premature Ejaculation Syndromes.

Although the personality traits (PT), patient-reported outcome (PRO), and chronic prostatitis (CP) symptoms in premature ejaculation (PE) have been evaluated, there was no study to assess their correlations in men with different PE syndromes. The purpose of this study was to assess the correlations between the PT, PRO, and CP symptoms in men with different PE syndromes. Between January 2019 and January 2021, a cross-sectional field study was conducted in our andrology clinic. Men with the complaints of PE were divided into lifelong PE (LPE), acquired PE (APE), variable PE (VPE), and subjective PE (SPE). All subjects were required to complete a verbal questionnaire with the PRO, National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and Temperament and Character Inventory (TCI-R). Finally, 479 men with the complaints of PE and 365 without the complaints of PE were enrolled. The incidence of PE syndromes in PE complaint group was as follows: LPE 16.70%, APE 48.85%, VPE 11.27%, and SPE 23.17%. Mean ages in PE complaint group were 42.53 ± 12.25 years. In the PE complaint group, the novelty seeking (NS) scores were strongest correlated with the personal distress and quality of life (QOL). The harm avoidance (HA) scores were strongest correlated with the severity of PE and pain syndromes. The self-transcendence (ST) scores were strongest correlated with the satisfaction with sexual intercourse and QOL. In addition, strongest association between the total scores of NIH-CPSI and the NS or ST scores was also found in the APE group. The HA scores were also strongest correlated with the total scores of NIH-CPSI in SPE. Strongest association between the total scores of NIH-CPSI and the NS/TI or ST/CI scores was also found in the APE group. The HA/TI scores were also strongest correlated with the total scores of NIH-CPSI in SPE.

Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1ß Signaling In Stress-induced Mice.

Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1ß signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1ß signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1ß expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.

An Effective Treatment of Perimenopausal Syndrome by Combining Two Traditional Prescriptions of Chinese Botanical Drugs.

Ethnopharmacological relevance: Two types of traditional Chinese formulas of botanical drugs are prescribed for treating perimenopausal syndrome (PMS), a disorder in middle-aged women during their transition to menopause. One is for treating PMS as kidney deficiency (KD) due to senescence and declining reproductive functions, and the other is for treating it as liver qi stagnation (LQS) in association with stress and anxiety. Despite the time-tested prescriptions, an objective attestation to the effectiveness of the traditional Chinese treatment of PMS is still to be established and the associated molecular mechanism is still to be investigated. Materials and methods: A model for PMS was generated from perimenopausal rats with chronic restraint stress (CRS). The effectiveness of traditional Chinese formulas of botanical drugs and a combination of two of the formulas was evaluated based on 1H NMR plasma metabolomic, as well as behavioral and physiological, indicators. To investigate whether the formulas contained ligands that could compensate for the declining level of estrogen, the primary cause of PMS, the ligand-based NMR technique of saturation transfer difference (STD) was employed to detect possible interacting molecules to estrogen receptors in the decoction. Results: Each prescription of the classical Chinese formula moderately attenuated the metabolomic state of the disease model. The best treatment strategy however was to combine two traditional Chinese formulas, each for a different etiology, to adjust the metabolomic state of the disease model to that of rats at a much younger age. In addition, this attenuation of the metabolomics of the disease model was by neither upregulating the estrogen level nor supplementing an estrogenic compound. Conclusion: Treatment of PMS with a traditional Chinese formula of botanical drugs targeting one of the two causes separately could ameliorate the disorder moderately. However, the best outcome was to treat the two causes simultaneously with a decoction that combined ingredients from two traditional prescriptions. The data also implicated a new paradigm for phytotherapy of PMS as the prescribed decoctions contained no interacting compound to modulate the activity of estrogen receptors, in contrast to the treatment strategy of hormone replacement therapy.