CRHR1 antagonist alleviated depression-like behavior by downregulating p62 in a rat model of post-stroke depression.

Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.

The petroleum ether extracts of Chloranthus fortunei(A. Gray) Solms-Laub.with bioactivities: A Rising Source in HCC Drug Treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular Carcinoma (HCC) is an aggressive killer worldwide with high incidence and mortality. The herb Chloranthus fortunei (A. Gray) Solms-Laub is known as "Si Ji Feng" and is classified as a Feng-type medicine in classic Yao medicines. According to Yao's medical beliefs, Chloranthus fortunei has the functions of dispelling Feng, regulating qi, detoxifying, promoting blood circulation, etc. Folk uses its decoctions to treat stagnant liver conditions, such as liver abscesses, cirrhosis, hepatitis, and liver cancer. However, the bioactivity and mechanisms of Chloranthus fortunei extract against HCC have not been reported. AIM OF THE STUDY: To investigate the anti-HCC bioactivity and potential mechanism of the extract of Chloranthus fortunei (CFS). MATERIALS AND METHODS: Using 70% ethanol for reflux extraction of CFS resulted in the CFS ethanol extract, followed by sequential extractions with petroleum ether, chloroform, ethyl acetate, and n-butanol, yielding four fractions. The CCK-8 assay was utilized to examine the cytotoxic effects of 4 fractions on MHCC97-H and HepG2 cells, exploring the most effective component, namely petroleum ether extracts of CFS (PECFS). The major active ingredients of PECFS were identified using LC/MS technology, and the impact on cell proliferation and apoptosis in HCC cells was studied. The key genes and proteins in the pathway were validated using RT-PCR and Western blotting. BALB/c nude mice were chosen for tumor xenotransplantation and PECFS therapy. hinders the proliferation of HCC cells and promotes apoptosis. RESULTS: Among the four fractions, it was found that PECFS have the highest antiproliferative activity against MHCC97-H and HepG2 cells (IC50 = 13.86, 10.55 µg/mL), with sesquiterpene compounds being the primary active constituents. The antiproliferative activity of PECFS on HCC cells was linked to the inhibition of cell cloning, invasion, and metastasis abilities, as well as the arrest of the cell cycle at the G2/M phase. Additionally, exerts pro-apoptotic effects on HCC cells by upregulating the pro-apoptotic protein Bax, downregulating the anti-apoptotic protein Bcl-2, and activating the expression of the Caspase family. Moreover, protein and m-RNA expression data showed that PECFS inhibits HCC cell proliferation and promotes apoptosis by regulating the PI3K/AKT/mTOR pathway. Besides, after PECFS treatment, tumor growth in nude mice was suppressed. CONCLUSION: PECFS can inhibit the viability of HCC cells by acting on the PI3K/AKT/mTOR pathway, demonstrating anti-tumor potential. This study's findings suggest that PECFS may represent a promising source of novel agents for liver cancer treatment, providing scientific evidence for the traditional application of CFS in treating HCC.

Total Synthesis of (-)-Piericone D.

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective ß-O-glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.

Wnt5a deficiency in osteocalcin-expressing cells could not alleviate the osteoarthritic phenotype in a mouse model of post-traumatic osteoarthritis.

Objectives: Wnt5a, which regulates the activities of osteoblasts and osteoclasts, is reportedly overexpressed in osteoarthritis (OA) tissues. The purpose of this study was to elucidate its role in the development of OA by deleting Wnt5a in osteocalcin (OCN)-expressing cells. Materials and Methods: Knee OA was induced by anterior cruciate ligament transection (ACLT) in OCN-Cre;Wnt5afl/fl knockout (Wnt5a-cKO) mice and control littermates. Eight weeks after surgery, histological changes, cell apoptosis, and matrix metabolism of cartilage were evaluated by toluidine blue, TUNEL staining, and im-immunohistochemistry analyses, respectively. In addition, the subchondral bone microarchitecture of mice was examined by micro-computed tomography (micro-CT). Results: Histological scores show substantial cartilage degeneration occurred in ACLT knees, coupled with decreased collagen type II expression and enhanced matrix metalloproteinase 13 expression, as well as higher proportions of apoptotic cells. Micro-CT results show that ACLT resulted in decreased bone mineral density, bone volume/trabecular volume, trabecular number, and structure model index of subchondral bones in both Wnt5a-cKO and control littermates; although Wnt5a-cKO mice display lower BMD and BV/TV values, no significant difference was observed between Wnt5a-cKO and control mice for any of these values. Conclusion: Our findings indicate that Wnt5a deficiency in OCN-expressing cells could not prevent an osteoarthritic phenotype in a mouse model of post-traumatic OA.

Dietary kaempferol exerts anti-obesity effects by inducing the browing of white adipocytes via the AMPK/SIRT1/PGC-1α signaling pathway.

Browning of white adipose tissue is a novel approach for the management of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a common dietary nutrient found abundantly in many fruits and vegetables and has been shown to have the potential to regulate lipid metabolism. However, the detailed mechanism by which it affects the browning of white adipose tissue remains unclear. In the present study, we sought to determine how KPF induces adipocytes to undergo a browning transformation by establishing a primary adipocyte model and an obese mouse model. Our results showed that KPF-treated mice were rescued from diet-induced obesity, glucose tolerance and insulin resistance, associated with increased expression of adaptive thermogenesis-related proteins. KPF-promoted white adipose browning correlated with the AMPK/SIRT1/PGC-1α pathway, as the use of an AMPK inhibitor in preadipocytes partially reversed the observed browning phenotype of KPF-treated cells. Taken together, these data suggest that KPF promotes browning of white adipose tissue through activation of the AMPK/SIRT1/PGC-1α pathway. This study demonstrates that KPF is a promising natural product for the treatment of obesity by promoting white fat browning.

Safety and efficacy of antioxidant therapy in children and adolescents with attention deficit hyperactivity disorder: A systematic review and network meta-analysis.

OBJECTIVE: To systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with attention deficit hyperactivity disorder (ADHD). METHODS: Randomized controlled trials and prospective studies on antioxidant therapy in children and adolescents with ADHD were searched in PubMed, Embase, and Cochrane Library from the inception of databases to November 12, 2022. Two investigators independently screened the literature, extracted data, and evaluated the quality of the included studies. Network meta-analysis (PROSPERO registration number CRD 42023382824) was carried out by using R Studio 4.2.1. RESULTS: 48 studies involving 12 antioxidant drugs (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) were finally included, with 3,650 patients. Network meta-analysis showed that omega-6 (0.18), vitamin D (0.19), and quercetin (0.24) were the top three safest drugs according to SUCRA. The omega-3 (SUCRA 0.35), pycnogenol (SUCRA 0.36), and vitamin D (SUCRA 0.27) were the most effective in improving attention, hyperactivity, and total score of Conners' parent rating scale (CPRS), respectively. In terms of improving attention, hyperactivity, and total score of Conners' teacher rating scale (CTRS), pycnogenol (SUCRA 0.32), phosphatidylserine+omega-3 (SUCRA 0.26), and zinc (SUCRA 0.34) were the most effective, respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Parent, the optimal agents were phosphatidylserine (SUCRA 0.39), resveratrol+MPH (SUCRA 0.24), and phosphatidylserine (SUCRA 0.34), respectively. In terms of improving attention, hyperactivity and total score of ADHD Rating Scale-Teacher, pycnogenol (SUCRA 0.32), vitamin D (SUCRA 0.31) and vitamin D (SUCRA 0.18) were the optimal agents, respectively. The response rate of omega-3+6 was the highest in CGI (SUCRA 0.95) and CPT (SUCRA 0.42). CONCLUSION: The rankings of safety and efficacy of the 12 antioxidants vary. Due to the low methodological quality of the included studies, the probability ranking cannot fully explain the clinical efficacy, and the results need to be interpreted with caution. More high-quality studies are still needed to verify our findings.

Effect of 10-year cumulative blood pressure exposure on atherosclerotic cardiovascular disease of different age groups: kailuan cohort study.

Background: The level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups. Methods: Cumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (<50, 50-59, 60-69, or ≥70 years). The association between TWA BP and the risk of ASCVD was assessed by age group using multivariate Cox models. The China-PAR prediction model was used to assess the ability of TWA BP to predict ASCVD. Results: In the group aged <50 years, the hazard ratios and 95% confidence intervals for the risk of ASCVD were 2.66 (1.04-6.80), 3.38 (1.54-7.43), and 3.13 (1.36-7.24) for the elevated BP, stage 1 hypertension, and stage 2 hypertension groups, respectively, when compared with the normal BP group. There was a significant difference in the risk of ASCVD between the age groups, with participants aged <50 years having the highest risk, followed by those aged 50-59, 60-69, and ≥70 years. Conclusions: The risk of ASCVD with high cumulative BP exposure was age-dependent, with a gradual decrease in risk with increasing age.

Protein succinylation: regulating metabolism and beyond.

Modifications of protein post-translation are critical modulatory processes, which alters target protein biological activity，function and/or location, even involved in pathogenesis of some diseases. So far, there are at least 16 types of post-translation modifications identified, particularly through recent mass spectrometry analysis. Among them, succinylation (Ksuc) on protein lysine residues causes a variety of biological changes. Succinylation of proteins contributes to many cellular processes such as proliferation, growth, differentiation, metabolism and even tumorigenesis. Mechanically, Succinylation leads to conformation alteration of chromatin or remodeling. As a result, transcription/expression of target genes is changed accordingly. Recent research indicated that succinylation mainly contributes to metabolism modulations, from gene expression of metabolic enzymes to their activity modulation. In this review, we will conclude roles of succinylation in metabolic regulation of glucose, fat, amino acids and related metabolic disease launched by aberrant succinylation. Our goal is to stimulate extra attention to these still not well researched perhaps important succinylation modification on proteins and cell processes.

CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver.

Increased de novo lipogenesis (DNL) in white adipose tissue is associated with insulin sensitivity. Under both Normal-Chow-Diet and High-Fat-Diet, mice expressing a kinase inactive Cyclin-dependent kinase 6 (Cdk6) allele (K43M) display an increase in DNL in visceral white adipose tissues (VAT) as compared to wild type mice (WT), accompanied by markedly increased lipogenic transcriptional factor Carbohydrate-responsive element-binding proteins (CHREBP) and lipogenic enzymes in VAT but not in the liver. Treatment of WT mice under HFD with a CDK6 inhibitor recapitulates the phenotypes observed in K43M mice. Mechanistically, CDK6 phosphorylates AMP-activated protein kinase, leading to phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme in DNL. CDK6 also phosphorylates CHREBP thus preventing its entry into the nucleus. Ablation of runt related transcription factor 1 in K43M mature adipocytes reverses most of the phenotypes observed in K43M mice. These results demonstrate a role of CDK6 in DNL and a strategy to alleviate metabolic syndromes.

Association of life's essential 8 and risk of fragility fractures: A large cohort study.

Cardiovascular health (CVH) score is not only associated with cardiovascular diseases, but also some disorders in other systems. This study aims to investigate the association between CVH score and the risk of fragility fractures. The analysis enrolled 89,464 participants at baseline in Kailuan study initiated in 2006-2007. All participants were then followed up every 2 years and the incidence of fragility fractures was recorded annually. A total CVH score was classified as low (0-49 points), moderate (50-79 points), and ideal (80-100 points). The primary outcome was incident fragility fractures before December 31, 2021. Kaplan-Meier was used to estimate cumulative incidence. Multivariable adjusted Cox proportional hazards regression models and time-dependent Cox hazards regression models were used to estimate fragility fracture hazard ratios (aHR) and 95% confidence intervals (95% CI). After 13.98 ± 2.84 years of follow-up, a total of 1534 cases of fragility fractures were identified, with an incidence density of 1.23 per 1000 person-years. Compared with the low CVH group, the risk of fragility fractures was significantly lower in moderate (aHR = 0.78, 95% CI: 0.66-0.92) and ideal CVH groups (aHR = 0.65, 95% CI: 0.51-0.83), particularly in the age <60 group (aHR = 0.72, 95% CI: 0.59-0.88; aHR= 0.55, 95% CI: 0.41-0.73, respectively). Time-dependent Cox hazards regression models, sensitivity analysis, and death competition model confirmed the reliability of these findings. The ideal CVH score is associated with a decreased risk of fragility fractures. With the increase of CVH score, the risk of fragility fracture decreases.

Incidence and trends of type 1 diabetes before and after 2000 in the Western Pacific Region: A systematic review and meta-analysis.

OBJECTIVES: To undertake a systematic review of publications describing Type 1 diabetes (T1DM) incidence, trends over time and associated factors in the Western Pacific Region (WPR). METHODS: As per the PROSPERO-registered (CRD42019122646) protocol English (MEDLINE, Embase, Global Health) and Chinese data-bases (China National Knowledge Infrastructure, VIP, Wanfang) from onset to 31/12/2019 were searched for T1DM incidence in the WPR. Country level data extracted included annual crude incidence rates by sex, number of new cases per annum (p.a.) and cumulatively, and the population at-risk. A meta-analysis for T1DM incidence was performed (by region and narrow age-bands, where possible) with subgroup analyses by time and by region. FINDINGS: Forty-five population-based studies (21 from China), published 1973-2017, estimated T1DM incidence, mostly in youth, in 11 WPR countries. After 2000, mean annual T1DM incidence/100,000 person years aged 0-14 years ranged from 0.9 (95 % confidence intervals (CI), 0.6-1.3) in Fiji to 23.2 (95 % CI, 21.3-25.2) in Australia. The mean annual increase over time ranged from 2.8 % in Australia (1990-2002) to 14.2 % in Shanghai (1997-2011). T1DM incidence increased most in China (2.7-fold over 30-years) then Thailand (2-fold over 15-years). Most studies documented increasing incidence with age, though only two studies included people aged ≥ 20 years. Many, but not all studies reported significantly higher T1DM incidence in females vs. males. CONCLUSION: T1DM incidence in the WPR is generally increasing, varying by age, sex, time and country. Results increase understanding of regional T1DM incidence and inform research and healthcare strategies.

Arterial stiffness and risk of new-onset fragility fracture in Chinese men and women: The Kailuan cohort study.

BACKGROUND: Previous studies have shown an association between increased arterial stiffness and reduced bone mineral density. However, the relationship between arterial stiffness and fragility fracture remains unclear. In this study, we explored the impact of arterial stiffness on the risk of new-onset fragility fracture. METHODS: The study included 53,107 participants in the Kailuan Study in whom brachial-ankle pulse wave velocity (baPWV) measurements were obtained between 2010 and 2021. All participants were free of fragility fractures at baseline. A Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for incident fragility fracture on the baseline baPWV groups: <1400 cm/s (reference), 1400 ≤ baPWV < 1800 cm/s, and ≥1800 cm/s. RESULTS: In total, 327 incident fragility fractures were recorded during an average follow-up of 4.99 ± 3.02 years. After adjustment for potential confounders, the HR for the risk of new-onset fragility fracture was 1.66 (95 % CI 1.14-2.42) for the arterial stiffness group in comparison with the normal baPWV group. The risk of fragility fracture was higher in men (HR 1.64, 95 % CI 1.05-2.57). There was a linear association between higher baPWV and fragility fracture. CONCLUSIONS: Arterial stiffness as measured by baPWV was associated with the risk of fragility fracture.

Cumulative exposure to remnant cholesterol and the risk of fragility fractures: a longitudinal cohort study.

Objective: To investigate the association between cumulative remnant cholesterol (cumRC) and the risk of new-onset fragility fractures. Methods: This study included individuals who participated in the 2006, 2008, and 2010 Kailuan health examinations. Baseline characteristics were compared between groups according to cumRC quartiles. The incidence density was calculated, and the log-rank test was used to compare the cumulative incidence. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI), and restricted cubic spline was used to examine the possibly non-linear relation between cumRC and the risk of fragility fractures. Additional analyses were performed with stratification by age (≥ or <65 years). Results: A total of 43,839 individuals were included in this study. During the median follow-up period of 10.97 years, a total of 489 fragility fractures occurred. Multivariable Cox proportional hazards regression model 3 showed that the Q1 and Q4 groups versus the Q2 group were associated with a higher HR of fragility fracture (HR 1.61, 95% CI: 1.23-2.11; HR 1.38, 95% CI: 1.06-1.81), and restricted cubic spline regression analysis showed a non-linear relationship between cumRC level and the risk of fragility fractures (P Overall association < 0.001, P Non-linear association = 0.001). The association was significant in the age group <65 years but not in the age group ≥65 years. The sensitivity analyses were consistent with the main results. Conclusions: Both too high and too low cumRC levels were associated with a greater risk of fragility fractures, and this association was more significant in young and middle-aged people.

Visible-Light-Driven α-Substituted Amines Enabled by In Situ Formation of Amine Substrate Aggregates.

A visible-light-driven, photocatalyst-free, air-promoted, α-substituted reaction of amines with varying nucleophiles is described. The amine substrate aggregates formed in situ through physical π-π stacking by H2O regulation in organic solvent can absorb visible light and then generate iminium ion intermediates, which undergo nucleophilic substitution reactions with varying nucleophiles to afford α-substituted amines. This reaction features catalyst-free, good functional group tolerance, simple operation procedure, and green reaction conditions.

Estrogen deficiency impedes fracture healing despite eliminating the excessive absorption of the posterior callus in a semi-fixed distal tibial fracture mouse model.

BACKGROUND: Treatment of distal tibial fractures is a challenge due to their specific anatomical location. However, there is no appropriate mouse model to simulate a clinical distal tibial fracture for basic research. The aim of this investigation was to evaluate the feasibility of simulating a clinical fracture of the distal tibia of mice and to investigate the effect of ovariectomy (OVX)-induced osteoporosis on fracture healing in this model. METHODS: Sixty female 8-week-old C57BL/6 mice were randomly divided into two groups, either sham or OVX. A semi-fixation distal tibia fracture was established in the right tibia after 8 weeks of OVX. The right tibias were collected at 7, 14, 21, and 28 days post fracture. RESULTS: In the semi-fixation distal tibia fracture model, the posterior callus in the sham group showed excessive bone resorption and lower bone mass phenotype compared with the anterior site; a similar trend was not found in the OVX group. At 28 days post fracture, the posterior callus was more mineralized than the anterior callus in the OVX group. Although the fracture healing of the sham group showed a special phenotype in this mode, the progress and quality of fracture healing were still better than those of the OVX group. CONCLUSION: A semi-fixed distal tibial closed fracture mouse model was successfully established. In this model, excess bone resorption of the posterior callus impaired normal fracture healing, but not in OVX-induced osteoporotic bone. Although the stress shielding effect was not observed in the OVX group, impaired bone healing caused by OVX was still present. Our results suggest that this fracture model may have potential for studies on distal tibial fractures and stress shielding.

CDK6 is essential for mesenchymal stem cell proliferation and adipocyte differentiation.

Background: Overweight or obesity poses a significant risk of many obesity-related metabolic diseases. Among all the potential new therapies, stem cell-based treatments hold great promise for treating many obesity-related metabolic diseases. However, the mechanisms regulating adipocyte stem cells/progenitors (precursors) are unknown. The aim of this study is to investigate if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. Methods: Cyclin-dependent kinase 6 (Cdk6) mouse models together with stem cells derived from stromal vascular fraction (SVF) or mouse embryonic fibroblasts (MEFs) of Cdk6 mutant mice were used to determine if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. Results: We found that mice with a kinase inactive CDK6 mutants (K43M) had fewer precursor residents in the SVF of adult white adipose tissue (WAT). Stem cells from the SVF or MEFs of K43M mice had defects in proliferation and differentiation into the functional fat cells. In contrast, mice with a constitutively active kinase CDK6 mutant (R31C) had the opposite traits. Ablation of RUNX1 in both mature and precursor K43M cells, reversed the phenotypes. Conclusion: These results represent a novel role of CDK6 in regulating precursor numbers, proliferation, and differentiation, suggesting a potential pharmacological intervention for using CDK6 inhibitors in the treatment of obesity-related metabolic diseases.

Impacts and mechanisms of PM2.5 on bone.

Osteoporosis is a metabolic bone disease, which is characterized by a decreased bone mass and deterioration of bone microstructure, resulting in increased bone fragility and a higher risk of fracture. The main pathological process of osteoporosis is the dynamic imbalance between bone absorption and bone formation, which can be caused by various factors such as air pollution. Particulate matter (PM)2.5 refers to the fine particles in the atmosphere, which are small in volume and large in specific surface area. These particles are prone to carrying toxic substances and have negative effects on several extrapulmonary organs, including bones. In this review, we present relevant data from studies, which show that PM2.5 is associated with abnormal bone turnover and osteoporosis. PM2.5 may cause or aggravate bone loss by stimulating an inflammatory response, inducing oxidative damage, reducing estrogen efficiency by competitive binding to estrogen receptors, or endocrine disorder mediated by binding with aromatic hydrocarbon receptors, and affecting the synthesis of vitamin D to reduce calcium absorption. The cellular and molecular mechanisms involved in these processes are also summarized in this review.

Kaempferol regulates the thermogenic function of adipocytes in high-fat-diet-induced obesity via the CDK6/RUNX1/UCP1 signaling pathway.

Activation of adipose tissue thermogenesis is a promising strategy in the treatment of obesity and obesity-related metabolic disorders. Kaempferol (KPF) is a predominant dietary flavonoid with multiple pharmacological properties, such as anti-inflammatory and antioxidant activities. In this study, we sought to characterize the role of KPF in adipocyte thermogenesis. We demonstrated that KPF-treated mice were protected from diet-induced obesity, glucose tolerance, and insulin resistance, accompanied by markedly increased energy expenditure, ex vivo oxygen consumption of white fat, and increased expression of proteins related to adaptive thermogenesis. KPF-promoted beige cell formation is a cell-autonomous effect, since the overexpression of cyclin-dependent kinase 6 (CDK6) in preadipocytes partially reversed browning phenotypes observed in KPF-treated cells. Overall, these data implicate that KPF is involved in promoting beige cell formation by suppressing CDK6 protein expression. This study provides evidence that KPF is a promising natural product for obesity treatment by boosting energy expenditure.

Acteoside improves adipocyte browning by CDK6-mediated mTORC1-TFEB pathway.

Adipocyte browning increases energy expenditure by thermogenesis, which has been considered a potential strategy against obesity and its related metabolic diseases. Phytochemicals derived from natural products with the ability to improve adipocyte thermogenesis have aroused extensive attention. Acteoside (Act), a phenylethanoid glycoside, exists in various medicinal or edible plants and has been shown to regulate metabolic disorders. Here, the browning effect of Act was evaluated by stimulating beige cell differentiation from the stromal vascular fraction (SVF) in the inguinal white adipose tissue (iWAT) and 3T3-L1 preadipocytes, and by converting the iWAT-SVF derived mature white adipocytes. Act improves adipocyte browning by differentiation of the stem/progenitors into beige cells and by direct conversion of mature white adipocytes into beige cells. Mechanistically, Act inhibited CDK6 and mTOR, and consequently relieved phosphorylation of the transcription factor EB (TFEB) and increased its nuclear retention, leading to induction of PGC-1α, a driver of mitochondrial biogenesis, and UCP1-dependent browning. These data thus unveil a CDK6-mTORC1-TFEB pathway that regulates Act-induced adipocyte browning.

Astrocytes in Post-Stroke Depression: Roles in Inflammation, Neurotransmission, and Neurotrophin Signaling.

Post-stroke depression (PSD) is a frequent and disabling complication of stroke that affects up to one-third of stroke survivors. The pathophysiology of PSD involves multiple mechanisms, including neurochemical, neuroinflammatory, neurotrophic, and neuroplastic changes. Astrocytes are a type of glial cell that is plentiful and adaptable in the central nervous system. They play key roles in various mechanisms by modulating neurotransmission, inflammation, neurogenesis, and synaptic plasticity. This review summarizes the latest evidence of astrocyte involvement in PSD from human and animal studies, focusing on the alterations of astrocyte markers and functions in relation to monoamine neurotransmitters, inflammatory cytokines, brain-derived neurotrophic factor, and glutamate excitotoxicity. We also discuss the potential therapeutic implications of targeting astrocytes for PSD prevention and treatment. Astrocytes could be new candidates for antidepressant medications and other interventions that aim to restore astrocyte homeostasis and function in PSD. Astrocytes could be new candidates for antidepressant medications and other interventions that aim to restore astrocyte homeostasis and function in PSD.