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BACKGROUND: Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)-mediated vasorelaxation is still unclear, and data about human vessels are limited. OBJECTIVE: To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA). RESULTS: NaHS (1 × 10-6-3 × 10-3 mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01). CONCLUSION: Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx.

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BACKGROUND: Pregnant women face significant physiological and psychological stressors, which can lead to mental health issues such as anxiety and depression. Despite the importance of professional psychological assistance, many pregnant women in China do not seek help due to various barriers. This study aims to explore the experiences and challenges of pregnant women in seeking psychological help in China through qualitative methods. METHODS: Purposive sampling was employed to select 20 pregnant women from a Class III Type A hospital in Hainan. Semi-structured in-depth interviews were conducted from July to August 2023, focusing on psychological states, help-seeking experiences, encountered challenges, and suggestions for improving psychological support. Colaizzi's 7-step method was used to synthesize the themes. RESULTS: We distilled five themes: (1) Psychological conditions during pregnancy, which includes stress and emotional fluctuations and anticipations of postpartum challenges; (2) Barriers to seeking help, underscored by societal misconceptions, limited professional access, and varied familial support; (3) Sources of psychological stress, highlighting physical changes, familial and work pressures, and societal expectations; (4) Expectations for psychological assistance, emphasizing the need for professional understanding and societal awareness; (5) Impact of psychological issues on daily life, such as decreased work efficiency and affected social activities. CONCLUSION: Pregnant women in China confront significant psychological stress and face multiple barriers in accessing help. There is an urgent need for personalized and professional psychological services for pregnant women. Addressing barriers such as societal stigma and poor accessibility, along with increasing public awareness and improving mental health services, is crucial. These findings provide a foundation for developing effective psychological support strategies aimed at enhancing the mental health of pregnant women in China.

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OBJECTIVES: To investigate the effects and molecular mechanisms of inhibition of the Ras homolog gene (Rho)/Rho-associated coiled-coil forming protein kinase (ROCK) pathway on the proliferation and migration of airway smooth muscle cells involving myocardin (MYOCD). METHODS: Human airway smooth muscle cells were infected with the adenoviral vector Ad-ZsGreen-shRNA-hROCK1 in vitro. The cells were randomly divided into four groups: ROCK1 gene silencing control (shNC) group, shNC + arachidonic acid (AA, Rho/ROCK pathway activator) group, ROCK1 gene silencing (shROCK1) group, and shROCK1 + AA group (n=3 each). Quantitative real-time polymerase chain reaction and Western blot were used to detect the expression levels of ROCK1 and MYOCD mRNA and protein. ELISA was employed to measure the levels of globular actin and filamentous actin, while immunofluorescent staining and scratch assays were utilized to assess cell proliferation and migration. RESULTS: Compared to the shNC + AA group, the shROCK1 + AA group exhibited decreased levels of ROCK1 and MYOCD mRNA and protein expression, reduced expression levels of globular actin and filamentous actin, and diminished cell proliferation and migration capabilities (P<0.05). CONCLUSIONS: Inhibition of the Rho/ROCK pathway suppresses the proliferation and migration of airway smooth muscle cells, which may be associated with the downregulation of MYOCD.

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An untargeted lipidomic analysis was conducted to investigate the lipid composition of human milk across different lactation stages and gestational ages systematically. A total of 25 lipid subclasses and 934 lipid species as well as 90 free fatty acids were identified. Dynamic changes of the lipids throughout lactation and gestational phases were highlighted. In general, lactation stages introduced more variations in the lipid composition of human milk than gestational ages. Most lipids decreased as the milk progressed from the colostral stage to the mature stage, with some reaching a peak at the transitional stage. Significant variations in lipid composition across gestational ages were predominantly evident during early lactation period. In mature milks, most of the lipids exhibited no discernible statistical differences among gestational ages. This elucidation offers valuable insights and guidance for tailoring precise nutritional strategies for infants with diverse health needs.

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Disrupted cholesterol homeostasis plays a critical role in the development of multiple diseases, such as cardiovascular disease and cancer. However, the role of cholesterol in inflammatory bowel disease (IBD) remains unclear. In the present study, we investigated whether and how high levels of cholesterol in the diet affect experimental colitis in mice. A normal diet supplemented with 1.25% cholesterol (high cholesterol diet) caused more severe colitis and aggravated the disruption of intestinal tight junction structure, accompanied by higher colonic tissue total cholesterol (TC) levels in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Cholesterol aggravated DSS-induced intestinal epithelial barrier impairment and nuclear sterol regulatory element-binding protein 2 (nSREBP2) inhibition both in vivo and in vitro. In addition, nSREBP2 overexpression ameliorated cholesterol-induced intestinal epithelial barrier disruption in Caco2 cells. Interestingly, inhibition of SREBP2 disrupted intestinal epithelial barrier in the absence of cholesterol. Furthermore, SREBP2 regulated the protein expression of tight junction proteins (occludin/Zo-1) via modulating caveolin-1-mediated endocytosis and lysosomal degradation. Analysis of UK Biobank data indicated that, in fully adjusted models, higher serum TC concentrations were an independent protective factor for IBD incidence. The sterol regulatory element-binding factor 2 (SREBF2) gene rs2228313 (G/C) genetic variant was associated with the incidence of IBD and the CC genotype of SREBF2 rs2228313 was associated with higher serum TC levels and decreased the risk of IBD. In summary, a high cholesterol diet aggravates DSS-induced colitis in mice by down-regulating nSREBP2 expression, thereby promoting the endocytic degradation of tight junction proteins. In humans, SREBF2 gene single nucleotide polymorphism rs2228313 and serum TC levels are associated with IBD incidence.

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INTRODUCTION: Asthma is a common chronic respiratory disease characterized by chronic airway inflammation and abnormal airway remodeling. The RhoA/ROCK pathway and myocardin-related transcription factor A (MRTF-A) demonstrate significant associations with the proliferation of airway smooth muscle cells (ASCMs), which tightly correlates with the process of airway remodeling. MYOCD, which is homologous to MRTF-A but specifically expressed in smooth muscle cells, potentially regulates RhoA/ROCK activated cell proliferation and subsequent airway remodeling. METHODS: The RhoA/ROCK overexpression and silencing cell lines were constructed in vitro, as well as MYOCD overexpression/silencing. The cytoskeleton alterations induced by RhoA/ROCK pathway were identified by the measuring of globular actin and filamentous actin. RESULTS: The comparison between controls for overexpression/silencing and ROCK overexpression/silencing revealed that MYOCD presented consistent change trends with cytoskeleton and RhoA/ROCK pathway. The ROCK1 facilitates the proliferation and migration of ASCMs. The MYOCD enhanced the proliferation and migration of HASMCs. CONCLUSION: Our study indicates that Rho/ROCK/MYOCD is a key pathway involved in the migration and proliferation of airway smooth muscle cells. Inhibition of Rho/ROCK may be an effective approach to breaking the vicious cycle of asthmatic ASCMs proliferation, providing a novel strategy in treating asthma airway remodeling.

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Chitosan-based biomass packaging materials are a promising material for food preservation, but their limited solubility, antioxidant capacity, UV resistance, and mechanical properties severely restrict their application. In this study, we developed a novel chitosan-based coating/packaging composite (QCTO) using quaternary ammonium salt and tannic acid (TA)-modified chitosan (QCS-TA) and oxidized chitosan (OCS). The introduction of quaternary ammonium salt and TA effectively improves the water solubility and antibacterial, antioxidant, and UV-resistant properties of chitosan. The Schiff-base bond formed between OCS and QCS-TA, along with the TA-mediated multiple interactions, conferred the prepared composite film with good mechanical properties (69.9 MPa tensile strength) and gas barrier performance to water (14.3 g·h-1·m-2) and oxygen (3.5 g·mm·m-2·h-1). Meanwhile, the prepared QCTO composites demonstrate excellent biocompatibility and safety and are applied as coatings for strawberries and bananas as well as packaging films for mushrooms. These preservation experiments demonstrated that the prepared composites are able to effectively reduce weight loss, prevent microbial growth, maintain color, and significantly prolong the shelf life of fresh products (bananas, strawberries, and mushrooms extended shelf life by 6, 5, and 6 days, respectively). Therefore, the developed QCTO coating/packaging film shows great potential for applications in the field of food preservation and packaging.

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We herein developed an effective approach for the construction of 2- or 4-(1,4-dioxan-2-yl) substituted quinazolines under mild conditions. A silver-K2S2O8 catalyzed direct CDC reaction between quinazolines and 1,4-dioxane for the synthesis of a series of 2- or 4-(1,4-dioxan-2-yl) substituted quinazoline hybrids is reported. The reaction proceeded well in water under mild conditions and showed a broad substrate scope and good functional group compatibility.

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Deep infection is the second most common complication of arthroplasty following loosening of the implant. Antibiotic-loaded bone cements (ALBCs) and high concentrations of systemic broad-spectrum antibiotics are commonly used to prevent infections following injury and surgery. However, clinical data fails to show that ALBCs are effective against deep infection, and negative side effects can result following prolonged administration of antibiotics. Additionally, the rise of multidrug resistant (MDR) bacteria provides an urgent need for alternatives to broad-spectrum antibiotics. Phage therapy, or the use of bacteriophages (viruses that infect bacteria) to target pathogenic bacteria, might offer a safe alternative to combat MDR bacteria. Application of phage therapy in the setting of deep infections requires formulation strategies that would stabilize bacteriophage against chemical and thermal stress during bone-cement polymerization, that maintain bacteriophage activity for weeks or months at physiological temperatures, and that allow for sustained release of phage to combat slow-growing, persistent bacteria. Here, we demonstrate the formulation of three phages that target diverse bacterial pathogens, which includes spray-drying of the particles for enhanced thermal stability at 37 °C and above. Additionally, we use atomic layer deposition (ALD) to coat spray-dried powders with alumina to allow for delayed release of phage from the dry formulations, and potentially protect phage against chemical damage during bone cement polymerization. Together, these findings present a strategy to formulate phages that possess thermal stability and sustained release properties for use in deep infections.

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The aim of this study is to determine the incidence and characteristics of football player injuries and illnesses during the 14th National Student Games of China. The results indicate that 32 illnesses were reported, with 17 (53%) involving the gastrointestinal system, primarily caused by environmental factors (24, 69%). The illness incidence rate was 4.3 cases per 100 players or 10.2 cases per 1,000 player-days. Regarding injuries, 122 cases were reported, yielding an overall injury incidence rate was 38.9 per 1,000 game hours, or 1.14 per game. Most injuries resulted from collisions with other players, occurring predominantly 15 minutes before the end of the first half, and 30 minutes before the end of the game. Most of the injuries were in the ankle, thigh, knee joint, and groin. In conclusion, the injury incidence of football players in the 14th National Student Games of China is high, occurring from a variety of mechanisms. Physical contact should be emphasized during training, core strength, and stability training should be enhanced alongside comprehensive injury management and prevention strategies.

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The kinetically retarded sulfur evolution reactions and notorious lithium dendrites as the major obstacles hamper the practical implementation of lithium-sulfur batteries (LSBs). Dual metal atom catalysts as a new model are expected to show higher activity by their rational coupling. Herein, the dual-atom catalyst with coupled Ni─Co atom pairs (Ni/Co-DAC) is designed successfully by programmed approaches. The Ni─Co atom pairs alter the local electron structure and optimize the coordination configuration of Ni/Co-DAC, leading to the coupling effect for promoting the interconversion of sulfur and guiding lithium plating/striping. The LSB delivers a remarkable capacity of 818 mA h g-1 at 3.0 C and a low degeneration rate of 0.053% per cycle over 500 cycles. Moreover, the LSB with a high sulfur mass loading of 6.1 mg cm-2 and lean electrolyte dosage of 6.0 µL mgS -1 shows a remarkable areal capacity of 5.7 mA h cm-2.

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AIM: Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease (ESKD). Remnant cholesterol has been investigated as a predictor for the progression of DN in type 1 diabetes mellitus patients, as well as the incidence of DN in type 2 diabetes mellitus (T2DM) patients. This study aimed to evaluate the longitudinal relationship between baseline remnant cholesterol and kidney outcomes using a Chinese T2DM with biopsy-confirmed DN cohort. METHODS: We included 334 patients with T2DM and biopsy-confirmed DN during 2010-2019 West China Hospital T2DM-DN cohort. Remnant cholesterol was defined by Martin-Hopkins equation. Patients were divided into four groups based on the median (IQR) remnant cholesterol concentration at the time of renal biopsy. The kidney outcome was defined as ESKD, which was defined as the need for chronic kidney replacement therapy or estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2. The relationship between remnant cholesterol and kidney outcome was analyzed using the Kaplan‒Meier method and Cox regression analysis. RESULTS: The mean age was 51.1 years, and 235 (70%) were men. During follow-up, a total of 121 (36.2%) patients reached ESKD. The Kaplan‒Meier analysis showed that patients in the highest quartile (quartile 4) group had lower cumulative renal survival (log-rank test, p = 0.033) and shorter median renal survival time [34.0 (26.4-41.6) vs. 55.0 (29.8-80.2) months] than patients in the lowest quartile (quartile 1) group. By univariate analysis, the high remnant cholesterol group was associated with a higher risk of progression to ESKD. Moreover, the risk of progression to ESKD in the highest quartile was still 2.857-fold (95% CI 1.305-6.257, p = 0.009) higher than that in the lowest quartile, and one-SD increase of remnant cholesterol was associated with a higher risk (HR = 1.424; 95% CI 1.075-1.886, p = 0.014) of progression to ESKD, after adjusted for confounding factors. CONCLUSIONS: High remnant cholesterol is independently associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive marker of ESKD. CLINICAL RELEVANCE: Calculated remnant cholesterol has the advantages of being economical and clinically accessible. Moreover, to our knowledge, there are no longitudinal cohort studies for investigating the risk of progression of T2DM-DN to ESKD. In our study, higher remnant cholesterol was associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive predictor of ESKD.

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Hydrogels as skin wound dressings have been extensively studied owing to their good flexibility and biocompatibility. Nevertheless, the mechanical performance, adhesive capability, antifouling and antibacterial properties of conventional hydrogels are still unsatisfactory, which hinder the application of hydrogel for cutaneous healing. Here, we developed a novel biocompatible multifunctional hydrogel with super flexible, fatigue resistant, antifouling and self-adhesive capability for effective wound healing, where naturally rigid polymers including quaternized chitosan (QCS) and Tunicate cellulose nanocrystals (TCNCs) are used as bioactive cross-linkers and reinforcers to endow the hydrogel with excellent mechanical and antibacterial property, and the synergistic contributions from the poly(acrylic acid/methacrylate anhydride dopamine/sulfobetaine methacrylate) (poly(AA/DMA/SBMA)) chains and QCS endow the hydrogel with excellent adhesive property, antioxidant, antifouling and pH-responsive sustained drug release capabilities. The optimized hydrogel exhibited high tensile strength (77.69 KPa), large tensile strain (889.9 %), large toughness (307.51KJ.m-3), high adhesive strength (35.57 KPa) and ideal compressive property. The in vivo infected full-thickness skin model demonstrated that the hydrogel with vanvomycin sustained release ability efficiently improved the granulation tissue formation, facilitating collagen deposition and reducing inflammatory expression, thus effectively accelerating wound healing. This superiorly skin-adhesive antibacterial biocompatible hydrogel appears to be a promising candidate for wound therapy.

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This study aims to assess the global prevalence of kinesiophobia and the potential influencing factors among patients with heart disease. A comprehensive search was conducted in PubMed, Embase, Web of Science, PsycINFO, and Scopus databases to identify studies reporting on the prevalence of kinesiophobia and its influencing factors in heart disease patients up to January 2024. A random-effects model was employed to aggregate prevalence rates. Heterogeneity sources were investigated through subgroup analysis, while differences in the prevalence of kinesiophobia across regions, types of heart disease, and gender were evaluated. Additionally, a qualitative analysis of the factors influencing kinesiophobia was performed. This research incorporated 15 studies from six countries, with 14 providing data on the prevalence of kinesiophobia and nine exploring its potential influencing factors. The findings indicated that the overall prevalence of kinesiophobia among heart disease patients was 61.0% (95% CI 49.4-72.6%). Subgroup analysis revealed that the prevalence in upper-middle-income countries was 71.8% (95% CI 66.2-77.4%), while it stands at 49.9% (95% CI 30.2-69.5%) in high-income countries. The prevalence rates among patients with coronary artery disease, heart failure, and atrial fibrillation were 63.2% (95% CI 45.2-81.3%), 69.2% (95% CI 57.6-80.8%), and 71.6% (95% CI 67.1-76.1%), respectively. Gender-wise, no significant difference was observed in the prevalence of kinesiophobia between men and women (52.2% vs. 51.8%). A total of 24 potential influencing factors of kinesiophobia were identified, with education level, monthly income, anxiety, and exercise self-efficacy being the most recognized. The prevalence of kinesiophobia in patients with heart disease is notably high and is influenced by a multitude of factors. Early implementation of targeted preventive measures is imperative to mitigate the incidence of kinesiophobia in this population.

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Although mangrove forests can uptake atmospheric CO2 and store carbon as organic matter called "blue carbon", it is also an important natural source of greenhouse gas methane. Methanogens are major contributors to methane and play important roles in the global carbon cycle. However, our understanding of the key microbes and metabolic pathways responsible for methanogenesis under specific substrates in mangrove sediments is still very limited. Here, we set an anaerobic incubation to evaluate the responses of methanogens in mangrove sediments from South China to the addition of diverse methanogenic substrates (H2/CO2, acetate, trimethylamine (TMA), and methanethiol (MT)) and further investigated the dynamics of the whole microbial community. Our results showed that diverse substrates stimulated methanogenic activities at different times. The stimulation of methanogenesis was more pronounced at early and late periods by the addition of methylotrophic substrates TMA and MT, respectively. The amplicon sequencing analysis showed that genus Methanococcoides was mainly responsible for TMA-utilized methanogenesis in mangrove sediment, while the multitrophic Methanococcus was most abundant in H2/CO2 and MT treatments. Apart from that, the bacteria enrichments of Syntrophotalea, Clostridium_sensu_stricto_12, Fusibacter in MT treatments might also be associated with the stimulation of methane production. In addition, the metagenomic analysis suggested that Methanosarcinaceae was also one of the key methanogens in MT treatments with different genomic information compared to that in TMA treatments. Finally, the total relative abundances of methanogenesis-related genes were also highest in TMA and MT treatments. These results will help advance our understanding of the contributions of different methanogenesis pathways and methanogens to methane emissions in mangrove sediments.

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INTRODUCTION: Identifying controllable risk factors for large-artery atherosclerosis (LAA) stroke is crucial due to its significant role as a leading cause of ischemic stroke. We aimed to validate the correlation of serum vitamin B12 with LAA stroke. METHODS: Inpatients with LAA stroke and healthy controls were retrospectively collected for a case-control study from January 2020 to May 2022. Serum vitamin B12 concentration and other blood indicators, demographic, lifestyle factors and comorbidities were investigated. Logistic regression analysis was used to identify the correlation of serum vitamin B12 concentrations with LAA stroke, meanwhile adjusted for confounding factors. RESULTS: Patients with LAA stroke had significantly lower serum vitamin B12 concentrations in comparison to those of controls. In the fully adjusted model, vitamin B12 (per 1 interquartile range increase, odds ratio [OR] = 0.84, 95 % confidence interval [CI]: 0.77-0.91), vitamin B12 < 200 pg/mL (OR=7.70, 95 %CI: 2.19-27.03) and vitamin B12 < 300 pg/mL (OR=4.19, 95 %CI: 1.82-9.66) were independently factors for LAA stroke. Furthermore, the optimal cut-off values for vitamin B12 to predict LAA stroke were 305.25 pg/mL (area under the curve [AUC] = 0.71) when unadjusted and 308.25 pg/mL when adjusted for age and sex (AUC=0.68). Lower vitamin B12 concentrations were significantly associated with male sex, smoking, older age, higher neutrophil count, higher creatinine, lower folate and higher total homocysteine. CONCLUSION: Results indicate that low concentration of serum vitamin B12 may be a strong predictor for the risk of LAA stroke.

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In this study, the effects of wheat flour treated with ball milling (BM) and maltodextrin on the oil absorption and textural characteristics of fried batter-coated cashews and almonds (BCAs) were investigated. The result showed that the crystallinity of the starch granules in wheat flour decreased after the BM treatment. Furthermore, the ΔH of the batter decreased as the BM time was elongated, but the addition of maltodextrin had no significant impact on ΔH. Both BM-treated wheat flour and maltodextrin increased the fracturability and decreased the oil content of the fried BCAs' batter. The addition of BM-treated wheat flour and maltodextrin decreased the oil content of the batter from 28.93% to 18.75% for batter-coated cashews and from 30.92% to 18.61% for batter-coated almonds. Overall, the addition of BM-treated wheat flour and maltodextrin in batter is an effective approach to decrease oil content and improve the textural quality of fried BCAs.

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BACKGROUND: Although only a few patients with severe mental disorders (SMD) can commit violent behaviour in the community, violent behaviour aggravates the stigma towards patients with SMD. Understanding the subtypes of violent behaviour may be beneficial for preventing violent behaviour among patients with SMD, but it has rarely been studied. METHODS: This longitudinal study investigated 1914 patients with SMD in the community at baseline, and the follow-up period ranged from February 2021 to August 2021. The Barratt Impulsiveness Scale Version-11, the Buss-Perry Aggression Questionnaire, the Impulsive/Premeditated Aggression Scale, the Personality Diagnostic Questionnaire and the MacArthur Community Violence Instrument were used at baseline. The Modified Overt Aggression Scale was used to assess the occurrence of violent behaviour (outcome) during the follow-up period. Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Latent class analysis was used to characterise the subtypes of patients with SMD who engaged in violent behaviour at follow-up. RESULTS: We found that 7.2% of patients with SMD presented violent behaviour within six months in the community. Younger age (OR = 0.98, 95% CI = 0.96-1.00, p = 0.016) and no economic source (OR = 1.60, 95% CI = 1.10-2.33, p = 0.014) were risk factors for violent behaviour. Patients with SMD who engaged in violent behaviour could be classified into three subtypes: one class characterised by a history of violence and impulsivity, another class characterised by high levels of aggression and motor impulsivity, and the last class characterised by median cognitive impulsivity. CONCLUSIONS: Socio-demographic factors were risk factors for violent behaviour among patients with SMD, which could eliminate the discrimination toward this group. Impulsivity played a vital role in identifying the three subtypes of patients with SMD who engaged in violent behaviour. These findings may be helpful for the development of a personalised violence risk management plan for patients with SMD who commit violent behaviour in the community.

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Objective: The uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes. To explore this, we employed human adipocytes differentiated from progenitor cells and examined their acute response to Rsg, to the adenylate-cyclase activator forskolin (Fsk), or to both simultaneously. Methods: Adipocytes generated from primary human progenitor cells were differentiated without exposure to PPARγ agonists, and treated for 3, 6 or 78 hours to Fsk, to Rsg, or to both simultaneously. Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 mediated knockout, oxygen consumption and western blotting were used to assess cellular responses. Results: UCP1 mRNA expression was induced within 3 hours of exposure to either Rsg or Fsk, indicating that Rsg's effect is independent on additional adipocyte differentiation. Although Rsg and Fsk induced distinct overall transcriptional responses, both induced genes associated with calcium metabolism, lipid droplet assembly, and mitochondrial remodeling, denoting core features of human adipocyte beiging. Unexpectedly, we found that Fsk-induced UCP1 expression was reduced by approximately 80% following CRISPR-Cas9-mediated knockout of PNPLA2 , the gene encoding the triglyceride lipase ATGL. As anticipated, ATGL knockout suppressed lipolysis; however, the associated suppression of UCP1 induction indicates that maximal cAMP-mediated UCP1 induction requires products of ATGL-catalyzed lipolysis. Supporting this, we observed that the reduction in Fsk-stimulated UCP1 induction caused by ATGL knockout was reversed by Rsg, implying that the role of lipolysis in this process is to generate natural PPARγ agonists. Conclusion: UCP1 transcription is known to be stimulated by transcription factors activated downstream of cAMP-dependent protein kinases. Here we demonstrate that UCP1 transcription can also be acutely induced through PPARγ-activation. Moreover, both pathways are activated in human adipocytes in response to cAMP, synergistically inducing UCP1 expression. The stimulation of PPARγ in response to cAMP occurs as a result of the production of natural PPARγ activating ligands through ATGL-mediated lipolysis.

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The skin stratum corneum (SC) barrier function will interfere with the absorption of topical treatment and reduce the drug's therapeutic effect on alopecia. Microneedles (MNs) can penetrate the skin barrier and deliver drugs to the dermis. Furthermore, MNs can mechanically stimulate the skin, which promotes hair growth. Thus, we designed a green and dissolvable composite microneedle made of hyaluronic acid (HA) and Bletilla striata polysaccharide (BSP) to encapsulate cholesterol-free ginsenoside Rg3 liposomes (Rg3-LPs) to avoid cholesterol metabolism-producing testosterone to inhibit hair regeneration and minimize the effect of the SC barrier on liposomes absorption. HA and BSP can enhance the mechanical strength of Rg3-MNs to ensure the transport of liposomes to the hair follicle (HF) region while causing minimal skin irritation and guaranteeing cell compatibility. In addition, HA increased hair density and was more conducive to hair regeneration. In telogen effluvium (TE) and testosterone-induced androgenetic alopecia (AGA) animals, Rg3-MNs achieved comparable efficacy to minoxidil with low-frequency treatment and the quality of regenerated hair was higher. Furthermore, quantitative characterization and transcriptome sequencing results showed that Rg3-MNs promoted hair regeneration by promoting the expression of Wnt3a and Wnt10b genes, activating the Wnt/ß-catenin pathway. Therefore, Rg3-MNs present broad prospects in the treatment of alopecia.