The effects of advanced glycation end-products on skin and potential anti-glycation strategies.

The advanced glycation end-products (AGEs) are produced through non-enzymatic glycation between reducing sugars and free amino groups, such as proteins, lipids or nucleic acids. AGEs can enter the body through daily dietary intake and can also be generated internally via normal metabolism and external stimuli. AGEs bind to cell surface receptors for AGEs, triggering oxidative stress and inflammation responses that lead to skin ageing and various diseases. Evidence shows that AGEs contribute to skin dysfunction and ageing. This review introduces the basic information, the sources, the metabolism and absorption of AGEs. We also summarise the detrimental mechanisms of AGEs to skin ageing and other chronic diseases. For the potential strategies for counteracting AGEs to skin and other organs, we summarised the pathways that could be utilised to resist glycation. Chemical and natural-derived anti-glycation approaches are overviewed. This work offers an understanding of AGEs to skin ageing and other chronic diseases and may provide perspectives for the development of anti-glycation strategies.

Nanoparticles for Augmenting Therapeutic Potential and Alleviating the Effect of Di(2-ethylhexyl) Phthalate on Gastric Cancer.

Changes in diet culture and modern lifestyle contributed to a higher incidence of gastrointestinal-related diseases, including gastritis, implicated in the pathogenesis of gastric cancer. This observation raised concerns regarding exposure to di(2-ethylhexyl) phthalate (DEHP), which is linked to adverse health effects, including reproductive and developmental problems, inflammatory response, and invasive adenocarcinoma. Research on the direct link between DEHP and gastric cancer is ongoing, and further studies are required to establish a conclusive association. In our study, extremely low concentrations of DEHP exerted significant effects on cell migration by promoting the epithelial-mesenchymal transition in gastric cancer cells. This effect was mediated by the modulation of the PI3K/AKT/mTOR and Smad2 signaling pathways. To address the DEHP challenges, our initial design of TPGS-conjugated fucoidan, delivered via pH-responsive nanoparticles, successfully demonstrated binding to the P-selectin protein. This achievement has not only enhanced the antigastric tumor efficacy but has also led to a significant reduction in the expression of malignant proteins associated with the condition. These findings underscore the promising clinical therapeutic potential of our approach.

A Parameter Reduction-Based Decision-Making Method with Interval-Valued Neutrosophic Soft Sets for the Selection of Bionic Thin-Wall Structures.

Bio-inspired thin-wall structures with excellent mechanical properties, high-energy absorption capabilities, and a desirable lightweight level have been extensively applied to the passive safety protection of transportation and aerospace. Collaboration matching and the selection of optional structures with different bionic principles considering the multiple attribute evaluation index and engineering preference information have become an urgent problem. This paper proposes a parameter reduction-based indifference threshold-based attribute ratio analysis method under an interval-valued neutrosophic soft set (IVNS-SOFT) to obtain the weight vector of an evaluation indicator system for the selection of bionic thin-wall structures, which can avoid the problem of an inadequate subjective evaluation and reduce redundant parameters. An IVNS-SOFT-based multi-attributive border approximation area comparison (MABAC) method is proposed to obtain an optimal alternative, which can quantify uncertainty explicitly and handle the uncertain and inconsistent information prevalent in the expert system. Subsequently, an application of five bio-inspired thin-wall structures is applied to demonstrate that this proposed method is valid and practical. Comparative analysis, sensitivity analysis, and discussion are conducted in this research. The results show that this study provides an effective tool for the selection of bionic thin-wall structures.

The Role of Country Image on Consumers' Willingness to Pay for Imported Beefsteak in China.

In recent years, the world has experienced conflict. When political conflicts affect consumers' emotions and alter their perceptions of a country's image, it can influence their preferences. This study deconstructs the notion of a country image into multiple dimensions and examines their impact on consumers' willingness to pay for imported beef from Australia, Brazil, and the United States. Using a rank-ordered probit model and data from a survey of 935 respondents, results show that consumers' perceptions of a country's friendliness, economy, environment, and quality all have a positive and statistically significant effect on their willingness to pay for beefsteak imported from that country. Among these dimensions of the country image, the quality is the most important, followed by the economy, friendliness, and the environment. This study also finds heterogeneity in consumer perception of friendliness towards the United States, Australia, and Brazil. This study provides valuable insights for assessing the real losses resulting from a deteriorating international environment and suggests policies to enhance competitiveness in the food market.

Identification of structural origins of complex charge heterogeneity in therapeutic ACE2Fc fusion protein facilitated by free-flow isoelectric focusing.

Fc Fusion protein represents a versatile molecular platform with considerable potential as protein therapeutics of which the charge heterogeneity should be well characterized according to regulatory guidelines. Angiotensin-converting enzyme 2 Fc fusion protein (ACE2Fc) has been investigated as a potential neutralizing agent to various coronaviruses, including the lingering SARS-CoV-2, as this coronavirus must bind to ACE2 to allow for its entry into host cells. ACE2Fc, an investigational new drug developed by Henlius (Shanghai China), has passed the Phase I clinical trial, but its huge amount of charge isoforms and complicated charge heterogeneity posed a challenge to charge variant investigation in pharmaceutical development. We employed offline free-flow isoelectric focusing (FF-IEF) fractionation, followed by detailed characterization of enriched ACE2Fc fractions, to unveil the structural origins of charge heterogeneity in ACE2Fc expressed by recombinant CHO cells. We adopted a well-tuned 3-component separation medium for ACE2Fc fractionation, the highest allowable voltage to maximize the FF-IEF separation window and a mild Protein A elution method for preservation of protein structural integrity. Through peptide mapping and other characterizations, we revealed that the intricate profiles of ACE2Fc charge heterogeneity are mainly caused by highly sialylated multi-antenna N-glycosylation. In addition, based on fraction characterization and in silico glycoprotein model analysis, we discovered that the large acidic glycans at N36, N73, and N305 of ACE2Fc were able to decrease the binding activity towards Spike (S) protein of SARS-CoV-2. Our study exemplifies the value of FF-IEF in highly complex fusion protein characterization and revealed a quantitative sialylation-activity relationship in ACE2Fc.

BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir.

Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.

Microwave-assisted solid-state pretreatment for fabrication of hemp fibres using ethanolamine at low temperature.

Conventional methods faced challenges in pretreating natural cellulose fibres due to their high energy consumption and large wastewater drainage. This research devised an efficient solid-state pretreatment method for pretreating hemp fibres using ethanolamine (ETA) assisted by microwave (MW) heating. This method produced a notable removal rate of lignin (85.4 %) with the highest cellulose content (83.0 %) at a high solid content (30 %) and low temperature (70 °C). Both FT-IR and XRD analyses indicated that the pretreatment did not alter the structure of cellulose within the hemp fibres but increased crystallinity as the CrI increased from 84 % in raw hemp fibre to 89 % in pretreated fibre. As a result, it produced hemp fibres with impressive fineness (4.6 dtex) and breaking strength (3.81 cN/dtex), meeting the requirement of textile fibre. In addition, an improvement in glucose concentration (15.6 %) was observed in enzymatic hydrolysis of the MW pretreated hemp fibres compared to the fibres pretreated without MW. Furthermore, the FT-IR and NMR data confirmed that the amination of lignin occurred even at low temperature, which contributed to the high lignin removal rate. Thus, this study presents a potentially effective energy-saving, and environmentally sustainable solid-state method for pretreating hemp fibres.

Characterization workflow for fragments detected in capillary electrophoresis sodium dodecyl sulfate analysis of therapeutic monoclonal antibodies.

Product-related fragments in monoclonal antibodies (mAbs) can have a significant impact on the efficacy and safety of the product. Capillary electrophoresis sodium dodecyl sulfate (CE-SDS) is a commonly used method for fragment quantification, but it has challenges in peak identification due to the inability to enrich components and the incompatibility of SDS with mass spectrometry (MS). This article presents a workflow for identifying peaks in CE-SDS analysis. The workflow involves comparing the migration time of peaks with that of standards and utilizing MS analysis to identify fragments. By employing this innovative systematic workflow, we successfully identified the CE-SDS impurity peaks of seven antibody products. Among them, four products exhibited characteristic fragments associated with disulfide bonds (light chain [LC], heavy-light [HL] chain, heavy-heavy [HH] chain, and HH-LC) and a glycosylation-related fragment non-glycosylated heavy chain. Additionally, one product showed a fragment formed by the connection of HC_C130 and HC_C130 , which is associated with a thioether bond. Furthermore, two other products displayed amino acid backbone breakage, with one product showing clipping at the HC region of A233 -G285 and the other product showing clipping at the HC regions of A97 -S158 and N342 -T366 . This workflow can be applied in early drug research, process development, or during the biologics license application stage to characterize fragments in therapeutic mAbs analyzed by CE-SDS.

An application of BWM for risk control in reverse logistics of medical waste.

The pollution posed by medical waste complicate the procedures of medical waste logistics (MWL), and the increasingly frequent occurrence of public health emergencies has magnified the risks posed by it. In this study, the authors established an index of the factors influencing the risks posed by MWL along five dimensions: the logistics business, emergency capacity, equipment, personnel, and management. The best-worst case method was used to identify the critical risk-related factors and rank them by importance. Following this, we assessed the risk posed by MWL in four major cities in China as an example and propose the corresponding measures of risk control. The results showed that the linking of business processes was the most important factor influencing the risk posed by MWL. The other critical risk-related factors included the location of the storage site, the capacity for emergency transportation, measures to manage emergencies, and the safety of packaging. Of the cities considered, Beijing was found to be a high-risk city, and its MWL needed to be improved as soon as possible in light of the relevant critical risks. Shanghai, Guangzhou, and Shenzhen were evaluated as general-risk cities, which meant that the risks of MWL were not a priority in these areas, and the other goals of urban development should be comprehensively considered during the long-term planning for MWL in these municipalities.

A Novel Splicing Mutation Leading to Wiskott-Aldrich Syndrome from a Family.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disease characterized by clinical symptoms such as eczema, thrombocytopenia with small platelets, immune deficiency, prone to autoimmune diseases, and malignant tumors. This disease is caused by mutations of the WAS gene encoding WASprotein (WASP). The locus and type of mutations of the WAS gene and the expression quantity of WASP were strongly correlated with the clinical manifestations of patients. We found a novel mutation in the WAS gene (c.931 + 5G > C), which affected splicing to produce three abnormal mRNA, resulting in an abnormally truncated WASP. This mutation led to a reduction but not the elimination of the normal WASP population, resulting in causes X-linked thrombocytopenia (XLT) with mild clinical manifestations. Our findings revealed the pathogenic mechanism of this mutation.

Meta-analysis of risk factors for posttraumatic stress disorder in myocardial infarction.

BACKGROUND: The aim of this study was to identify the risk factors for posttraumatic stress disorder in patients with myocardial infarction. METHODS: Cohort, case-control, and cross-sectional studies on posttraumatic stress disorder (PTSD) in patients with myocardial infarction were searched from PubMed, Embase, Cochrane Library, Web of Science, China Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and Technology Journal database. The Newcastle-Ottawa Quality Assessment Scale was used to score the quality of the included literature in the cohort and case-control studies, and the cross-sectional studies were scored using the American Agency for Health Care Quality and Research cross-sectional study quality evaluation criteria. The literature was screened independently by 2 researchers, and if there was no consensus, the inclusion was decided by a third party. The extraction content included first author, publication year, sample size, PTSD assessment tool, PTSD assessment time, PTSD incidence, influencing factors, and study type. Meta-analysis of data was performed using Stata17.0 software. RESULTS: Ten studies were included, including 2 cohort studies, 7 cross-sectional studies, and 1 case-control study, with a total sample size of 2371 patients, including 26 influencing factors. The results of meta-analysis showed that the prevalence of PTSD in patients with myocardial infarction was 21.2%. Statistically significant influencing factors were gender (odd ratio [OR] = 3.124), neuroticism score (OR = 2.069), and age (OR = 0.913). CONCLUSIONS: The prevalence of PTSD in patients with myocardial infarction in China is higher than that in other countries. Female and neurotic personality are risk factors for developing PTSD in patients with myocardial infarction, and old age is protective factor for developing PTSD in patients with myocardial infarction. Targeted measures should be taken to prevent and reduce the occurrence and development of PTSD in patients with myocardial infarction in the future.

Time-delay control scheme with adaptive fixed-time convergent super-twisting fractional-order nonsingular terminal sliding mode for piezoelectric displacement amplifier.

Piezoelectric displacement amplifiers (PDAs) have been widely used in precision positioning fields. However, the inherent hysteresis and creep nonlinear effect of piezoelectric actuators (PEAs) and time-varying lumped disturbances bring extreme challenges to the precise motion control of PDAs. Although various control schemes based on PEAs have been developed and have shown significant results. However, due to the high sensitivity of precision positioning to environmental variations, the development and identification of accurate models and the control timeliness often become obstacles in engineering. To realize precise motion control of PDAs under complex lumped disturbances, a new time-delay control scheme (AFSTA-FONTSM) using an adaptive fixed-time convergent super-twisting algorithm (AFSTA) and a fractional-order nonsingular terminal sliding mode (FONTSM) is proposed. Specifically, the time-delay information obtained by time-delay estimation technology is used to estimate the lumped dynamic characteristic of the system, thus establishing a simple control framework without a system dynamic model. FONSTM is constructed as a sliding mode manifold, and satisfactory error dynamic characteristic is obtained. A new AFSTA is designed as the reaching law in the sliding mode phase. AFSTA has fixed-time convergence when the upper bound of lumped disturbances exists, which ensures the control timeliness. Benefiting from the newly designed adaptive algorithm, the upper bound value of lumped disturbances is no longer needed to determine the control gains, which effectively prevents overestimation of the control gains. Correspondingly, the convergence time of AFSTA is estimated, and the stability of the closed-loop system is analyzed by the Lyapunov theory. Three existing time-delay control schemes, namely MSTA-FONTSM, AMSTA-FONTSM, and ASTA-FONTSM are selected, and four scenes are designed for comparative experiments. The experimental results show that MSTA-FONTSM has the worst control performance among the four control schemes. For the step, and continuous cosine trajectories with periods of T = 1 s and T = 2 s, the root-mean-square error of the proposed AFSTA-FONTSM is reduced by 56.86%, 54.03%, and 50.24% compared with MSTA-FONTSM. For disturbance experiments under different loads, the control performance of the proposed AFSTA-FONTSM is still superior to the other three control schemes without load.

Associations Between Serum TNF-α, IL-6, hs-CRP and GLMD in Obese Children and Adolescents: A Cross-Sectional Study.

Purpose: To explore the relationships between serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) levels and glucolipid metabolism disorders (GLMD) in obese children and adolescents. Patients and Methods: In this cross-sectional study, 105 obese children and adolescents were selected for the detection of TNF-α, IL-6, hs-CRP, and glycolipid metabolism indicators. All participants were divided into elevated TNF-α group (≥8.1 pg/mL; n=49) and normal TNF-α group (<8.1 pg/mL; n=56), elevated IL-6 group (≥5.9 pg/mL; n=13) and normal IL-6 group (<5.9 pg/mL; n=92), elevated hs-CRP group (≥3.0 mg/L; n=44) and normal hs-CRP group (<3.0 mg/L; n=61), respectively. Results: Low-density lipoprotein cholesterol (LDL-C) in the elevated TNF-α group was higher than that in the normal TNF-α group (P=0.010). TNF-α was positively correlated with LDL-C (P=0.005). Fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR) in the elevated IL-6 group were higher than those in the normal IL-6 group (all for P <0.05), while high-density lipoprotein cholesterol (HDL-C) in the elevated IL-6 group was lower than that in the normal IL-6 group (P<0.001). IL-6 was positively correlated with FINS, 2-hour postprandial insulin, HOMA-IR and triglyceride (all for P <0.01), while was negatively correlated with HDL-C (P=0.006). Moreover, hs-CRP was positively correlated with FINS and HOMA-IR (all for P <0.05). Conclusion: There may be correlations between serum TNF-α, IL-6, hs-CRP levels and GLMD in obese children and adolescents. Attention should be paid to monitoring serum inflammatory factors and preventing their elevation in obese children and adolescents, thus reducing the occurrence of GLMD.

Arabidopsis PDE1 confers phosphate-deficiency tolerance in primary root growth.

KEY MESSAGE: PDE1 acts as a mediator of primary root growth in response to Pi deficiency. Phosphorus is commonly considered as a limiting nutrient for plant growth, which is mainly due to the immobility and uneven distribution of phosphate (Pi) in soils so that available Pi is not adequate in the rhizosphere. Although various mediators have been identified in Pi sensing and response, more details need to be uncovered in plant Pi-deficiency tolerance. Here, we isolated a mutant, termed pde1 (phosphate-deficiency sensitive 1), showing the hypersensitive Pi-deficiency-induced growth inhibition of primary roots. PDE1 encodes a hydroxyphenylpyruvate reductase with rare activity in vitro and repressed by Pi deficiency. Histochemical analysis displayed that Pi-deprived pde1 accumulated more Fe and reactive oxygen species (ROS) in primary roots than the wild type (WT). Addition of ferrozine, a Fe2+ chelator, or a ROS scavenger (e.g., thiourea and potassium iodide), alleviated the sensitivity of Pi-deficiency in pde1 primary roots. By contrast, pde1 showed reduced cotyledon expansion rate with treatment of H2O2 compared to WT. Taken together, these results suggested that PDE1 is responsible for regulating primary root growth in response to Pi deficiency, which is associated with ROS.

CaRH57, a RNA helicase, contributes pepper tolerance to heat stress.

RNA helicases (RHs) are required for most aspects of RNA metabolism and play an important role in plant stress tolerance. Heat stress (HS) causes the deleterious effects on plant cells, such as membrane disruption and protein misfolding, which results in the inhibition of plant growth and development. In this study, CaRH57 was identified from pepper (Capsicum annuum) and encodes a DEAD-box RH. CaRH57 was induced by HS, and overexpression of CaRH57 in Atrh57-1 rescued the glucose-sensitive phenotype of Atrh57-1, suggesting the functional replacement of CaRH57 to AtRH57. The nucleolus-localized CaRH57 possessed a RH activity in vitro. CaRH57 knockdown impaired pepper heat tolerance, showing severe necrosis and enhanced ROS accumulation in the region of the shoot tip. Additionally, accumulation of aberrant-spliced CaHSFA1d and CaHSFA9d was enhanced, and the corresponding mature mRNA levels were reduced in the TRV2 (Tobacco rattle virus)-CaRH57-infected plants compared with the control plants under HS. Overall, these results suggested that CaRH57 acted as a RH to confer pepper heat tolerance and was required for the proper pre-mRNA splicing of some HS-related genes.

Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation.

BACKGROUND: High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation. RESULTS: Murine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice. CONCLUSIONS: Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.

An organic-inorganic hybrid material [Me3NCH2CH2F]FeBr4 exhibits three-step SHG on/off.

A novel solid-state second harmonic generation (SHG) organic-inorganic hybrid switch [Me3NCH2CH2F]FeBr4 (1) exhibits genuine three-step "on-off-on-off" SHG-switching above-room temperature, which has potential applications in multi-step optical devices.

The physiology of drought stress in two grapevine cultivars: Photosynthesis, antioxidant system, and osmotic regulation responses.

Drought stress impedes viticultural plant growth and development by modifying various metabolic pathways. However, the regulatory network response underlying drought stress is not yet clear. In this study, the leaves and roots of "Shine Muscat" ("SM," Vitis labruscana × Vitis vinifera) and "Thompson Seedless" ("TS," V. vinifera L. cv.) were subjected to drought stress to study the regulatory network used by drought stress. Morphophysiological results showed that the malondialdehyde content after 28 days of drought stress increased more significantly in "TS" than "SM." Furthermore, the multiomics analysis studies showed that a total of 3036-6714 differentially expressed genes and 379-385 differentially abundant metabolites were identified in "SM" and "TS" grapevine cultivars under drought stress. Furthermore, the retained intron was the major form of differential alternative splicing event under drought stress. The photosynthesis pathway, antioxidant system, plant hormone signal transduction, and osmotic adjustment were the primary response systems in the two grapevine cultivars under drought stress. We have identified GRIK1, RFS2, and LKR/SDH as the hub genes in the coexpression network of drought stress. In addition, the difference in the accumulation of pheophorbide-a reveals different drought resistance mechanisms in the two grapevine cultivars. Our study explained the difference in drought response between cultivars and tissues and identified drought stress-responsive genes, which provides reference data for further understanding the regulatory network of drought tolerance in grapevine.

Projections of mortality risk attributable to short-term exposure to landscape fire smoke in China, 2021-2100: a health impact assessment study.

BACKGROUND: Landscape fire smoke, including smoke from all vegetation burning in natural and cultural landscapes, remains a threat to the health of the population. However, the future health impacts of landscape fire smoke in China have not been sufficiently investigated. We aimed to estimate the mortality risk attributable to landscape fire-related PM2·5 under different scenarios. METHODS: In this health impact assessment study, we used the projected population and landscape fire-related PM2·5 concentration to calculate deaths attributable to short-term exposure to landscape fire smoke PM2·5 during 2021-2100. We did the analysis in three defined future periods: 2021-40 (near term), 2051-70 (medium term), and 2081-2100 (long term), with 1986-2005 as the historical period. We used fire-specific short-term epidemiological functions with the regional parameters specific to China. We assessed the mortality risks of landscape fire-related smoke and further identified their spatiotemporal distribution under two shared socioeconomic pathway (SSP) scenarios: SSP1-2·6, an optimistic scenario with strict control of carbon emissions, and SSP2-4·5, an intermediate scenario with weaker control of carbon emissions. FINDINGS: The national mortality rate attributable to short-term exposure (ie, a few days) to landscape fire-related PM2·5 is projected to increase compared with historical values. The national deaths attributable to landscape fire smoke PM2·5 could peak in 2021-40, with increases of 28·10% (95% CI 14·08-53·11) under the SSP1-2·6 scenario and 37·38% (14·08-53·11) under the SSP2-4·5 scenario. Deaths would then decrease slightly during 2051-70 and 2081-2100. The provinces with the highest projected number of deaths attributable to landscape fire-related PM2·5 are located in east and south-central China, and those with the largest percentage increase in projected deaths are located in northwest and southwest China. INTERPRETATION: Our results suggest that global warming could increase the contribution of landscape fire smoke to the total PM2·5 concentration, leading to an increase in the mortality rate in China. Our findings could help policy makers implement effective interventions in hotspot areas during different periods to reduce the impact of landscape fire smoke on human health. FUNDING: The National Natural Science Foundation of China, National Key Research and Development Program of China, and the Wellcome Trust.

Hydroxy-α-sanshool from the fruits of Zanthoxylum bungeanum Maxim. promotes browning of white fat by activating TRPV1 to induce PPAR-γ deacetylation.

BACKGROUND: Accumulating evidence suggested increasing energy expenditure is a feasible strategy for combating obesity, and browning of white adipose tissue (WAT) to promote thermogenesis might be one of the attractive ways. Hydroxy-α-sanshool (HAS), a natural amide alkaloid extracted from the fruits of Zanthoxylum bungeanum Maxim, possesses lots of benefits in lipid metabolism regulation. METHODS: The anti-obesity effect of HAS was investigated by establishing an animal model of obesity and a 3T3-L1 differentiation cell model. Effects of HAS on the whole-body fat and liver of obese mice, and the role of HAS in inducing browning of white fat were studied by Micro CT, Metabolic cage detection, Cell mitochondrial pressure detection, transmission electron microscopy and cold exposure assays. Furthermore, the Real-time PCR (qPCR), digital PCR (dPCR), western blot, Co-immunoprecipitation (Co-IP), molecular docking, drug affinity responsive target stability (DARTS), Cellular thermal shift assay (CETSA) and other methods were used to investigate the target and mechanisms of HAS. RESULTS: We found that treatment with HAS helped mice combat obesity caused by a high fat diet (HFD) and improve metabolic characteristics. In addition, our results suggested that the anti-obesity effect of HAS is related to increase energy consumption and thermogenesis via induction of browning of WAT. The further investigations uncovered that HAS can up-regulate UCP-1 expression, increase mitochondria number, and elevate the cellular oxygen consumption rates (OCRs) of white adipocytes. Importantly, the results indicated that browning effects of HAS is closely associated with SIRT1-dependent PPAR-γ deacetylation through activating the TRPV1/AMPK pathway, and TRPV1 is the potential drug target of HAS for the browning effects of WAT. CONCLUSIONS: Our results suggested the HAS can promote browning of WAT via regulating AMPK/SIRT-1/PPARγ signaling, and the potential drug target of HAS is the membrane receptor of TRPV1.