Catalytic and Base-free Suzuki-type α-Arylation of Cyclic 1,3-Dicarbonyls via a Cyclic Iodonium Ylide Strategy.

To date, it remains challenging to achieve a general and catalytic α-arylation of cyclic 1,3-dicarbonyls, particularly ubiquitous heteroaromatic ones. In most cases, the preparation of their medically significant arylated derivatives requires multistep synthetic sequences. Herein, we introduce a new, convenient strategy involving the conversion of cyclic 1,3-dicarbonyls to cyclic iodonium ylides (CIYs), followed by rhodium-catalyzed α-arylation with arylboronic reagents via carbene coupling. This approach is mild, operationally simple, base-free, biocompatible, and exhibits broad substrate scope (>100 examples), especially with respect to various heteroaromatic 1,3-dicarbonyls and ortho-substituted or base-sensitive arylboronic acids. Importantly, owing to the excellent compatibility with various arylboronic acids or boronate esters (ArBpin, ArBneop, or ArBF3K), this method allows the late-stage installation of heterocyclic 1,3-dicarbonyl motifs in highly complex settings. The utility of this transformation is further demonstrated through significantly simplifying the synthesis of several bioactive molecules and natural products.

Methamphetamine induces cardiomyopathy through GATA4/NF-κB/SASP axis-mediated cellular senescence.

With the world pandemic of methamphetamine (METH), METH-associated cardiomyopathy (MAC) has become a widespread epidemic and is also recognized as a cause of heart failure in young people. The mechanism of occurrence and development of MAC is not clear. In this study, firstly, the animal model was evaluated by echocardiography and myocardial pathological staining. The results revealed that the animal model exhibited cardiac injury consistent with clinical alterations of MAC, and the mice developed cardiac hypertrophy and fibrosis remodeling, which led to systolic dysfunction and left ventricular ejection fraction (%LVEF) < 40%. The expression of cellular senescence marker proteins (p16 and p21) and senescence-associated secretory phenotype (SASP) was significantly increased in mouse myocardial tissue. Secondly, mRNA sequencing analysis of cardiac tissues revealed the key molecule GATA4, and Western blot, qPCR and immunofluorescence results showed that the expression level of GATA4 was significantly increased after METH exposure. Finally, knockdown of GATA4 expression in H9C2 cells in vitro significantly attenuated METH-induced cardiomyocyte senescence. Consequently, METH causes cardiomyopathy through cellular senescence mediated by the GATA4/NF-κB/SASP axis, which is a feasible target for the treatment of MAC.

Single-cell transcriptome analysis reveals liver injury induced by glyphosate in mice.

BACKGROUND: Glyphosate (GLY), as the active ingredient of the most widely used herbicide worldwide, is commonly detected in the environment and living organisms, including humans. Its toxicity and carcinogenicity in mammals remain controversial. Several studies have demonstrated the hepatotoxicity of GLY; however, the underlying cellular and molecular mechanisms are still largely unknown. METHODS: Using single-cell RNA sequencing (scRNA-seq), immunofluorescent staining, and in vivo animal studies, we analyzed the liver tissues from untreated and GLY-treated mice. RESULTS: We generated the first scRNA-seq atlas of GLY-exposed mouse liver. GLY induced varied cell composition, shared or cell-type-specific transcriptional alterations, and dysregulated cell-cell communication and thus exerted hepatotoxicity effects. The oxidative stress and inflammatory response were commonly upregulated in several cell types. We also observed activation and upregulated phagocytosis in macrophages, as well as proliferation and extracellular matrix overproduction in hepatic stellate cells. CONCLUSIONS: Our study provides a comprehensive single-cell transcriptional picture of the toxic effect of GLY in the liver, which offers novel insights into the molecular mechanisms of the GLY-associated hepatotoxicity.

Evaluating the efficiency of primary health care institutions in China: an improved three-stage data envelopment analysis approach.

BACKGROUND: Primary health care (PHC) institutions are key to realizing the main functions of the health care system. Since the new health care reform in 2009, the Chinese government has invested heavily in PHC institutions and launched favorable initiatives to improve the efficiency of such institutions. This study is designed to gauge the efficiency of PHC institutions by using 2012-2020 panel data covering 31 provinces in China. METHODS: This study applied an improved three-stage data envelopment analysis (DEA) model to evaluate the efficiency of PHC institutions in China. Unlike the traditional three-stage DEA model, the input-oriented global super-efficiency slack-based measurement (SBM) DEA model is used to calculate the efficiency in the first and third stages of the improved three-stage DEA model, which not only allows the effects of environmental factors and random noise to be taken into account but also deal with the problem of slack, super-efficiency and the comparability of interperiod efficiency values throughout the efficiency measurement. RESULTS: The results show that the efficiency of PHC institutions has been overestimated due to the impact of external environmental factors and random noise. From 2012 to 2020, the efficiency of PHC institutions displayed a downward trend. Moreover, there are significant differences in the efficiency of PHC institutions between regions, with the lowest efficiency being found in the northeast region. The efficiency of PHC institutions is significantly affected by residents' annual average income, per capita GDP, population density, the percentage of the population aged 0-14, the percentage of the population aged 65 and older, the number of people with a college education and above per 100,000 residents, and the proportion of the urban population. CONCLUSIONS: Substantial investment in PHC institutions has not led to the expected efficiency gains. Therefore, more effective measures should be taken to improve the efficiency of PHC institutions in China based on local conditions. This study provides a new analytical approach to calculating the efficiency of PHC institutions, and this approach can be applied to efficiency evaluation either in other fields or in other countries.

Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.

Reduction of air pollutants and associated mortality during and after the COVID-19 lockdown in China: Impacts and implications.

Although strict lockdown measurements implemented during the COVID-19 pandemic have dramatically reduced the anthropogenic-based emissions, changes in air quality and its health impacts remain unclear in China. We comprehensively described air pollution during and after the lockdown periods in 2020 compared with 2018-2019, and estimated the mortality burden indicated by the number of deaths and years of life lost (YLL) related to the air pollution changes. The mean air quality index (AQI), PM10, PM2.5, NO2, SO2 and CO concentrations during the lockdown across China declined by 18.2 (21.2%), 27.0 µg/m3 (28.9%), 10.5 µg/m3 (18.3%), 8.4 µg/m3 (44.2%), 13.1 µg/m3 (38.8%), and 0.3 mg/m3 (27.3%) respectively, when compared to the same periods during 2018-2019. We observed an increase in O3 concentration during the lockdown by 5.5 µg/m3 (10.4%), and a slight decrease after the lockdown by 3.4 µg/m3 (4.4%). As a result, there were 51.3 (95%CI: 32.2, 70.1) thousand fewer premature deaths (16.2 thousand during and 35.1 thousand after the lockdown), and 1066.8 (95%CI: 668.7, 1456.8) thousand fewer YLLs (343.3 thousand during and 723.5 thousand after the lockdown) than these in 2018-2019. Our findings suggest that the COVID-19 lockdown has caused substantial decreases in air pollutants except for O3, and that substantial human health benefits can be achieved when strict control measures for air pollution are taken to reduce emissions from vehicles and industries. Stricter tailored policy solutions of air pollution are urgently needed in China and other countries, especially in well-developed industrial regions, such as upgrading industry structure and promoting green transportation.

The interplay of haze characteristics on mortality in the Pearl River Delta of China.

To estimate the mortality risk from haze and the modifying effects by three characteristics of haze (intensity, duration and timing), data on haze and mortality in the Pearl River Delta region from 2013 to 2016 were collected. We first estimated mortality risk during haze days compared with non-haze days. Then we classified haze into several categories by considering one or any two of the three haze characteristics together, and further calculated the mortality risks separately. The mortality risk increased 5.0% (95% confidence intervals (CI): 3.1%-6.9%) during hazy days compared with non-haze days, with larger effect for the elderly ≥ 85 years old (Excess risk (ER): 8.7%, 95% CI: 3.9%-13.6%) than other age groups. Mortality risk increased in longer haze (ER: 4.4%, 95% CI: 2.9%-6.0%) compared with shorter haze (ER: 1.9%, 95% CI: 0.7%-3.2%). The greatest effect of any two of haze characteristics was observed when haze was intense and long (ER: 4.8%, 95% CI: 3.0%-6.6%). Our study indicates that haze significantly increased mortality risk in the Pearl River Delta. The health effects of haze may be under-estimated when using a single air pollutant concentration during haze periods to assess health risk of haze events. The haze intensity, duration, and time of occurrence should be accounted for in appropriate risk assessment of haze.

Associations of maternal ozone exposures during pregnancy with maternal blood pressure and risk of hypertensive disorders of pregnancy: A birth cohort study in Guangzhou, China.

Although studies have assessed the associations of maternal exposure to ozone (O3) during pregnancy with blood pressure and the risk of hypertensive disorders of pregnancy (HDP), the results were inconsistent. Furthermore, no studies have been conducted in China where the ambient O3 concentration continuedly increased. The present study aimed to estimate the effects of maternal exposure to O3 during pregnancy on the HDP risk, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP). All participants of pregnant women were selected from the prospective birth cohort study on Prenatal Environments and Offspring Health conducted in Guangzhou, China. A spatiotemporal land-use-regression model was used to estimate individual monthly air pollution exposure from three months before pregnancy to childbirth date. Information on HDP, SBP, DBP and PP was obtained from maternal medical records. A Logistic regression model and a mixed linear model were used to estimate the associations of maternal exposure to O3 with the risk of HDP and blood pressure (SBP, DBP and PP), respectively. We found significant associations of maternal exposure to O3 during the third (OR = 1.31, 95%CI: 1.07, 1.60) and the second month (OR = 1.25, 95%CI: 1.02, 1.51) before pregnancy with the risk of HDP. Observed significantly positive associations of O3 exposures with SBP, DBP and PP during the two months before pregnancy and during the early pregnancy. The peak effects of O3 exposure on SBP, DBP and PP were respectively observed during the second month of pregnancy (ß = 1.07  mmHg, 95%CI: 0.84, 1.31  mmHg), the first month before pregnancy (ß = 0.40  mmHg, 95%CI: 0.21, 0.50  mmHg) and the second month of pregnancy (ß = 0.78  mmHg, 95%CI: 0.59, 0.97  mmHg). Our results suggest that maternal exposure to O3 were positively associated with blood pressure and the risk of HDP, and the period from three months before pregnancy to the first trimester might be the critical exposure window.

The association between multimorbidity and health-related quality of life: a cross-sectional survey among community middle-aged and elderly residents in southern China.

BACKGROUND: Multimorbidity is common among the middle-aged and elderly residents. And it is associated to the reduction of health-related quality of life (HRQoL), including physical and psychological dimensions. However, there are few studies that have paid attention to the HRQoL of residents with multimorbidity in China. Therefore, this study aims to investigate the relationships between different multimorbidity patterns and HRQoL among middle-aged and elderly adults in China. METHODS: Based on a cross-sectional survey, the information regarding 18,137 adults, who were at least 45 years of age, was collected through interviews. Self-perceived HRQoL was assessed with the EQ-5D-3 L instrument, and the EQ-5D-3 L index score was calculated using the Chinese EQ-5D-3 L value set. The Tobit regression was used to explore the impacts of multimorbidity groups on HRQoL. RESULTS: Of 18,137 respondents, more than a fifth (3773,20.8%) of people had multimorbidity. Mean (SD) of EQ-5D index and VAS values were 0.95(0.14) and 76.02(13.66), respectively. Significant correlations were found between a lower HRQoL and increasing numbers of chronic conditions (P < 0.001). Most of chronic diseases co-occurred frequently, and the association between hypertension and diabetes mellitus was the strongest (adjusted OR = 3.82). The most prevalent disease is hypertension (5052,27.9%), and the most prevalent chronic diseases pair is hypertension and diabetes mellitus (841,4.6%). Among those chronic diseases with high prevalence, the effects on HRQoL ranged from chronic pain to hypertension (adjust b = - 0.036 to - 0.008). In the common multimorbidity patterns, co-occurrence of chronic pain and bone disease (adjust b = - 0.039) had the greatest impact on HRQoL. CONCLUSIONS: The HRQoL of middle-aged and elderly adults declines by multimorbidity. More attention should be paid to the HRQoL of residents with multimorbidity in China. The effect of different multimorbidity patterns on HRQoL is not simply added by two diseases, but changes by the different combination. Identifying different multimorbidity patterns of residents can provide more targeted measures to improve the HRQoL.

Morbidity burden of respiratory diseases attributable to ambient temperature: a case study in a subtropical city in China.

BACKGROUND: There are significant associations between ambient temperature and respiratory disease mortality. However, few studies have assessed the morbidity burdens of various respiratory diseases that are attributable to different temperature ranges in subtropical regions. METHODS: Daily outpatient visits, weather variables, and air pollution data were collected from January 2013 to August 2017 in a hospital in Dongguan city. A standard time series quasi-Poisson regression with a distributed lag non-linear model (DLNM) was applied to estimate the associations between daily mean temperature and morbidity for total respiratory diseases, bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma. Attributable fractions were then calculated to quantify disease burden relative to different temperature components. Finally, we conducted stratified analysis by age group. RESULTS: Both low and high temperatures were associated with an increased risk of morbidity secondary to respiratory diseases. Compared with the optimum temperature, the accumulated relative risk (RR) during the seven lag days was 1.13 with a 95% confidence interval (CI) of 1.01-1.26 for extreme heat and 1.02 (95% CI: 0.99-1.05) for extreme cold. Heat-related respiratory morbidity risk was higher than cold-related risk for the total population, but an opposite result was observed for the elderly. About 8.4% (95% CI: 2.8-13.3%) of respiratory morbidity was attributable to non-optimal temperatures, and moderate heat was responsible for most of the excess respiratory morbidity (7.5, 95% CI: 2.4-12.2%). CONCLUSIONS: We found that exposure to non-optimal temperatures increased the risk of respiratory morbidity in subtropical region, and moderate heat contributed to most of the temperature-related respiratory morbidities. This indicates a need for further examination of moderate, rather than extreme, heat in subtropical region.

Associations between objectively assessed physical fitness levels and sleep quality in community-dwelling elderly people in South China.

PURPOSE: The aim of this study was to explore associations between objectively assessed physical fitness levels and sleep quality in community-dwelling elderly people in South China. METHODS: One thousand one hundred thirty-six (504 males and 632 females) community-dwelling adults aged ≥ 50 years old in Dongguan City, South China, were included in the cross-sectional study. All the participants were asked to complete all prepared multi-instrument questionnaire, including the Pittsburgh Sleep Quality Index (Chinese version), for the assessment of the sleep quality and information regarding socio-demographic characteristics, lifestyle, and physical health data. Physical fitness was measured by grip strength, one-leg standing test (OLST) with eyes open, back scratch test, and the forced vital capacity (FVC). RESULTS: The percentage of poor sleep quality among elderly people (≥ 50 years old) was up to 18.2%. Lower FVC was associated with the poorer sleep quality (adjusted OR = 0.74 per SD increase; P = 0.009), and participants with lower performance in back scratch test were more likely to suffer poor sleep quality (adjusted OR = 1.17 per SD increase; P = 0.035). The independent contribution of physical fitness tests results on the risk of poor sleep quality was 22.1%. CONCLUSIONS: Our results indicated that sleep quality was strongly associated with physical fitness among community-dwelling elderly people; the lower of the physical fitness predicted poorer sleep quality.

Ephrin type-B receptor 4 is an essential mediator in drug-resistance of acute myeloid leukemia cells to Adriamycin.

OBJECTIVE: Ephrin type-B receptor 4 (EphB4) plays an important role in human carcinogenesis. This study investigated the effects of EphB4 expression in drug-resistance of acute myeloid leukemia cells to Adriamycin using myeloid leukemia cell lines with different degrees of differentiation, including an Adriamycin-resistant HL60 cell line as a model. The data showed that the EphB4 protein was differentially expressed in these myeloid leukemia cell lines, which expression was associated with sensitivity of myeloid leukemia cells to Adriamycin treatment in vitro. Furthermore, EphB4 protein stimulated by EphrinB2-Fc sensitized HL60/ADM cells to Adriamycin in a dose-dependent manner. Specifically, pre-incubation of HL60/ADM with 4 µg/ml EphrinB2-Fc protein for 30 min significantly sensitized tumor cell to Adriamycin treatment by reduction of tumor cell viability and induction of apoptosis (p<0.001), while there was no significant change in other groups (p>0.05). These data provided a proof-of-principle for further development of the EphB4-based strategy for treatment of drug-resistant leukemia.

Development of an immunochromatographic assay as a screen for detection of total phthalate acid esters in cooking oil.

Phthalate acid esters (PAEs) contamination raised concerns as a result of migration from food packaging and environmental exposure. Because of the adverse effects of PAE reported in humans, the aim of this study was to examine the ability to screen for the detection these chemicals as an indicator of potential exposure. Too develop a sensitive screening test to determine PAE, a specific polyclonal antibody against phthalic acid (PA), the hydrolysate of PAEs, was used as a marker of total PAEs. This method involved the use of 4-aminophthalic acid (APA) as an immunizing hapten to generate antibody. Subsequently, this antibody conjugated with labeled gold nanoparticles (GNPs) was then used to develop an immunochromatographic assay (ICA) for visually detecting PA. After establishing optimal assay conditions, the ICA strip detected visually PA at 3 µg/ml rapidly in less than 5 min. Further, this assay exhibited reliable specificity for PA with no apparent cross-reactivity with structurally related PAEs. A significant correlation between data obtained with the ICA strip and high-performance liquid chromatography (HPLC) analysis was achieved using cooking oils as model spiked samples. The proposed use of ICA offers an effective tool for rapid on-site screening for total PAEs in cooking oils.

EphB4-VAV1 signaling pathway is associated with imatinib resistance in chronic myeloid leukemia cells.

Imatinib (IM) resistant Chronic Myeloid Leukemia (CML) is an important issue to be addressed while treating CML patients. The present study analyzes the role of EphB4-VAV1 signaling in IM-resistant CML. EphB4 and VAV1 were overexpressed in IM-resistant CML patients and K562-R cell line (K562-R). Then, we established stable under-expressing EphB4 cell line K562-R-EphB4-sh. VAV1 was down-regulated in K562-R-EphB4-sh cells. K562-R-EphB4-sh cells gained re-sensitivity to IM and K562-R cells showed mild IM resistance. However, EphB4 was no changed when the VAV1 was down-regulated. EphB4 and VAV1 were overexpressed in IM-resistant CML, VAV1might be the downstream moleculars of EphB4. These results suggest a potential role of EphB4-VAV1 signaling as therapeutic target of IM-resistant CML.

An ex vivo liver training model continuously perfused to simulate bleeding for suture skills involved in laparoscopic liver resection: development and validity.

BACKGROUND: Suture skills are essential to laparoscopic liver resection. The current suture training models are not ideal enough. The aim of this study is to develop and verify a highly simulated-bleeding continuously perfused training model (CPTM) and to evaluate its training efficacy. METHODS: CPTM was constructed using fresh lamb liver whose portal veins were perfused with red-dyed liquid gelatin. Construct validity of CPTMs was tested in 33 participants with three levels of laparoscopic experience (experts, intermediates, and novices) who were demanded to finish one superficial stitch and one deep stitch for suture hemostasis on CPTMs. The CPTMs were also evaluated by the experts. CPTMs were compared with dry box training models (DBTMs) regarding training efficacy among the novices who were assigned to DBTM and CPTM groups to, respectively, complete a 10-day training on CPTMs or DBTMs. Before and after their assignments, their superficial stitches were assessed by completion time, suture accuracy, and suture knot performance while their deep stitches by completion time and bleeding control. RESULTS: CPTM proved to be construct valid by both superficial and deep stitches. Significant differences were found regarding completion time (763, 271, 174 s), suture accuracy (4.4, 1.8, 0.2 mm), and suturing knot performance (12.1, 21.5, 22.0) for superficial stitches (p < 0.001), as well as regarding completion time (807, 423, 277 s) for deep stitches (p < 0.001). Positive comments were given by all experts. CPTMs helped novices to acquire laparoscopic suture skills. Their training efficacy was significantly better than that of DBTMs (p < 0.05). Learning curves of CPTM group plateaued at the sixth round for superficial stitches and at the seventh round for deep stitches. CONCLUSION: CPTM offers trainees a highly simulated-bleeding means to acquire advanced laparoscopic suture skills. The suture skills learned on CPTMs may improve significantly at the seventh round.

[The outcome of thirteen patients with nonmalignant hematologic diseases treated with HLA haploidentical stem cell transplantation].

OBJECTIVE: To evaluate the clinical efficacy and safety of human leukocyte antigen (HLA) haploidentical stem cell transplantation in nonmalignant hematologic diseases. METHOD: To analyze the outcome of 13 patients with nonmalignant hematologic diseases who underwent HLA haploidentical stem cell transplantation from September 2001 to October 2013. RESULTS: Thirteen patients including 9 of severe aplastic anemia, 3 of severe ß thalassemia, 1 of congenital pure red cell aplastic anemia underwent HLA haploidentical stem cell transplantation. Three HLA loci mismatched in 4 cases, two HLA loci mismatched in 8 cases and one HLA locus mismatched in 1 case. The conditioning regime consisted of Fludarabine (30 mg×m(-2)×d(-1)×5 d ), Busulfan(0.8 mg×kg(-1)×6h(-1)×4 d), Cyclophosphamide (60 mg×kg(-1)×d(-1)×2 d ), rabbit anti-human lymphocyte globulin ( 2.5 mg×kg(-1)×d(-1)×5 d ). To prevent from graft-versus-host disease (GVHD), cyclosporin A and short term methotrexate (MTX) were used. All patients were successfully engrafted. The incidence of grade 1-2 acute graft-versus-host disease (aGVHD) was 3/13, and that of grade 3-4 was 1/13. The cumulative incidence of total chronic GVHD (cGVHD) was 3/13. Eleven patients survived free of disease at a median follow-up period of 13 months (2-145). CONCLUSION: HLA haploidentical stem cell transplantation is an effective and safe therapy for nonmalignant hematologic diseases.

Sleep restriction promotes brain oxidative stress and inflammation, and aggravates cognitive impairment in insulin-resistant mice.

Sleep deprivation and insulin resistance (IR) are two risk factors for Alzheimer's disease. As the population of people with IR increases and sleep restriction (SR) due to staying up late becomes the "new normal", it is necessary to investigate the effects and molecular pathogenesis of chronic SR on cognitive function in insulin resistance. In this study, 4-week-old mice were fed a high-fat diet (HFD) for 8 weeks to establish IR model, and then the mice were subjected to SR for 21 days, and related indicators were assessed, including cognitive capacity, apoptosis, oxidative stress, glial cell activation, inflammation, blood-brain barrier (BBB) permeability and adiponectin levels, for exploring the potential regulatory mechanisms. Compared with control group, IR mice showed impaired cognitive capacity, meanwhile, SR not only promoted Bax/Bcl2-induced hippocampal neuronal cell apoptosis and Nrf2/HO1- induced oxidative stress, but also increased microglia activation and inflammatory factor levels and BBB permeability, thus aggravating the cognitive impairment in IR mice. Consequently, changing bad living habits and ensuring sufficient sleep are important intervention strategies to moderate the aggravation of IR-induced cognitive impairment.

Discovery, biosynthesis, organic synthesis, and bioactivities of meroterpenoids from Rhododendron species.

Meroterpenoids discovered in Rhododendrons species possess unique chemical structures and biological activities and are expected to become new drug targets for Alzheimer's disease, metabolic disorders, and chronic kidney disease, and these compounds have attracted increasing attention in recent years. In this study, Rhododendron meroterpenoids and their structures, classifications, racemate distribution, biosynthetic pathways, chemical synthesis, and bioactivities are reviewed prior to 2023.

Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is among the deadliest malignancies worldwide and still a pressing clinical problem. Icaritin, a natural compound obtained from the Epimedium genus plant, has garnered significant attention as a potential therapeutic drug for HCC therapies. Mitophagy plays a crucial role in mitochondrial quality control through efficiently eliminating damaged mitochondria. However, the specific mechanisms of the interplay between mitophagy and apoptosis in HCC is still unclear. We aimed to explore the cross-talk between icaritin-induced mitophagy and apoptosis in HCC cells and investigate its potential mechanisms. Firstly, we confirmed that icaritin inhibits proliferation and migration while inducing mitochondrial damage and reactive oxygen species (ROS) production in HCC cells. Secondly, based on proteomics analysis, we discovered that icaritin inhibits the growth of tumor cells and disrupts their mitochondrial homeostasis through the regulation of both mitophagy and apoptosis. Thirdly, icaritin causes mitophagy mediated by PINK1-Parkin signaling via regulating feedforward loop. Furthermore, knockdown of PINK1/Parkin leads to inhibition of mitophagy, which promotes cell death induced by icaritin in HCC cells. Finally, autophagy/mitophagy inhibitors remarkably enhance icaritin-induced cell death and anticancer efficacy. Collectively, our findings reveal that icaritin suppresses growth, proliferation and migration of HCC cell through induction of mitophagy and apoptosis, while inhibition of mitophagy significantly increased the anti-cancer and pro-apoptotic effects of icaritin, indicating that targeting autophagy or mitophagy is a novel approach to overcome drug resistance and enhance anticancer therapies.

Mortality burden attributable to temperature variability in China.

BACKGROUND: Several studies have investigated the associations between temperature variability (TV) and death counts. However, evidence of TV-attributable years of life lost (YLL) is scarce. OBJECTIVES: To investigate the associations between TV and YLL rates (/100,000 population), and quantify average life loss per death (LLD) caused by TV in China. METHODS: We calculated daily YLL rates (/100,000 population) of non-accidental causes and cardiorespiratory diseases by using death data from 364 counties of China during 2006-2017, and collected meteorological data during the same period. A distributed lag non-linear model (DLNM) and multivariate meta-analysis were used to estimate the effects of TV at national or regional levels. Then, we calculated the LLD to quantify the mortality burden of TV. RESULTS: U-shaped curves were observed in the associations of YLL rates with TV in China. The minimum YLL TV (MYTV) was 2.5 °C nationwide. An average of 0.89 LLD was attributable to TV in total, most of which was from high TV (0.86, 95% CI: 0.56, 1.16). However, TV caused more LLD in the young (<65 years old) (1.87, 95% CI: 1.03, 2.71) than 65-74 years old (0.85, 95% CI: 0.40-1.31) and ≥75 years old (0.40, 95% CI: 0.21-0.59), cerebrovascular disease (0.74, 95% CI: 0.36, 1.11) than respiratory disease (0.54, 95% CI: 0.21, 0.87), South (1.23, 95% CI: 0.77, 1.68) than North (0.41, 95% CI: -0.7, 1.52) and Central China (0.40, 95% CI: -0.02, 0.81). TV-attributed LLD was modified by annual mean temperature, annual mean relative humidity, altitude, latitude, longitude, and education attainment. SIGNIFICANCE: Our findings indicate that high and low TVs are both associated with increases in premature death, however the majority of LLD was attributable to high TV. TV-related LLD was modified by county level characteristics. TV should be considered in planning adaptation to climate change or variability. IMPACT: (1) We estimated the associations of TV with YLL rates, and quantified the life loss per death (LLD) caused by TV. (2) An average of 0.89 years of LLD were attributable to TV, most of which were from high TVs. (3) TV caused more LLD in the young, cerebrovascular disease, and southern China. (4) The mortality burdens were modified by county level characteristics.