Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro.

The toxic effects of four cationic porphyrins on various human cells were studied in vitro. It was found that, under dark conditions, porphyrins are almost nontoxic, while, under the action of light, the toxic effect was observed starting from nanomolar concentrations. At a concentration of 100 nM, porphyrins caused inhibition of metabolism in the MTT test in normal and cancer cells. Furthermore, low concentrations of porphyrins inhibited colony formation. The toxic effect was nonlinear; with increasing concentrations of various porphyrins, up to about 1 µM, the effect reached a plateau. In addition to the MTT test, this was repeated in experiments examining cell permeability to trypan blue, as well as survival after 24 h. The first visible manifestation of the toxic action of porphyrins is blebbing and swelling of cells. Against the background of this process, permeability to porphyrins and trypan blue appears. Subsequently, most cells (even mitotic cells) freeze in this swollen state for a long time (24 and even 48 h), remaining attached. Cellular morphology is mostly preserved. Thus, it is clear that the cells undergo mainly necrotic death. The hypothesis proposed is that the concentration dependence of membrane damage indicates a limited number of porphyrin targets on the membrane. These targets may be any ion channels, which should be considered in photodynamic therapy.

Albendazole-induced autophagy blockade contributes to elevated apoptosis in cholangiocarcinoma cells through AMPK/mTOR activation.

Albendazole (ABZ) is a broad-spectrum anti-parasitic drug that exhibits antitumor effects against several carcinomas. The effects of ABZ on cholangiocarcinoma (CCA) and its underlying mechanisms are still unclear. Our study aims to investigate the role of ABZ in inducing autophagy-mediated apoptosis of cholangiocarcinoma cells. The antitumor effects of ABZ were evaluated against CCA cells and HIBEC intrahepatic biliary epithelial cells. Furthermore, the apoptosis rates, and autophagy flux in RBE and FRH-0201 cells treated with ABZ were investigated. ABZ inhibited proliferation, induced cell death and apoptosis in CCA cells in vitro. In vivo, tumors from ABZ- treated BALB/c nude mice were significantly smaller than untreated mice. ABZ also induced the initiation of autophagy via AMPK/mTOR pathways, resulting in the formation of autophagosome. In addition, ABZ blocked autophagic flux by inhibiting the fusion of autophagosome-lysosome, which increased the apoptotic death of CCA cells. However, the apoptotic death of CCA cells induced by ABZ was reversed by 3-methyladenine (3-MA), an autophagosome formation inhibitor, but increased by chloroquine (CQ), an autophagosome-lysosome fusion inhibitor.Our work provides novel mechanisms for anti-tumor effects of ABZ on CCA, suggesting that ABZ may be used as a potent autophagy inhibitor in the treatment of CCA.

Global burden of non-communicable diseases attributable to dietary risks in 1990-2019.

BACKGROUND: Dietary risks have raised attention worldwide during recent decades. The present burden-of-disease study aimed to evaluate the global dietary risks for non-communicable diseases (NCDs) from 1990 to 2019 and quantify their impact on mortality and disability-adjusted life-years (DALYs). Data from the 2019 Global Burden of Disease Study on deaths and DALYs from NCDs attributable to worldwide dietary risks were obtained and underwent deep analysis by year, age, gender, location, leading risks and leading causes, and their associations were examined. The socio-demographic index (SDI) was used as an indicator of national socio-economic status, as well as the relationships between age-standardised rates of deaths or DALYs and socio-economic status. RESULTS: In 2019, 7.9 million deaths and 187.7 million DALYs were attributable to dietary risk factors. High intake of sodium and low intake of whole grains and fruits were leading dietary risks for deaths and DALYs worldwide. However, both indices showed a decreasing trend by year, an increase by age and a higher disease burden in males. The main distribution of dietary-related NCDs was located in highly populated countries. A negative association between the SDI and disease burden and a positive association between the SDI and male preponderance were found. CONCLUSIONS: Dietary risk factors for NCDs increased significantly and varied across regions during 1990-2019. Therefore, greater efforts are needed to raise public awareness of interventions and improve dietary practices aiming to reduce the disease burden caused by suboptimal dietary intake, especially in developing countries and among males.

In Vitro Proliferation and Anti-Apoptosis of the Papain-Generated Casein and Soy Protein Hydrolysates towards Osteoblastic Cells (hFOB1.19).

Casein and soy protein were digested by papain to three degrees of hydrolysis (DH) 7.3%-13.3%, to obtain respective six casein and soy protein hydrolysates, aiming to clarify their in vitro proliferation and anti-apoptosis towards a human osteoblastic cell line (hFOB1.19 cells). Six casein and soy protein hydrolysates at five levels (0.01-0.2 mg/mL) mostly showed proliferation as positive 17ß-estradiol did, because they conferred the osteoblasts with cell viability of 100%-114% and 104%-123%, respectively. The hydrolysates of higher DH values had stronger proliferation. Casein and soy protein hydrolysates of the highest DH values altered cell cycle progression, and enhanced cell proportion of S-phase from 50.5% to 56.5% and 60.5%. The two also antagonized etoposide- and NaF-induced osteoblast apoptosis. In apoptotic prevention, apoptotic cells were decreased from 31.6% to 22.6% and 15.6% (etoposide treatment), or from 19.5% to 17.7% and 12.4% (NaF treatment), respectively. In apoptotic reversal, soy protein hydrolysate decreased apoptotic cells from 13.3% to 11.7% (etoposide treatment), or from 14.5% to 11.0% (NaF treatment), but casein hydrolysate showed no reversal effect. It is concluded that the hydrolysates of two kinds had estradiol-like action on the osteoblasts, and soy protein hydrolysates had stronger proliferation and anti-apoptosis on the osteoblasts than casein hydrolysates.

Phytochrome interacting factor ZmPIF6 simultaneously enhances chilling tolerance and grain size in rice.

Chilling is a prevalent type of abiotic stress that adversely affects agricultural productivity worldwide. Phytochrome interacting factors (PIFs) are a group of transcription factor that are crucial for plant abiotic stress response. Our research reveals that the maize PIF family gene ZmPIF6 is responsive to chilling stress, which mitigates the negative impacts of chilling through reducing reactive oxygen species content and enhancing cell membrane stability at the physiological and biochemical levels. We also found that the ZmPIF6 overexpression lines showed a significant increase in grain size, encompassing both length and width, which mainly due to the increase in cell size. In addition, digital gene expression results suggested that ZmPIF6 regulates the expression of cold-related and grain size-related genes in rice. In light of these findings, ZmPIF6 has a hopeful prospect as a candidate gene of chilling tolerance and crop productivity in the transgenic breeding.

Effects of simulated heliox diving at high altitudes on blood cells, liver functions and renal functions.

The aim of the present study was to examine the effects of simulated heliox diving at high altitudes on divers' blood cells, liver functions and renal functions. In this experiment, four divers lived for nine consecutive days in a dual-function high-low pressure chamber, which simulated air pressure at an altitude of 3,000 meters and at a 30-meter depth; an altitude of 4,000 meters and 30-meter depth; and at an altitude of 5,200 meters and 30 meters and 50 meters in depth. Total time underwater was 60 minutes. The subjects breathed heliox (with oxygen at 40% and helium at 60%) during the simulated 30-meter dive from zero altitude to 30 meters and while remaining underwater; they breathed air while ascending from 30 meters to 18. They breathed heliox (with oxygen at 26.7% and helium at 73.3%) in the simulated dive from zero altitude to 50 meters underwater, in remaining underwater and in ascending from 50 meters to 29; air while ascending from 29 meters to 18. Pure oxygen was breathed while ascending from 18 meters to the surface; then air. Results indicated: (1) the correlating indices of routine blood, liver and renal functions, and urine routine were all within normal reference ranges; and (2) the indices tested at other periods of time were not significantly different (p > 0.05) from the results at zero-meter level and 3,000-meter level. The study suggests that the heliox diving processes at different high altitudes simulated in this experiment have no significant impact upon divers' blood routine, liver functions and renal functions.

Clonorchis sinensis granulin promotes malignant transformation of human intrahepatic biliary epithelial cells through interaction with M2 macrophages via regulation of STAT3 phosphorylation and the MEK/ERK pathway.

BACKGROUND: Clonorchis sinensis granulin (CsGRN), a component of the excretory/secretory products of this species, is a multifunctional growth factor that can promote the metastasis of cholangiocarcinoma cells. However, the effect of CsGRN on human intrahepatic biliary epithelial cells (HIBECs) is unclear. Here, we investigated the effect of CsGRN on the malignant transformation of HIBECs and its possible underlying mechanism. METHODS: The malignant transformation phenotypes of HIBECs after CsGRN treatment were estimated by EdU-488 incorporation assay, colony formation assay, wound-healing assay, Transwell assay and western blot. The biliary damage of CsGRN-treated mice was detected by western blot, immunohistochemical staining and hematoxylin and eosin staining. The phenotypes of the macrophages [human monocytic leukemia cell line (THP-1)] were analyzed by flow cytometry, immunofluorescence and immunohistochemistry, both in vitro and in vivo. A co-culture system was developed to explore the interaction between THP-1 and HIBECs in CsGRN-containing medium. Enzyme-linked immunosorbent assay and western blot were used to detected the activation of interleukin 6 (IL-6), phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. An inhibitor of the MEK/ERK pathway, PD98059, was used to determine whether this pathway is involved in CsGRN-mediated cell interactions as well as in STAT3 phosphorylation and malignant transformation of HIBECs. RESULTS: Excessive hyperplasia and abnormal proliferation of HIBECs, enhanced secretion of hepatic pro-inflammatory cytokines and chemokines, as well as biliary damage, were observed in vitro and in vivo after treatment with CsGRN. The expression of the markers of M2 macrophages significantly increased in CsGRN-treated THP-1 cells and biliary duct tissues compared with the controls. Moreover, following treatment with CsGRN, the HIBECs underwent malignant transformation in the THP-1-HIBECs co-culture group. In addition, high expression of IL-6 was observed in the CsGRN-treated co-culture media, which activated the phosphorylation of STAT3, JAK2, MEK and ERK. However, treatment with an inhibitor of the MEK/ERK pathway, PD98059, decreased expression of p-STAT3 in CsGRN-treated HIBECs and further repressed the malignant transformation of HIBECs. CONCLUSIONS: Our results demonstrated that, by inducing the M2-type polarization of macrophages and activating the IL-6/JAK2/STAT3 and MEK/ERK pathways in HIBECs, CsGRN promoted the malignant transformation of the latter.

Amino Acid Composition of a Chum Salmon (Oncorhynchus keta) Skin Gelatin Hydrolysate and Its Antiapoptotic Effects on Etoposide-Induced Osteoblasts.

A gelatin hydrolysate with a hydrolysis degree of 13.7% was generated using the skin gelatin of chum salmon (Oncorhynchus keta) and papain-catalyzed enzymatic hydrolysis. The results of analysis demonstrated that four amino acids, namely Ala, Gly, Pro, and 4-Hyp, were the most abundant in the obtained gelatin hydrolysate with measured molar percentages ranging from 7.2% to 35.4%; more importantly, the four amino acids accounted for 2/3 of the total measured amino acids. However, two amino acids, Cys and Tyr, were not detected in the generated gelatin hydrolysate. The experimental results indicated that the gelatin hydrolysate at a dose of 50 µg/mL could combat etoposide-induced apoptosis in human fetal osteoblasts (hFOB 1.19 cells), causing a decrease in the total apoptotic cells from 31.6% to 13.6% (via apoptotic prevention) or 13.3% to 11.8% (via apoptotic reversal). Meanwhile, the osteoblasts exposed to the gelatin hydrolysate showed expression changes for 157 genes (expression folds > 1.5-fold), among which JNKK, JNK1, and JNK3 were from the JNK family with a 1.5-2.7-fold downregulated expression. Furthermore, the protein expressions of JNKK, JNK1, JNK3, and Bax in the treated osteoblasts showed a 1.25-1.41 fold down-regulation, whereas JNK2 expression was not detected in the osteoblasts. It is thus suggested that gelatin hydrolysate is rich in the four amino acids and has an in vitro antiapoptotic effect on etoposide-stimulated osteoblasts via mitochondrial-mediated JNKK/JNK(1,3)/Bax downregulation.

Association between sociodemographic status and the T2DM-related risks in China: implication for reducing T2DM disease burden.

Objective: Analyzing the association between sociodemographic status and the type 2 diabetes mellitus (T2DM)-related risks in China to reduce the disease burden of T2DM. Methods: We downloaded data from the Global Burden of Disease Study 2019 to estimate the disease burden of T2DM in China. Secondary analyses were performed by year, age, gender, summary exposure value (SEV), and sociodemographic index (SDI). Results: In China, it is estimated that 3.74 (3.44-4.10) million incidence, 90.0 (82.3-98.5) million prevalence, 168.4 (143.2-194.0) thousand deaths, and 9.6 (7.6-11.9) million DALYs occurred in 2019, showing an increase of 96.8, 156.7, 162.8, and 145.4% compared to 1990. An inverse U-shaped curve was observed for the correlations between T2DM-related burden and SDI. A heavier burden was found in males. The top four risk factors were high body mass index (HBMI), dietary risks, air pollution and tobacco. HBMI, as the key risk, accounted for half of the disease burden of T2DM in China. Lower degree of SEV and higher level of attributable T2DM-related burden could be found in main risks, meaning their critical role of them in the development and progression of T2DM. An inverse U-shaped curve could be found in the association between age-standardized incidence, mortality, DALYs rate, and SDI. Conclusion: The disease burden of T2DM has rapidly increased in China. Gender disparities, different age distributions and inconsistent socioeconomic levels all played an important role in it. The key risk was HBMI. With the improvement of socioeconomic level, the main risk factors for T2DM have changed from environmental factors to lifestyle factors. Targeted control and preventative strategies to address adjustable risk factors could put an end to this soaring burden.

Sewage sludge derived biochar for environmental improvement: Advances, challenges, and solutions.

With the rapid growth yield of global sewage sludge, rational and effective treatment and disposal methods are becoming increasingly needed. Biochar preparation is an attractive option for sewage sludge treatment, the excellent physical and chemical properties of sludge derived biochar make it an attractive option for environmental improvement. Here, the current application state of sludge derived biochar was comprehensively reviewed, and the advances in the mechanism and capacity of sludge biochar in water contaminant removal, soil remediation, and carbon emission reduction were described, with particular attention to the key challenges involved, e.g., possible environmental risks and low efficiency. Several new strategies for overcoming sludge biochar application barriers to realize highly efficient environmental improvement were highlighted, including biochar modification, co-pyrolysis, feedstock selection and pretreatment. The insights offered in this review will facilitate further development of sewage sludge derived biochar, towards addressing the obstacles in its application in environmental improvement and global environmental crisis.

Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming.

Thermogenic adipocytes have been extensively investigated because of their energy-dissipating property and therapeutic potential for obesity and diabetes. Besides serving as fuel sources, accumulating evidence suggests that intermediate metabolites play critical roles in multiple biological processes. However, their role in adipocyte differentiation and thermogenesis remains unexplored. Here, we report that human and mouse obesity is associated with marked downregulation of glutamine synthetase (Glul) expression and activity in thermogenic adipose tissues. Glul is robustly upregulated during brown adipocyte (BAC) differentiation and in brown adipose tissue (BAT) upon cold exposure and Cl316,243 stimulation. Further genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels reveal that glutamine cells autonomously stimulate BAC differentiation and function and BAT remodeling and improve systemic energy homeostasis in mice. Mechanistically, glutamine promotes transcriptional induction of adipogenic and thermogenic gene programs through histone modification-mediated chromatin remodeling. Among all the glutamine-regulated writer and eraser genes responsible for histone methylation and acetylation, only Prdm9, a histone lysine methyltransferase, is robustly induced during BAC differentiation. Importantly, Prdm9 inactivation by shRNA knockdown or a selective inhibitor attenuates glutamine-triggered adipogenic and thermogenic induction. Furthermore, Prdm9 gene transcription is regulated by glutamine through the recruitment of C/EBPb to its enhancer region. This work reveals glutamine as a novel activator of thermogenic adipocyte differentiation and uncovers an unexpected role of C/EBPb-Prdm9-mediated H3K4me3 and transcriptional reprogramming in adipocyte differentiation and thermogenesis.

Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling.

Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling.

The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice.

Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.

Predicting Current Potential Distribution and the Range Dynamics of Pomacea canaliculata in China under Global Climate Change.

Pomacea canaliculata is one of the 100 worst invasive alien species in the world, which has significant effects and harm to native species, ecological environment, human health, and social economy. Climate change is one of the major causes of species range shifts. With recent climate change, the distribution of P. canaliculata has shifted northward. Understanding the potential distribution under current and future climate conditions will aid in the management of the risk of its invasion and spread. Here, we used species distribution modeling (SDM) methods to predict the potential distribution of P. canaliculata in China, and the jackknife test was used to assess the importance of environmental variables for modeling. Our study found that precipitation of the warmest quarter and maximum temperature in the coldest months played important roles in the distribution of P. canaliculata. With global warming, there will be a trend of expansion and northward movement in the future. This study could provide recommendations for the management and prevention of snail invasion and expansion.

The Burden of Diabetes-Related Chronic Kidney Disease in China From 1990 to 2019.

Objective: To analyze the trends in disease burden of diabetes-related chronic kidney disease (CKD) by year, age, gender and types of diabetes in China from 1990 to 2019. Methods: Data on prevalence, deaths and disability-adjusted life years (DALYs) for diabetes-related CKD were extracted from the Global Burden of Disease (GBD) 2019 study. Analyses were performed by year, age, gender and types of diabetes. Results: In China, the numbers of deaths and DALYs of diabetes-related CKD continuously increased but the age-standardized rates (per 100,000 population) decreased over 30 years, in which the numbers of deaths and DALYs attributable to type 1 diabetes mellitus (T1DM)-related CKD barely changed and the age-standardized rates decreased over the years; and the number of deaths and DALYs attributable to type 2 diabetes mellitus (T2DM)-related CKD continuously increased, but the age-standardized rates also decreased. In 2019, 76.03 (58.24-95.61) thousand deaths and 2.13 (1.65-2.67) million DALYs were attributable to diabetes-related CKD, of which, T2DM accounted for 83.32% and 77.0% respectively, and T1DM accounted for the rest. Increasing gender disparity was seen, with males being more heavily impacted. The burden of diabetes-related CKD varied among different age groups, with the numbers of deaths and DALYs attributable to T1DM-related CKD peaking between 45 and 54 years of age and T2DM-related CKD peaking between 75 and 79 years of age; and the crude rates of deaths and DALYs attributable to T1DM-related CKD peaking between 70 and 79 years of age and 40 to 54 years of age, respectively, and T2DM-related CKD peaking over 90 years of age. Among neighboring and G20 countries, the burden of diabetes-related CKD in China was relatively controlled reflected by the ranking of adjusted death and DALYs rates. Conclusions: The burden of diabetes-related CKD in China worsens and shows gender disparities and different age distribution. Greater efforts are needed to improve the health outcomes of these patients, especially among males.

Performance and microbial community of MBBRs under three maintenance strategies for intermittent stormwater treatment.

Maintaining microbial activities is a critical problem for biological treatment processes of stormwater runoff because of its intermittent nature. In this study, the suitability of the moving bed biofilm reactor (MBBR) was assessed for stormwater treatment by long-term dry - rainy alternation operation. Three strategies to maintain microbial activities during the dry period, including keeping idle (MBBRI), introducing river water throughout the period (MBBRC), and ahead of a rainy day (MBBRM), were investigated. COD and NH4+-N removal efficiencies declined linearly from 94.2 % and 94.7 % to 51.7 % and 64.6 %, respectively, after the 61-day operation with microbial activity and biomass decreased. Introducing river water adversely affected the process performance as MBBRC presented the highest declining rates of COD and NH4+-N removal efficiencies. Most genera in MBBRs decayed and their microbial communities developed towards individualization, especially in MBBRM because of its highest environmental variability. Keeping idle slightly alleviated the performance decline and formed a more stable microbial community structure. However, significantly deteriorating performance in all MBBRs after the long-term operation indicated that MBBRs were unsuitable for treating stormwater independently of intermittent nature.

The Global Burden of Osteoporosis, Low Bone Mass, and Its Related Fracture in 204 Countries and Territories, 1990-2019.

Background: Low bone mineral density (LBMD), including osteoporosis and low bone mass, has becoming a serious public health concern. We aimed to estimate the disease burden of LBMD and its related fractures in 204 countries and territories over the past 30 years. Methods: We collected detailed information and performed a secondary analysis for LBMD and its related fractures from the Global Burden of Disease Study 2019. Numbers and age-standardized rates related to LBMD of disability-adjusted life-years (DALYs) and deaths in 204 countries and territories were compared by age, gender, socio-demographic index (SDI), and location. Results: Global deaths and DALYs number attributable to LBMD increased from 207 367 and 8 588 936 in 1990 to 437 884 and 16 647 466 in 2019, with a raise of 111.16% and 93.82%, respectively. DALYs and deaths number of LBMD-related fractures increased 121.07% and 148.65% from 4 436 789 and 121248 in 1990 to 9 808 464 and 301 482 in 2019. In 2019, the five countries with the highest disease burden of DALYs number in LBMD-related fractures were India (2 510 288), China (1 839 375), United States of America (819 445), Japan (323 094), and Germany (297 944), accounting for 25.59%, 18.75%, 8.35%, 3.29%, and 3.04%. There was a quadratic correlation between socio-demographic index (SDI) and burden of LBMD-related fractures: DALYs rate was 179.985-420.435SDI+417.936SDI2(R2 = 0.188, p<0.001); Deaths rate was 7.879-13.416SDI+8.839 SDI2(R2 = 0.101, p<0.001). Conclusions: The global burden of DALYs and deaths associated with LBMD and its related fractures has increased significantly since 1990. There were differences in disease burden between regions and countries. These estimations could be useful in priority setting, policy-making, and resource allocation in osteoporosis prevention and treatment.

Dietary intervention preserves ß cell function in mice through CTCF-mediated transcriptional reprogramming.

Pancreatic ß cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of ß cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of ß cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues ß cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention-induced preservation of ß cell function. CTCF expression is markedly decreased in ß cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate ß cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for ß cell glucose metabolism and stress response.

Factors affecting the prognosis of patients with delayed encephalopathy after acute carbon monoxide poisoning.

OBJECTIVE: Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a disease with poor prognosis. The present study was conducted to determine the factors that affect the prognosis of DEACMP patients. METHODS: In a retrospective study, 46 DEACMP patients were chosen by the following criteria: (1) a clear history of acute carbon monoxide poisoning, a distinct "lucid interval," and neuropsychologic symptoms; (2) first-time admittance to a hospital (within 1 week of onset of disease); and (3) completion of standard treatment period in our hospital. All patients received hyperbaric oxygen (HBO(2)) treatments. RESULTS: Fifty percent (23 of 46) of the DEACMP patients showed improvements after HBO(2) treatments. Age, lucid interval, danger-activities of daily living scores (assessed at worst conditions), and complications were related (P < .05) to the prognosis of DEACMP patients, whereas sex, fundamental diseases, HBO(2) treatment in acute stage, intoxication time, unconsciousness duration, and GM1 ganglioside administration were not (P > .05) related to prognosis. CONCLUSION: Hyperbaric oxygen treatment appears useful in treating DEACMP patients; and patients with greater age and more complications, but shorter lucid interval and less danger-activities of daily living scores, are more likely to have poor prognosis.

Global burden and gender disparity of vision loss associated with diabetes retinopathy.

PURPOSE: To assess the trend patterns and gender disparity in global burden of vision loss due to diabetic retinopathy (DR) by year, age, region and socioeconomic status using prevalence and years lived with disability (YLDs) from Global Burden of Disease (GBD) study 2017. METHODS: Prevalence and YLDs data of vision loss attributable to DR were extracted from GBD Study 2017 in 195 countries and territories. Socio-demographic Index (SDI) in 2017 was cited as indicators of socioeconomic status. Kruskal-Wallis test, Dunn's multiple comparisons and Pearson linear correlation were adopted to evaluate the gender disparity and association with socioeconomic levels. RESULTS: Globally, total age-standardized prevalence and YLDs rates of vision loss due to DR peaked around 2005, with prevalence rate of 58.98 [95% uncertainty interval (UI) 50.95-68.56] and YLDs rate of 5.00 (95% UI 3.51-6.84) per 100 000 population, respectively. The burden were expected to increase to 65.74 (95% UI 60.14-70.86) and 5.68 (95% UI 4.07-7.22) by 2050. The burden would increase according to our projection based on current epidemiological situation. However, gender disparity has existed since 1990 and been enlarging in recent years, with female being more heavily impacted. This pattern remained with ageing among different stages of vision impairments and varied through GBD super regions. Gender difference (females minus males) of age-standardized prevalence rates was positively related to SDI (r = 0.1661, p = 0.0203). Diabetes has become a more important risk over the past 3 decades among the leading causes of vision loss. CONCLUSIONS: The DR-related vision loss burden tended to increase under ageing population according to our projection with significant gender disparity. Public awareness of DR and gender sensitive health policy should be emphasized.