Metabolic syndrome and its relation to dietary patterns among a selected urbanised and semi-urbanised Tibetan population in transition from nomadic to settled living environment.

OBJECTIVE: To explore the scope of metabolic syndrome (MetS) and its relationship to the major dietary patterns among an urbanised and semi-urbanised Tibetan population in transition from nomadic to settled settings. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: Urbanised and semi-urbanised Tibetan adults (n 920, aged 18-90 years), who have moved from nomadic to settled living environments, answered questionnaires on food consumption frequency and lifestyle characteristics through structured face-to-face interviews and completed anthropometric measurement and metabolic biomarker tests. RESULTS: MetS prevalence was 30·1 % in males and 32·1 % in females. Low HDL-cholesterol and central obesity were the leading metabolic abnormalities (86·3 and 55·8 %, respectively). Three major dietary patterns - urban, western and pastoral - were identified. Beef/mutton was an important food group for all three identified dietary patterns. In addition, the urban dietary pattern was characterised by frequent consumption of vegetables, tubers/roots and refined carbohydrates; the western pattern was characterised by sweetened drinks, snacks and desserts; and the pastoral pattern featured tsamba (roasted Tibetan barley), Tibetan cheese, butter tea/milk tea and whole-fat dairy foods. Individuals in the highest quintile of urban dietary pattern scores were found to be at a higher risk of developing MetS (OR 2·43, 95 % CI 1·41, 4·18) and central obesity (OR 1·91, 95 % CI 1·16, 3·14) after controlling for potential confounders. CONCLUSIONS: MetS was common among urbanised and semi-urbanised Tibetan adult population in transition. The urban dietary pattern, in particular, was a risk factor for MetS. To prevent MetS, nutrition interventions need to be tailored to address the variety of local diet patterns to promote healthy eating.

Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin ß1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue.

Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca2+ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinß1/FAK pathway and disrupting the intracellular Ca2+ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

The Mechanism of Leptin on Inhibiting Fibrosis and Promoting Browning of White Fat by Reducing ITGA5 in Mice.

Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson's trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-ß (TGF-ß) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism.

Curcumin upregulates the Nrf2 system by repressing inflammatory signaling-mediated Keap1 expression in insulin-resistant conditions.

Both oxidative stress and inflammation contribute to the development of insulin resistance (IR). Curcumin (Cur) not only has an anti-inflammatory effect but also has an antioxidative stress effect via the activation of NF-E2-related factor 2 (Nrf2). Since there is close cross-communication between inflammation and oxidative stress, we examined whether Cur could modulate Nrf2 function via its anti-inflammatory ability and investigated its underlying mechanism. In this study, we show that Cur inhibits inflammatory signaling and Kelch-like ECH-associated protein 1 (Keap1) expression, which is accompanied by the activation of the Nrf2 system. We further identified that the proinflammatory cytokine tumor necrosis factor alpha (TNFα) could stimulate Keap1 synthesis and increase Nrf2 polyubiquitination, but these effects could be significantly inhibited by Cur treatment. This study demonstrates that Cur-induced Nrf2 activation occurs through the inhibition of inflammatory signaling-mediated upregulation of Keap1, contributing to its beneficial effects on redox homeostasis and insulin sensitivity.

Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice.

Modulating T-cell alloreactivity has been a main strategy to reduce graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Genetic deletion of T-cell Ezh2, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), inhibits GVHD. Therefore, reducing Ezh2-mediated H3K27me3 is thought to be essential for inhibiting GVHD. We tested this hypothesis in mouse GVHD models. Unexpectedly, administration of the Ezh2 inhibitor GSK126, which specifically decreases H3K27me3 without affecting Ezh2 protein, failed to prevent the disease. In contrast, destabilizing T-cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT. In vivo administration of AUY922 selectively induced apoptosis of activated T cells and decreased the production of effector cells producing interferon γ and tumor necrosis factor α, similar to genetic deletion of Ezh2. Introduction of Ezh2 into alloreactive T cells restored their expansion and production of effector cytokines upon AUY922 treatment, suggesting that impaired T-cell alloreactivity by inhibiting Hsp90 is achieved mainly through depleting Ezh2. Mechanistic analysis revealed that the enzymatic SET domain of Ezh2 directly interacted with Hsp90 to prevent Ezh2 from rapid degradation in activated T cells. Importantly, pharmacological inhibition of Hsp90 preserved antileukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T-cell responses and an effective target for controlling GVHD.

Major dietary patterns and their relationship to obesity among urbanized adult Tibetan pastoralists.

BACKGROUND AND OBJECTIVES: This study investigated major dietary patterns and their relationship to obesity among urbanized Tibetan pastoralists. METHODS AND STUDY DESIGN: Using a cross-sectional design, this study assessed 782 urbanized Tibetan pastoralists aged 18-84 y. A food frequency questionnaire and anthropometric measurements were conducted in 2018. Principal component analysis was used to identify dietary patterns. Logistic regression was applied to compare the risks for overweight (BMI >=24 kg/m2), obesity (BMI >=28 kg/m2), and central obesity (waist circumference >=80 cm for women and >=85 cm for men) across quintiles of dietary pattern scores after controlling for gender, age, education, medical insurance, smoking status, alcohol consumption and physical activity. RESULTS: This study identified three major dietary patterns: an urban pattern characterized by high intake of vegetables, tubers/roots, and refined carbohydrates; a western pattern characterized by sugary drinks, snacks, and desserts; and a pastoral pattern characterized by tsamba (roasted Tibetan barley), Tibetan cheese, and buttered/milk tea. Subjects in the highest quintile of urban pattern scores were more likely to be overweight (OR=2.58, 95% CI 1.48-4.49) (p-for-trend=0.001), obese (2.94, 1.57-5.49) (p-for-trend=0.001), and centrally obese (1.94, 1.12-3.36) (p-for-trend=0.019) compared to those in the lowest quintile with confounders controlled. The western dietary pattern was positively associated with overweight (p-for-trend=0.037). No clear association was observed for the pastoral dietary pattern. CONCLUSIONS: Urban and western dietary patterns independently predict the likelihood of being overweight. Improved nutrition education may contribute to healthier eating behaviors, thus reducing or preventing obesity.

Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation.

Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c(+) DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.

Ezh2 regulates transcriptional and posttranslational expression of T-bet and promotes Th1 cell responses mediating aplastic anemia in mice.

Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-γ-producing Th1 CD4(+) T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4(+) T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases.

The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.

Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.

Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice.

Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4(high)) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4(high) i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4(high) i-DCs were CD11c(+)B220(+)PDCA-1(+), resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4(high) i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4(low)) i-DCs were CD11c(+)B220(-)PDCA-1(-), and had low levels of Jagged1. In vitro assays showed that Dll4(high) i-DCs induced significantly more IFN-γ- and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4(low) i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4(high) i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4(low) i-DCs. Furthermore, Dll4 and Dll4(high) i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4(high) i-DCs.

Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells.

Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell-mediated inflammatory disorders in a broad context.

[Effect of Tibetan medicine zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2].

To study the effect of Tibetan medicine Zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2, three different doses (1.2, 3.8 and 12 mg x kg(-1)) of Zuotai were administrated orally to rats once a day or once daily for twelve days, separately. Rats were administrated orally caffeine (CF) on the second day after Zuotai administration, and the urine concentration of CF metabolite 5-acetylamino-6-formylamino-3-methyl-uracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), 1, 7-dimethylxanthine (17U) at 5 h after study drug administration was determined by RP-HPLC. The activity of CYP1A2 and NAT2 was evaluated by the ratio of metabolites (AFMU+1X+1U)/17U and the ratio of AFMU/(AFMU+1X+1U), respectively. The protein and mRNA expression of CYP1A2 and NAT2 were determined by ELISA and RT-PCR method, respectively. After single administration of Zuotai 3.8 mg x kg(-1) and repeated administration of Zuotai 3.8 and 12 mg x kg(-1), the activity of CYP1A2 and NAT2 decreased significantly compared with control group and there was no significant difference between other dose group and control group. The protein expression of CYP1A2 was significant lower than that in control group after repeated administration of Zuotai 12 mg x kg(-1), and the mRNA expression of CYP1A2 decreased significantly compared with that of control group after single administration of Zuotai 3.8 mg x kg(-1) and repeated admistration of Zuotai 12 mg x kg(-1), separately. The protein expression of NAT2 decreased significantly compared with that of control group after single and repeated administration of Zuotai 3.8 mg x kg(-1), respectively, and the mRNA expression of CYP1A2 decreased significantly compared with control group after single administration of Zuotai 3.8 mg x kg(-1). This study found that Tibetan medicine Zuotai had significant effect on the activity, protein and mRNA expression of CYP1A2 and NAT2.

miRNA-381-3p Functions as a Tumor Suppressor to Inhibit Gastric Cancer by Targeting Fibroblast Growth Factor Receptor-2.

Objectives: MicroRNAs possess essential effects on gastric cancer (GC), whereas the underlying mechanisms have not been fully uncovered. The present work focused on investigating the role of miR-381-3p in GC cellular processes and the possible mechanisms. Materials and Methods: miR-381-3p levels within GC tissues and cells were measured through quantitative real-time polymerase chain reaction (qRT-PCR). This study measured cell proliferation, apoptosis, and metastasis through EdU, colony formation, flow cytometry, and Transwell assays separately. TargetScan was adopted to predict the miR-381-3p targets, whereas luciferase reporter assay was adopted for confirmation. Results: miR-381-3p levels were decreased, whereas fibroblast growth factor receptor-2 (FGFR2) expression was increased in GC. miR-381-3p upregulation inhibited proliferation, migration, and invasion and it promoted the apoptosis of GC cells. Further, FGFR2 overexpression partly reversed the miR-381-3p-mediated impacts on GC cellular processes. Conclusions: This study provides an experimental basis, suggesting the potential of using miR-381-3p as the novel marker for GC. Clinical Trial Registration number: 2020-05.

Comparison of the pharmacokinetics of sulfamethoxazole in native Han and Tibetan male Chinese volunteers living at high altitude.

The aim of this study was to investigate the pharmacokinetics of sulfamethoxazole in native Han and Tibetan healthy Chinese subjects living chronically at high altitude. An open-labeled, controlled, prospective study was conducted in healthy Chinese male volunteers. Sulfamethoxazole 1,200 mg was administered orally to two groups: native Han and Tibetan volunteers living at high altitude (2,500-3,900 m [8,200-12,800 ft]). Blood samples were collected from an indwelling venous catheter into heparinized tubes before (baseline) study drug administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h after study drug administration. Sulfamethoxazole in whole blood, plasma, and plasma water, and metabolite N (4)-acetyl-sulfamethoxazole in plasma were determined by HPLC. Tolerability was determined using blood chemistry testing, continuous 12-lead electrocardiogram, and blood pressure monitoring. The protein binding was significantly higher in the native Tibetan group (70.5 %) compared to the native Han group (67.3 %) (p < 0.05). The binding of sulfamethoxazole to red blood cells was 7.4 and 8.3 % in the native Han and native Tibetan groups, respectively. There was no significant difference between the two groups. The AUC(0-∞) was significantly lower in the native Tibetan group compared to the native Han group (p < 0.05), and other pharmacokinetics parameters were found to have no significant difference between the two groups. This study found little changes in the disposition of sulfamethoxazole in these native healthy Tibetan Chinese subjects living at high altitude in comparison to native healthy Han Chinese subjects living at high altitude.

[Effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19].

This study is to investigate the effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19. Rats from plain (P) and rats with acute middle altitude hypoxia (AMH), chronic middle altitude hypoxia (CMH), acute high altitude hypoxia (AHH) and chronic high altitude hypoxia (CHH) were administered orally phenytoin sodium (PHT) and omeprazole (OMZ) to evaluate the activity of CYP2C9 and CYP2C19, separately. The serum concentrations of PHT and metabolite 4'-hydroxyphenytoin (HPPH) at 12 h after treatment and the serum concentrations of OMZ and metabolite 5-hydroxy omeprazole (5-OHOMZ) at 3 h after treatment were determined by RP-HPLC. The activity of CYP2C9 and CYP2C19 was evaluated by the ratio of HPPH to PHT and the ratio of 5-OHOMZ to OMZ, respectively. The protein expressions of CYP2C9 and CYP2C19 were determined by ELISA method. The activities of CYP2C9 (HPPH/PHT) in P, AMH, CMH, AHH and CHH were 0.67 +/- 0.31, 0.75 +/- 0.29, 0.76 +/- 0.23, 0.79 +/- 0.31 and 0.75 +/- 0.18, respectively, and the activities of CYP2C19 (5-OHOMZ/OMZ) in P, AMH, CMH, AHH and CHH were 0.17 +/- 0.06, 0.20 +/- 0.10, 0.11 +/- 0.05, 0.37 +/- 0.13 and 0.19 +/- 0.05, respectively. The protein expressions of CYP2C9 in P, AMH, CMH, AHH and CHH were 4.20 +/- 1.27, 3.95 +/- 0.81, 3.93 +/- 1.11, 4.32 +/- 1.03 and 4.12 +/- 0.86 ng x g(-1), respectively, and the protein expressions of CYP2C19 in P, AMH, CMH, AHH and CHH were 3.91 +/- 1.82, 3.63 +/- 2.07, 2.55 +/- 0.85, 4.78 +/- 2.37 and 3.51 +/- 1.03 ng x g(-1), respectively. The activities and protein expressions of CYP2C9 in AMH, CMH, AHH and CHH were not significantly different with those of P. The protein expressions of CYP2C19 in AMH, CMH, AHH and CHH were not significantly different with those of P, but the activity of CYP2C19 in AHH was significantly higher than that of P. This study found significant changes in the activity of CYP2C19 under the special environment of acute high altitude hypoxia.

Associations between NKX2-5 gene polymorphisms and congenital heart disease in the Chinese Tibetan population.

BACKGROUND: The pathogenesis of congenital heart disease (CHD) has not been fully elucidated, and this study considers the interaction between inheritance and the environment as the main cause of CHD. Previous studies have found that the incidence of CHD in the Tibetan plateau population is significantly higher than in low-altitude populations. Numerous reports have confirmed that NKX2-5 gene mutations can lead to coronary heart disease, but the relationship between NKX2-5 and Tibetan nationality has not yet been reported. OBJECTIVE: To explore the relationship between NKX2-5 gene polymorphisms and CHD in Tibetan people. METHODS: Blood samples were collected retrospectively from Tibetan patients diagnosed with CHD as well as healthy Tibetans, and the exons of NKX2-5 were sequenced. The MassARRAY technique was used to detect and genotype candidate tag single nucleotide polymorphisms (SNPs) in the non-coding regions of NKX2-5. RESULTS: Exon sequencing revealed no difference in the coding regions of the NKX2-5 gene between the CHD and control groups. In the non-coding regions of NKX2-5, rs6882776 and rs2546741 differed significantly between the two groups. Strong linkage disequilibrium was found between the selected sites of NKX2-5. CONCLUSIONS: The NKX2-5 exons do not associate with CHD in Tibetans. Rs6882776 and rs2546741 in the non-coding regions of NKX2-5 may protect against CHD in Tibetans. The NKX2-5 haplotype associated with CHD occurrence in the Tibetan population.

Hsa-let-7d-5p Promotes Gastric Cancer Progression by Targeting PRDM5.

Gastric cancer (GC) is a common malignant tumor in the digestive system and a significant health burden worldwide. In this study, we found that hsa-let-7d-5p was upregulated in GC cells, promoted GC cell proliferation, migration, and invasion, and reduced apoptosis. Moreover, we found that the expression of PRDM5 (PR domain protein 5) was downregulated in GC cells and upregulated in GC cells treated with hsa-let-7d-5p inhibitor. Further investigation showed that hsa-let-7d-5p was the target of PRDM5, and the functions of hsa-let-7d-5p on GC progression were rescued by PRDM5 overexpression in GC cells. Collectively, our findings suggested that hsa-let-7d-5p promoted the development of GC by targeting PRDM5, indicating that hsa-let-7d-5p could be a promising therapeutic molecule for the treatment of gastric cancer.

Lnc-hipk1 inhibits mouse adipocyte apoptosis as a sponge of miR-497.

Noncoding RNAs (ncRNAs) such as microRNAs (miRNAs), long noncoding RNAs (lncRNA), and circular RNAs are closely related to the biological processes related to obesity. As a miRNA that widely present in different cell types, miR497 is proved to be involved in cell development. However, research on the role of miR-497 as a key factor in regulating the development of adipocytes is still in gap. The role of miR-497 in the apoptosis and proliferation of mouse-derived adipocytes was detected by RNA-seq analysis, RT-qPCR, Western blot, immunofluorescence, and dual-luciferase reporter assay. Using miR-497 mimics to treat 3T3-L1 cells, we found that miR-497 targeted Bcl-2 to promote adipocyte apoptosis through the mitochondrial pathway, and this effect was consistent in the apoptosis model composed of palmitic acid (PA) and hydrogen peroxide (H2 O2 ). LncRNA homeodomain-interacting protein kinase 1 (lnc-hipk1) sponged miR-148b to weaken its silencing of Bcl-2, forming the competitive endogenous RNAs (CeRNAs) regulatory network. Furthermore, overexpression of lnc-hipk1 inhibited the apoptosis of adipocytes by targeting miR-497/Bcl-2. Co-treatment of miR-497 and lnc-hipk1 showed that lnc-hipk1 reversed the apoptosis of adipocytes caused by miR-497 overexpression. And in vivo experiments further confirmed that this effect was also achieved by the CeRNA system of lnc-hipk1/miR-497/Bcl-2. In summary, lnc-hipk1 targets miR-497/Bcl-2 to regulate adipocyte apoptosis through the mitochondrial pathway. This research enriches the research content of ncRNAs and CeRNA in adipocyte development, and provides new targets for the treatment of obesity and other metabolic syndromes.

Leptin: an entry point for the treatment of peripheral tissue fibrosis and related diseases.

Leptin is a small peptide mainly secreted by adipocyte, which acts on the central nervous system of the hypothalamus to regulate the body's energy balance by inhibiting food intake, it also can directly act on specific cells through leptin receptors (for example, ObRa, which exists in the blood-brain barrier or kidneys), thereby affect cell metabolism. Excessive deposition of extracellular matrix (ECM) causes damage to normal tissues or destruction of organ structure, which will eventually lead to tissue or organ fibrosis. The sustainable development of fibrosis can lead to structural damage and functional decline of organs, and even exhaustion, which seriously threatens human health and life. In recent years, studies have found that leptin directly alleviates the fibrosis process of various tissues and organs in mammals. Therefore, we speculate that leptin may become a significant treatment for fibrosis of various tissues and organs in the future. So, the main purpose of this review is to explore the specific mechanism of leptin in the process of fibrosis in multiple tissues and organs, and to provide a theoretical basis for the treatment of various tissues and organs fibrosis and related diseases caused by it, which is of great significance in the future.