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Background/Aims@#Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. @*Methods@#A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. @*Results@#Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. @*Conclusions@#In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.
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Organoids are complex tiny organ-like model systems formed by three-dimensional culture in vitro, based on the self-renew and self-organization of stem cells. This article reviewed the recent progress in organoids construction from tissues involved in the regulation of glucose homeostasis and chronic diabetic microvascular complications, and their applications in diabetes mellitus. Organoid technology is expected to further promote the progress of diabetes research in disease modeling, personalized medicine, and regenerative medicine.
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Background& AimsThe Coronavirus Disease 2019 (COVID-19) has become a global epidemic and has caused a lasting and huge loss of life security, economic development and social stability in more than 180 countries around the world. Unfortunately, there is still no specific treatment for COVID-19 till now, therefore, at this point, all potential therapies need to be critically considered. LL-37 is one of the best-studied human antimicrobial peptide (AMPs) that has a broad-spectrum activity against bacteria and viruses. The use of living, genetically modified organisms (GMOs) is an effective approach for delivery of therapeutic proteins. The aim of this study was to determine the safety and efficacy of the Lactococcus lactis which has been genetically modified to produce the therapeutic human antimicrobial peptide LL-37 (herein after referred to cas001) in the patients of COVID-19. MethodsFirstly we constructed genetically modified food-grade probiotic, Lactococcus lactis, with sequence of seven tandem repeats of mature human LL-37 under control of the nisin-inducible nisA promoter to produce the cas001. A total of 20 healthy SD rats, half male and half female (There were five male and five female in the control group, the same in treatment group) were used to observe the acute toxic reaction and death after daily administration of cas001 for three weeks, which helps to provide necessary reference basis for clinical dose selection, verificaition of toxic reaction and possible target organs. According to the estimated clinical dosage of 1 x 108CFU /kg/day, considering the conversion of body surface area, the dose for rats should be multiplied by 6.17 to 6 x 108 CFU/kg/day. We administrated 100 times higher dose at 6 x 1010 CFU/ /kg/day to rats. In order to investigate the pharmacokinetics of cas001, male SD rats (body weight 250-300g, 1 x 1010 /animal, n=3) were given oral administration of LL-37 bacteria powder. The concentration of LL-37 in the blood before and after gavage was detected by ELISA kit (Hycult biotechnology Cat# HK321). Human clinical study was approved by Ethics committee of Chinese PLA General Hospital (S2020-074-04) and a total of 11 patients with mild symptoms were enrolled in Wuhan hankou hospital and Huoshenshan hospital. They were enrolled voluntarily and all patients signed informed consent. Among them, there were 5 males and 6 females, aged 55 {+/-} 12 (36-70) years old, and the duration from onset to medication enrollment was 35 {+/-} 19 (5-68) days. 6 patients were nucleic acid positive and 5 patients were nucleic acid negative when they were enrolled. All patients received the oral drug cas001 treatment according to requirement(1 x 109 CFU/capsule, 3 capsules/time, three times a day for 3weeks), with an average follow-up time of 33 {+/-} 15 days (see table 1 for the results). O_TBL View this table: org.highwire.dtl.DTLVardef@1845d29org.highwire.dtl.DTLVardef@1004b38org.highwire.dtl.DTLVardef@4a741aorg.highwire.dtl.DTLVardef@c73d5org.highwire.dtl.DTLVardef@188b563_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1.C_FLOATNO O_TABLECAPTIONSerum biochemical detection in rats two weeks after gavage Serum biochemistry detection of rats at the end of two weeks (Vehicle[male] v.s. LL-37[male], n=5; Vehicle[female] v.s. LL-37[female], n=5). *represent p value<0.05. C_TABLECAPTION C_TBL FindingsWestern blot analysis shows that reasonable amount of LL-37 were induced by different concentrations of nisin, which means we have successfully constructed cas001. In the pre-clinical safety evaluation test, after three weeks administration of cas001, no adverse effects were observed on the rats body weight, food and water intake, hematological or serum biochemical parameters. The results showed that the LD50 of cas001 was higher than that of the 100 times of the expected clinical dose of 6 x 1010 CFU/day. These results showed that cas001 could be safe in animal experiments. In addition, rat pharmacokinetics results showed that the serum concentration of LL-37 reached peak 2 hours after gavage of cas001 and returned to basal level 6 hours after gavage. During study period, the volunteers did not feel any discomfort while taking the cas001 capsules, and two hours after oral administration, the concentration of LL-37 were increased in healthy volunteers. cas001 shows definite effect in the improvement of gastrointestinal symptoms and is possible to have effects in improving the systemic symptoms and respiratory symptoms and may play a role in the improvement of results of nucleic acid test and lung CT test. 11 patients enrolled showed good compliance, tolerance, subjective feeling and actively interacted with the doctors. None of the patients had any adverse reactions. ConclusionsBased on above observations, we conclude here that as an oral anti-viral agent, cas001 displayed good safety profiles. It is very hard to reach conclusion of clinical outcomes related to the cas001, although changes of several symptoms indicate encouraging findings.
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Bone marrow adipose tissue (MAT) is formed by the accumulation of adipocytes in the bone marrow cavity. Previously, the function of MAT is mainly considered to be filled with bone marrow cavity for the mechanical support. However,with the in-depth study of MAT,it has been gradually understood that MAT is not only a part of the bone marrow microenvironment,may also be a new endocrine "organ". The main component of bone marrow adipocytes(BMA) plays a regulatory role in bone marrow and systemic metabolism through the autocrine and paracrine secretion of adiponectin, leptin, interleukin-6, and a series of cytokines. Though its biological characteristics are somewhat similar with white fat adipose tissue(WAT) and brown adipose tissue(BAT),there are some significant differences,so MAT is thought to be a special adipose tissue. MAT is also involved in the development of hematological diseases,metabolic diseases,degenerative diseases,and may affect their outcomes. MAT may be the auxiliary diagnostic criteria and treatment targets of such diseases. This article will review the MAT's own biological characteristics,the differences and associations among three types of adipose tissue and the link between MAT and the diseases,which aims to explore the new research direction through the profound understanding of MAT.
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Objective To investigate the prevalence of dyslipidemia and the relationship between breakfast frequency and dyslipidemia in residents over 40 years old in Yiling area of Yichang City in Hubei Province. Methods A random sampling was conducted, and 10 420 inhabitants were investigated during 2011 to 2012. Results The morbidity of dyslipidemia was 64. 0%. It was significantly higher in female than in male (65. 9% vs 60. 6%). Compared with regular breakfast eaters, non-breakfast eaters had significantly higher morbidity of higher blood low density lipoprotein-cholesterol(LDL-C) and hypertriglyceridemia(P<0. 05). The risk of elevated serum LDL-C was higher in the non-breakfast eaters group(OR=2. 382, 95%CI 1. 300-4. 367, P=0. 019) after adjusted by age, sex, smoking, drinking, etc. Conclusions Compared with regular breakfast eaters, breakfast skippers had significantly higher morbidity of dyslipidemia. Eating breakfast on daily basis may have a significant protective effect on preventing dyslipidemia.
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ObjectiveTo investigate the effects of adult catch-up growth on insulin sensitivity and stress in rats, as well as the probable mechanism of insulin resistance. MethodsMale Sprague-Dawley rats were divided into 6 groups:caloric restriction group ( R4, caloric restriction for 4 weeks) and normal controls for 4 weeks ( NC4 ) ; catchup growth group refed with normal chow( RN4, refeeding for 4 weeks after caloric restriction for 4 weeks), catch-up growth group refed with high-fat diet( RH4, refeeding for 4 weeks after caloric restriction for 4 weeks ), normal chow (NC8) or high-fat diet( HF8 ) controls for 8 weeks. The animal model of catch-up growth was devoloped by way of refeeding after caloric restriction as scheduled. The glucose infusion rate( GIR ), 2-deoxyglucose uptake and insulinsitmulated insulin signaling in skeletal muscle during hyperinsulinemic-euglycemic clamp, plasma corticosterone, and 11β-hydroxysteroid dehydrogenase type 1 ( 11β-HSD1 ) mRNA expression level in skeletal muscle were determined.ResultsAfter caloric restriction for 4 weeks, plasma corticosterone and 1 1 β-HSD1 mRNA expression in skeletal muscle were significantly higher in R4 group compared with NC4 group( both P＜0. 05 ), but there were no differences in 2-deoxyglucose uptake and Ser473 phosphorylation of Akt in skeletal muscle between two groups. The plasma corticosterone and 11β-HSD1 mRNA expression in skeletal muscle in RN4 group were significantly higher than those in NC8 group, and were higher in RH4 group than those in NC8 and HF8 groups; while the 2-deoxyglucose uptake and insulin-stimulated Ser473 phosphorylation of Akt in skeletal muscle during the clamp in RN4 were remarkably lower than those in NC8 group, and were lower in RH4 than those in NC8, HF8, and RN4 groups (all P ＜ 0. 05 ).ConctusionsCatch-up growth rats refed with normal chow or high-fat diet are characterized by significant insulin resistance and stress in the whole body and skeletal muscle. These changes are more evident in catch-up growth rats refed with high-fat diet. The interaction of increased stress and diet might be of utmost importance in the etiology of insulin resistance in catch-up growth animals.
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The current study was designed to determine the safety, tolerability and pharmacokinetic parameters of recombinant human parathyroid hormone [rhPTH (1-84)] used for the treatment of osteoporosis. In the single-dose format pharmacokinetic study, thirty-six healthy male volunteers received three dose levels of rhPTH (1-84) subcutaneously: 1, 2, and 4 mug/kg. The blood was timing drawn and the serum concentration of rhPTH (1-84) was determined by enzyme linked immunosorbent assay (ELISA). Serum concentration-time curves of PTH (1-84) exhibited a double-peak pattern, the first peak appearing about 10 to 30 min after administration and the second peak occurring about 1.5 to2 h after administration. Serum terminal half-time of PTH (1-84) was approximately 2 h. The parameters indicated the serum levels were directly proportional to the administered dose, with the mean C(max) and AUC(0-24) ranging from approximately 543.47 to 1845 pg/mL and 2358.6 to 9232.12 pg.h.mL(-1) over the dose range. The drug was well tolerated, the clinical symptoms were generally mild and of short duration.
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Objective To investigate the effect of ovariectomy and estrogen on secretion function and number of pancreatic islet beta cell in low-dose streptozotocin-induced diabetic rats. Methods Thirty female SD rats were randomly divided into five groups: normal control(NC) group, streptozotocin(STZ) group, ovariectomized(OVX) group, OVX + STZ(OS) group and OVX+STZ+estradiol(OSE) group. OVX, OS and OSE groups underwent ovariectomy, while NC and STZ groups underwent just sham operation. After surgery, OSE group was treated subcutaneously with estradiol 0.2 mg/kg twice weekly. At the end of 3 weeks, STZ, OS and OSE groups were induced by a single intraperitoneal injection of 40 mg/kg STZ. Then eight days later, plasma glucose and insulin levels were tested. The insulin protein, the average beta cell area and the relative beta cell mass were tested by streptavidin peroxidase conjugation method (SP). The quantification of beta cell apoptosis was performed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expressions of proliferating cell nuclear antigen(PCNA) protein, Bax and Bcl-2 were tested. Results With the administration of low-dose STZ, the plasma glucose was significantly higher and the insulin secretion curve after glucose loading, △I30/△G30 and modified beta cell function index(MBCI) were lower in OVX group than in other groups(all P<0.05). At the same time, the insulin protein, the relative beta cell mass and the beta cell area were dramatically decreased(all P<0.05). The beta cell apoptotic index was increased (t = 2.957, P< 0.05), the expression ratio of Bcl-2/Bax was decreased (0.41±0.03 vs. 0.76±0.05, P<0.05). Estrogen replacement therapy could obviously inhibit these changes. Compared with OS group, glucose disturbances and insulin secretion were improved dramatically in OSE group(all P<0.05); the insulin content, the relative beta cell mass and the average beta cell area were all enhanced (all P<0.05); the beta cell apoptotic rate was decreased(t =2.482, P<0.05), and the expression tatio of Bcl-2/Bax was increased (0.71±0.05 vs. 0.41±0.03, P<0.05). Conclusions The ovx rats are significantly more susceptible to low-dose STZ toxicity than in control rats. Under the effect of STZ, the ability of insulin secretion of beta cell is obviously decreased, while apoptosis is increased, which induces a higher glucose level and a lower insulin secretion. Administration of estrogen may protect OVX rats from the metabolic disturbances.
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dation, transiently inercasod food efficiency,and a faster growth rate of visceral adipose tissue versus body weight after nutritional rehabilitation. These findings are consistent with the characteristics of human catch-up growth.
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Objective To observe the glucose utilization in adipose tissue and skeletal muscle during catch-up growth, and to explore the mechanism of catch-up growth of adipose tissue. Methods Male Wistar rats were randomly divide into normal control group(NC)and catch-up group(RN). Rats in RN group received 50%of food consumed by NC group for 4 weeks, then were re-fed spontaneously as the rats in NC group. In the end of the fifth week(NC1 group and RN1 group)and the sixth week(NC2 group and RN2 group), the experiment was performed. [3]-2-deoxy-glucose was used for detecting the glucose uptake rate. RT-PCR and Western-blot were used for detecting the levels of mRNA and membrane protein of glucose transporter-4(Glut4). Results The glucose uptake rates in adipose tissue and skeletal muscle of RN1 group increased by 189.6%(P<0.01)and reduced by 36.5%(P<0.05)respectively, as compared with NC1 group. After 2 weeks of catch-up growth, the glucose uptake rates in adipose tissue of RN2 group increased by 157.3%(P<0.01)and decreased by 41.5%(P<0.05) in skeletal muscle as compared with NC2 group. However. no significant difference in Glut4 mRNA levels in muscle or in adipose tissue between NC and RN groups were found. The membrane protein of GIut4 after insulin-stimulating in RN1 group and RN2 group reduced by about 46.5%(P<0.01)and 32.1%(P<0.05)in muscle and increased by 116.5%(P<0.01)and 89.9%(P<0.01)in adipose tissue respectively. Conclusion There exists the redistribution of glucose from skeletal muscle to adipose tissue during the early stage of catch-up growth, which results in the catch-up growth of adipose tissue. This change is induced by the tissue-specific alteration of insulin-stimulated Glut4 protein translocation.
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Objective To investigate whether the effect of pioglitazone on TNF-α-induced insulin resistance is associated with altering IRS-1-induced signaling. Methods 3T3-L1 adipocytes were treated with TNF-α for 24 hours with or without being pretreated with 10μM piglitazone for 6 hours or with pioglitazone alone.Insulin-stimulated glucose uptake of 3T3 adipocytes was measured by using 2-deoxy 3H glucose.The Western blot was used to measure IRS-1, PKB, PKC-λ protein and tyrosine phosphorylation on IRS-1, PKB and PKC-λ phosphorylation. Results Both TNF-α and pioglitazone increased glucose uptake of 3T3 adipocytes under basal status.On TNF-α treated cells, insulin-stimulated glucose uptake was decreased by about 50%, accompanied with the reductions of IRS-1 protein level, tyrosine-phosphorylation of IRS-1 and PKB phosphorylation.TNF-α treatment had no effect on PKC-λ phosphorylation. Pioglitazone pretreatment was able to antagonize TNF-α-induced insulin resistance in 3T3 adipocytes partly reverse IRS-1 protein, increase insulin-stimulated tyrosine phosphorylation of IRS-1,and increase phosphorylations of PKB and PKCλ. Conclusion TNF-α-induced insulin resistance in 3T3-L1 adipocytes is related to impaired tyrosine phosphorylation of IRS-1. Pioglitazone antagonizes the above TNF-α induced insulin resistance.
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Aim To study the effects of dexamethasone(DXM)and peroxisome-proliferation activated receptor?(PPAR?)agonist pioglitazone on intracellular cytokines expression of T_H1/T_H2 and the mechanism of that in asthma model,and compare the difference between two drugs.Methods 24 Balb/c mice were divided into 4 groups randomly: control group,asthma group,DXM group,and pioglitazone group,with 6 mice in each group.The expression of T-bet and GATA3 of lung were detected using western blot,and the intracellular cytokines interluekin 4 and interferon ? expressions of CD~(4+)Tcell were measured using flowcytometry.Results Compared with control group,the level of the expression of T-bet of lung in asthma group increased significantly(P0.05),while both of GATA3 and T-bet decreased after DXM treatment,and the decreasing degree of GATA3 was more than that of T-bet.The results of flowcytometry indicated that the ratio of intracellular cytokines IL-4/IFN? of CD~(4+) T cell in asthma group was much higher than that of control group(P
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Objective:To investigate glucose uptake and IRS-1-associated signaling pathway by stimulated insulin under TNF-? treatment.Methods:3T3-L1 adipocytes were treated with TNF-? within 6 hours and 24 hours respectively. 2-deoxy ~3H glucose was used to measure glucose uptake and western blot was used to measure IRS-1, PKB protein, tyrosine and serine307 phosphorylation on IRS-1, and PKB phosphorylation.Results:On basal status, glucose uptake of 3T3-L1 cells and phospho-tyrosine of IRS-1, PKB phosphorylation, and serine307 phosphorylation on IRS-1 were all low. Insulin stimulation induced glucose uptake and IRS-1 tyrosine phosphorylation, serine307 phosphorylation, PKB phosphorylation rapidly. TNF-? inhibited insulin-induced glucose uptake, tyrosine phosphorylation of IRS-1 and PKB phosphorylation. Rapamycin reversed the effects of TNF-?. Treated with TNF-? within 6 hours increased serine307 phosphorylation but had no effect on IRS-1 protein level. TNF-?-induced serine307 phosphorylation of IRS-1 was not affected by rapamycin. IRS-1 level was decreased under 24 hours TNF-? treatment and rapamycin can reverse the effect.Conclusion:TNF-? induced insulin resistance in 3T3-L1 adipocytes mightbe related to impaired IRS-1 tyrosine phosphorylation, rapamycin could reverse the effects of TNF-?. Treated with TNF-? within 6 hours stimulate phosphrylation of serine307 of IRS-1 and 24 hours treatment decreased IRS-1 protein level. Rapamycin antagonist TNF-?-induced loses of IRS-1.
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17β-estradiol(E2), progesterone (P) and testosterone (T) were investigated for their effects on the proliferation and differentiation of primary rat calvarial osteoblasts in vitro. Rat calvarial osteoblasts were cultured with l0-10 mol/L E2, 10-9-10-6 mol/L P and l0-10 mol/L T for 20days. Cell proliferation was determined by 3H-thymidine incorporation and cell counting. Cell differentiation was examined by measuring alkaline phosphatase (ALP) activity, osteocalcin gene expression and production, bone nodule formation in different periods of culture. Our results showed that no effect of three sex hormones was observed on cell proliferation, but, the responses of cell differentiation to the hormones were more or less different. Among these three hormones used in this study, P appeared to have multi-stimulating effect on cell differentiation. Effect of T seemed not so significant as that of P on cell differentiation. Although ALP activity and osteocalcin production were increased significantly by T, it had slight effect on osteocalcin mRNA and bone nodule formation. Besides, E2 did not demonstrate any effect on cell differentiation. It is concluded that the proliferation of rat calvarial osteoblasts was independent of the presence of sex hormones. However, the differentiation of these cells were stimulated in different levels and to different extent either by P or T. P appeared to be a multi-stimulator on differentiation of such cells.
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17β-estradiol(E2), progesterone (P) and testosterone (T) were investigated for their effects on the proliferation and differentiation of primary rat calvarial osteoblasts in vitro. Rat calvarial osteoblasts were cultured with l0-10 mol/L E2, 10-9-10-6 mol/L P and l0-10 mol/L T for 20days. Cell proliferation was determined by 3H-thymidine incorporation and cell counting. Cell differentiation was examined by measuring alkaline phosphatase (ALP) activity, osteocalcin gene expression and production, bone nodule formation in different periods of culture. Our results showed that no effect of three sex hormones was observed on cell proliferation, but, the responses of cell differentiation to the hormones were more or less different. Among these three hormones used in this study, P appeared to have multi-stimulating effect on cell differentiation. Effect of T seemed not so significant as that of P on cell differentiation. Although ALP activity and osteocalcin production were increased significantly by T, it had slight effect on osteocalcin mRNA and bone nodule formation. Besides, E2 did not demonstrate any effect on cell differentiation. It is concluded that the proliferation of rat calvarial osteoblasts was independent of the presence of sex hormones. However, the differentiation of these cells were stimulated in different levels and to different extent either by P or T. P appeared to be a multi-stimulator on differentiation of such cells.
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AIM: To study the effects of dexamethasone (DXM) on intracellular expression of TH1/TH2 cytokines and the mechanism of that during the development of asthma. METHODS: Eighteen BALB/c mice were divided into 3 groups at random: control group, asthma group, and DXM treated group, with 6 mice in each. The expressions of T-box expressed in T cells (T-bet) and GATA-binding protein-3 (GATA-3) in lung tissue were detected by Western blotting. The expressions of intracellular cytokines interleukin-4 and interferon-? in CD4+ T cell were measured by flowcytometry.RESULTS: The results of flow cytometry indicated that the ratio of intracellular cytokines IL-4/IFN-? in CD4+ T cells in asthma group was much higher than that in control group (P