ObjectiveTo investigate the effect of dapagliflozin on liver lipid metabolism and gut microecology in mice with metabolic associated fatty liver disease （MAFLD）， and to clarify its potential mechanism. MethodsA total of 50 male C57 mice were randomly divided into Control group， type 2 diabetes+MAFLD group （MAFLD group）， dapagliflozin group （DAPA group）， meldonium group （THP group）， and dapagliflozin+meldonium group （DAPA+THP group）， with 10 mice in each group. High-fat diet combined with streptozotocin was used to establish a mouse model of MAFLD. Treatment outcomes were assessed based on histopathology and biochemical parameters such as blood glucose and blood lipid levels， and the transcriptomic and metagenomic analyses were used to identify differentially expressed genes and the changes in gut microbiota. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the least significant difference t-test was used for comparison between two groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups， and the Nemenyi test was used for comparison between two groups. ResultsHistopathological examination showed that the mice in the MAFLD group had excessive lipid deposition and hepatocyte steatosis； compared with the MAFLD group， the DAPA group had a significant improvement in hepatocyte steatosis， while the THP group and the DAPA+THP group had a less significant improvement compared with the DAPA group. Compared with the Control group， the MAFLD group had a significant increase in fasting blood glucose （P<0.05）， significant increases in the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， malondialdehyde， total cholesterol， triglyceride， and low-density lipoprotein cholesterol （P<0.05）， and a significant reduction in high-density lipoprotein cholesterol （P<0.05）. Compared with the MAFLD group， the DAPA group， the THP group， and the DAPA+THP group had significant reductions in the serum levels of ALT and AST （P<0.05）. The results of 16S rRNA sequencing showed that compared with the Control group， the MAFLD group had significant changes in gut microbiota， with an increase in Firmicutes and a reduction in Bacteroidetes， as well as reductions in S24-7 and Erysipelotrichaceae and an increase in Lactobacillaceae. The levels of the above flora were upregulated to normal levels in the DAPA group， the THP group， and the DAPA+THP group. The liver transcriptomic analysis showed that the enriched metabolic pathways included steroid hormone biosynthesis， bile secretion， inflammatory mediator regulation of TRP， fatty acid elongation， and lipid biodegradation processes， and the related genes mainly involved the key targets of lipid metabolism such as Acot2， Angptl4， Scd2， and Npc1l1. ConclusionDapagliflozin can alleviate MAFLD through the pathways such as steroid hormone biosynthesis， bile secretion， inflammatory mediator regulation of TRP， and fatty acid elongation， as well as by regulating gut microbiota homeostasis.

Background::Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.Methods::Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.Results::ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). Conclusions::Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.Trial registration::Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Sepsis-associated encephalopathy (SAE) is the most common neurological complication of sepsis, with an incidence of up to 70% in sepsis, and contributes to the increased mortality and disability in sepsis. To date, the exact pathogenesis of SAE is not clear. Most of current researches indicated that blood-brain barrier (BBB) dysfunction, active neuroinflammation, glial cell over activation as well as cerebral microcirculation dysfunction contributed to the pathophysiology of SAE. BBB, as a complex cellular structure between the central nervous system and the peripheral system, strictly controls the entrance and discharge of substances and plays an important role in maintaining the balance between biochemical system and immune system of central system. During the progress of sepsis, inflammatory cytokines and reactive oxygen species resulting from peripheral system directly or indirectly resulted in the damage to the integrity and structure of BBB, which helped above species easily enter into the central system. Above these damages caused glial cell activation (microglia and astrocyte), the imbalance of neurotransmitters, mitochondrial dysfunction and neural apoptosis, which also reversely contributed to the damage to the integrity and permeability of BBB via decreasing the expression of tight junctional protein between cells. Therefore, this review focuses on the structural and functional changes of BBB in SAE, and how these changes lead to the development of SAE, in order to seek a BBB-targeted therapy for SAE.

Objective To investigate the protective effect of curcumin (Cur) against arsenic-induced neuroimmune toxicity and the underlying molecular mechanisms in vivo. Methods Eighty SPF female C57BL/6 mice were randomly assigned to four groups: a control group, an arsenic-treated group, a Cur-treated group and an arsenic+Cur group, with 20 mice in each group. The control group received distilled water; the arsenic-treated group was given 50 mg/L NaAsO₂ in the drinking water; the Cur-treated group was gavaged with 200 mg/kg of curcumin for 45 days; and the arsenic+Cur group received distilled water and was gavaged with 200 mg/kg of curcumin. Y-maze and Morris water maze experiments were conducted to assess the learning and memory ability of the mice. Western blot analysis was used to detect protein levels of blood-brain barrier tight junction proteins zonula occludens protein 1(ZO-1) and claudin 5, T lymphocyte subpopulation CD4 and CD8, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway-related molecules JAK2 and STAT3. Real-time PCR was used to assess the mRNA levels of CD4⁺ T lymphocyte subsets type 1 T helper (Th1), Th2, Th17 and regulatory T cells (Treg) transcription factors and cytokines in hippocampus. Results Compared with the control group, the arsenic-treated group showed a significantly decreased correct rate, increased latency to reach the platform on the third and fifth days, and reduced times of crossing the platform. The expression of ZO-1 and claudin 5 protein decreased significantly, and the protein levels of CD4 and CD8 were up-regulated. The mRNA levels of Th1, Th17, and Treg transcription factor T-box expressed in T cell(T-bet), retinoid-related orphan receptor gamma t(RORγt), and forkhead box protein 3(FOXP3) in the arsenic-treated group were decreased. Th1 and Th17 cytokines interferon γ(IFN-γ) and interleukin 17(IL-17) were markedly decreased. In contrast, the mRNA levels of the Th2 transcription factor GATA binding protein 3(GATA3) and cytokine IL-4 in arsenic-treated group were higher than those in the control group. Furthermore, the protein levels of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) increased. Compared with the arsenic-treated group, the arsenic+Cur group demonstrated a significantly increased correct rate, decreased latency to reach the platform on the third and fifth days, and increased times of crossing the platform. The protein expression levels of ZO-1 and claudin 5 increased significantly, and the protein levels of CD4 and CD8 were down-regulated. The mRNA levels of Th2 transcription factor GATA3 and cytokine IL-4 were decreased. The mRNA levels of Th17 transcription factor RORγt and cytokine IL-17 were markedly increased. Furthermore, the protein levels of p-JAK2 and p-STAT3 decreased. Conclusion Through inhibiting the JAK2/STAT3 signaling pathway, curcumin could improve arsenic-induced decline in learning and memory abilities in mice, reverse the destruction of blood-brain barrier permeability of innate immune system components in arsenic-exposed mice, and antagonize arsenic-induced increase in the number of renal CD4 and CD8 molecule as well as the imbalance of CD4⁺ T lymphocyte subsets (Th1, Th2, Th17 and Treg), ultimately counteracting arsenic-induced neurotoxicity.
Animals ; Janus Kinase 2/genetics* ; STAT3 Transcription Factor/genetics* ; Female ; Curcumin/pharmacology* ; Signal Transduction/drug effects* ; Mice, Inbred C57BL ; Mice ; Arsenic/toxicity*

Objective:To explore the effect of core stability training on rehabilitation of patients after lumbar fusion.Methods:From June 2018 to December 2019, 90 patients with lumbar fusion admitted to Wuxi Second Hospital Affiliated to Nanjing Medical University were selected by convenience sampling. The patients were divided into control group and training group according to the method of random number table, with 45 cases in each group. The control group received routine postoperative rehabilitation nursing, while the training group carried out postoperative core stability training nursing. The rehabilitation effects of the two groups were observed.Results:The scores of Numerical Rating Scale (NRS) in the training group were lower than those in the control group at 2, 4, 12 and 24 weeks postoperatively, and the difference were statistical ( P<0.05) . The scores of Oswestry Disability Index (ODI) in the training group 12 and 24 weeks after operation were lower than those in the control group, with statistically significant differences ( P<0.05) . Conclusions:The core stability training nursing is helpful to improve the functional recovery after lumbar fusion, reduce the degree of postoperative pain, and then increase the rehabilitation effect of patients.

Spermatogenesis is a continual process that occurs in the testes, in which diploid spermatogonial stem cells (SSCs) differentiate and generate haploid spermatozoa. This highly efficient and intricate process is orchestrated at multiple levels. N⁶-methyladenosine (m⁶A), an epigenetic modification prevalent in mRNAs, is implicated in the transcriptional regulation during spermatogenesis. However, the dynamics of m⁶A modification in non-rodent mammalian species remains unclear. Here, we systematically investigated the profile and role of m⁶A during spermatogenesis in pigs. By analyzing the transcriptomic distribution of m⁶A in spermatogonia, spermatocytes, and round spermatids, we identified a globally conserved m⁶A pattern between porcine and murine genes with spermatogenic function. We found that m⁶A was enriched in a group of genes that specifically encode the metabolic enzymes and regulators. In addition, transcriptomes in porcine male germ cells could be subjected to the m⁶A modification. Our data show that m⁶A plays the regulatory roles during spermatogenesis in pigs, which is similar to that in mice. Illustrations of this point are three genes (SETDB1, FOXO1, and FOXO3) that are crucial to the determination of the fate of SSCs. To the best of our knowledge, this study for the first time uncovers the expression profile and role of m⁶A during spermatogenesis in large animals and provides insights into the intricate transcriptional regulation underlying the lifelong male fertility in non-rodent mammalian species.
Animals ; Male ; Mice ; Cell Differentiation/genetics* ; Mammals/metabolism* ; Methylation ; RNA, Messenger/metabolism* ; Spermatogenesis/genetics* ; Spermatozoa/metabolism* ; Swine/genetics* ; Testis/metabolism* ; Transcriptome ; RNA Methylation/genetics*

Objective: To observe the efficacy of electroacupuncture (EA) in treating dry eye syndromes (DES) and its regulatory effects on patient's quality of life (QOL), anxiety, and depression.Methods: By following a randomized controlled study design, eligible DES patients were allocated to an EA group (EAG) or an acupuncture group (AG). Patients in the AG were intervened by acupuncture alone, while in the EAG, electrical stimulation was applied to Cuanzhu (BL2) and Taiyang (EX-HN5) in addition to the same treatment in the AG. Changes in clinical manifestations, ocular surface disease index (OSDI), Schirmer tear test-1 (STT-1), tear-film break-up time (TF-BUT), cornea fluorescein staining (CFS), and corneal sensitivity (CS) were observed, as well as changes in the short-form 36-item health survey (SF-36) and hospital anxiety and depression scale (HADS) scores. Results: The scores of clinical symptoms, OSDI, and CFS decreased significantly in both EAG and AG when compared with the baseline values (P<0.05), respectively, while the TF-BUT and CS increased significantly (P<0.05), and the tear secretion of patients in the EAG increased (P<0.05). Compared with those before treatment, the scores of physical role functioning, general health perception, emotional role functioning, and mental health of patients in both EAG and AG showed significant increases after treatment (P<0.05), together with a marked decrease in the score of anxiety (P<0.05). Compared with the AG, the EAG obtained a more significant increase in STT-1 (P<0.05).Conclusion: DES patients respond well to both EA and acupuncture treatments, manifested by prolonged TF-BUT and improvement of CS. Meanwhile, the two approaches can improve QOL and reduce anxiety. Furthermore, EA appears more effective in increasing tear secretion than acupuncture alone.

Objective:To compare the clinical and imaging characteristics of patients with stage I coal worker's pneumoconiosis (CWP) .Methods:All 347 cases of coal workers' pneumoconiosis diagnosed in the Third Hospital of Peking University from January 2014 to December 2018 were included in the study. According to different working posts, the subjects were divided into three categories: mining, tunneling and mixing workers. Dust exposure duration, initial dust exposure age, diagnosis age, latency, small shadow shape and lung regions distribution in X-ray chest film of different categories of CWP patients were analyzed.Results:Among the 347 patients, 216 were mining workers (62.2%) , 77 were tunneling workers (22.2%) and 54 were mixing workers (15.6%) . The dust exposure duration of mining, tunneling and mixing workers were (14.5±7.0) , (16.3±8.2) and (19.0±8.8) years, respectively. There are statistically significant differences in dust exposure duration between different categories of workers ( P<0.05) . There were no significant difference in the age of diagnosis, initial dust exposure age and the latency between different categories of workers ( P>0.05) . The X-ray films of mining, tunneling and mixing workers showed small round shadow, accounting for 50.9% (110/216) , 96.1% (74/77) and 96.3% (52/54) respectively. 48.1% (104/216) of the mining workers and 38.9% (21/54) of mixing workers, the distribution of small shadow in chest X-ray films reached middle and lower lung regions, while in the 48.1% (37/77) of the tunneling workers, the distribution of small shadow in chest X-ray films reached lower lung regions. There were differences in above indicators among workers with different categories ( P<0.05) . Conclusion:The dust exposure duration, the shape and the distribution of lung area on chest X-ray films are different in stage I CWP patients of different occupational categories.

Objective:To explore the correlation between occupational gasoline exposure and metabolic syndrome (MS) .Methods:In September 2019, a total of 147 occupational gasoline exposure workers from a oil sales company in Beijing were selected as the observation group by using cluster sampling method, 158 people without gasoline exposure from the company were selected as the control group. Occupational health examination were performed to measure body mass, blood pressure and fasting plasma glucose (FPG) , triglycerides (TG) , high-density lipoprotein cholesterol (HDL-C) and other data. General demographic characteristics, occupational history, past medical history and personal history were analyzed either.Results:The levels of systolic blood pressure, diastolic blood pressure, FPG, TG and BMI in the observation group were all higher than those in the control group ( P<0.05) . The detection rates of MS, obesity and hypertension in the observation group were all higher than those in the control group ( P<0.05) . There were no significant differences in age, gender, working age, drinking, smoking, marital status, HDL-C level, detection rates of abnormal TG and HDL-C between the observation group and the control group ( P>0.05) . The odds ratio ( OR) of MS in the observation group was 1.988 times that in the control group ( P<0.05) . Conclusion:Occupational gasoline exposure is associated with the increasing detection rate of MS.

Objective:To compare the clinical and imaging characteristics of patients with stage I coal worker's pneumoconiosis (CWP) .Methods:All 347 cases of coal workers' pneumoconiosis diagnosed in the Third Hospital of Peking University from January 2014 to December 2018 were included in the study. According to different working posts, the subjects were divided into three categories: mining, tunneling and mixing workers. Dust exposure duration, initial dust exposure age, diagnosis age, latency, small shadow shape and lung regions distribution in X-ray chest film of different categories of CWP patients were analyzed.Results:Among the 347 patients, 216 were mining workers (62.2%) , 77 were tunneling workers (22.2%) and 54 were mixing workers (15.6%) . The dust exposure duration of mining, tunneling and mixing workers were (14.5±7.0) , (16.3±8.2) and (19.0±8.8) years, respectively. There are statistically significant differences in dust exposure duration between different categories of workers ( P<0.05) . There were no significant difference in the age of diagnosis, initial dust exposure age and the latency between different categories of workers ( P>0.05) . The X-ray films of mining, tunneling and mixing workers showed small round shadow, accounting for 50.9% (110/216) , 96.1% (74/77) and 96.3% (52/54) respectively. 48.1% (104/216) of the mining workers and 38.9% (21/54) of mixing workers, the distribution of small shadow in chest X-ray films reached middle and lower lung regions, while in the 48.1% (37/77) of the tunneling workers, the distribution of small shadow in chest X-ray films reached lower lung regions. There were differences in above indicators among workers with different categories ( P<0.05) . Conclusion:The dust exposure duration, the shape and the distribution of lung area on chest X-ray films are different in stage I CWP patients of different occupational categories.