Change in healthy lifestyle and subsequent risk of cognitive impairment among Chinese older adults: a National Community-Based Cohort Study.

BACKGROUND: The association between change in lifestyle and cognitive impairment remains uncertain. OBJECTIVE: To investigate the association of change in lifestyle with cognitive impairment. METHODS: In this study, 4,938 participants aged 65 or above were involved from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) for years of 2008-2018. A weighted healthy lifestyle score was derived from four lifestyle factors (smoking, alcohol consumption, physical activity, and diet). Multivariable Cox proportional hazards regression models were applied to investigate the associations between 3-year changes in healthy lifestyle (2008-2011) and cognitive impairment (2011-2018). RESULTS: We documented 833 new-onset of cognitive impairments over 20,097 person-years of follow-up. Compared with in persistently unhealthy group, those in the improved and persistently healthy groups had a lower risk of cognitive impairment, with the multivariate-adjusted hazard ratios (HRs) of 0.67 (95% confidence interval (CI): 0.55, 0.83) and 0.53 (95% CI: 0.40, 0.71), respectively. Furthermore, a significant interaction was observed between change in lifestyle and sex (P-interaction = 0.032); the HRs were 0.48 (95% CI, 0.34, 0.69) for the improved group and 0.41 (95% CI: 0.26, 0.64) for persistently healthy group among male vs 0.81 (95%CI, 0.63, 1.04) and 0.64 (95%CI, 0.44, 0.92) among female, respectively. CONCLUSION: This study suggests that improving or maintaining a healthy lifestyle can significantly mitigate the risk of cognitive impairment in Chinese elderly adults. Additionally, our findings emphasize the significance of maintaining a healthy lifestyle and highlights the potential positive impact of improving previous unhealthy habits, especially for elderly women.

Using Gaussian accelerated molecular dynamics combined with Markov state models to explore the mechanism of action of new oral inhibitors on Complex I.

In this study, our focus was on investigating H-1,2,3-triazole derivative HP661 as a novel and highly efficient oral OXPHOS inhibitor, with its molecular-level inhibitory mechanism not yet fully understood. We selected the ND1, NDUFS2, and NDUFS7 subunits of Mitochondrial Complex I as the receptor proteins and established three systems for comparative analysis: protein-IACS-010759, protein-lead compound 10, and protein-HP661. Through extensive analysis involving 500 ns Gaussian molecular dynamics simulations, we gained insights into these systems. Additionally, we constructed a Markov State Models to examine changes in secondary structures during the motion processes. The research findings suggest that the inhibitor HP661 enhances the extensibility and hydrophilicity of the receptor protein. Furthermore, HP661 induces the unwinding of the α-helical structure in the region of residues 726-730. Notably, key roles were identified for Met37, Phe53, and Pro212 in the binding of various inhibitors. In conclusion, we delved into the potential molecular mechanisms of triazole derivative HP661 in inhibiting Complex I. These research outcomes provide crucial information for a deeper understanding of the mechanisms underlying OXPHOS inhibition, offering valuable theoretical support for drug development and disease treatment design.

Metabolic risks remain a serious threat to cardiovascular disease: findings from the Global Burden of Disease Study 2019.

Metabolic factors are major and controllable risk factors for cardiovascular diseases (CVD), and few studies have described this burden. We aim to assess it from 1990 to 2019 and predict the trends through 2034. Global Burden of Disease (GBD) provides data on sex, age, and socio-demographic index (SDI) levels. Numbers, age-standardized death rates (ASDR) and estimated annual percentage change (EAPC) were used. Future trends were estimated by NORDPRED model. The deaths cases of metabolic-related CVD increased from 8.61 million (95% UI: 7.91-9.29) to 13.71 million (95% UI: 12.24-14.94) globally. The ASDR continued to decline globally (EAPC = -1.36). The burden was heavier in male and middle-aged people and elderly people. CVD-related ASDR caused by high systolic blood pressure (SBP) had a downward trend globally (EAPC = -1.45), while trends of high body mass index (BMI) (EAPC = 1.29, 1.97, 0.92) and fasting plasma glucose (FPG) (EAPC = 0.95, 1.08, 0.46) were increasing in the middle, low-middle, and low SDI regions, respectively. Compared to 2015-2019, cumulative deaths will increase by 27.85% from 2030 to 2034, while ASDR will decrease 10.47%. The metabolic-related CVD burden remained high globally and deaths will continue to rise in the future. Men, middle-aged and elderly people were focus of concern. High SBP was globally well-managed over the past 30 years, but the CVD burden due to high BMI and FPG remained high. Exceptional initiatives are needed to regarding interventions targeting high BMI and FPG in middle and lower SDI regions.

Global, regional, and national incidence trends of depressive disorder, 1990-2019: An age-period-cohort analysis based on the Global Burden of Disease 2019 study.

BACKGROUND: Depressive disorder is a severe global public health problem. It is crucial to evaluate the global incidence trends of depressive disorder. METHODS: The incidence data were drawn from the Global Burden of Disease Study (GBD) 2019. Estimates were presented by global and sociodemographic index (SDI) quintiles, and the age-period-cohort (APC) model was used to estimate the incidence trends. RESULTS: APC analysis indicated a decline in depressive disorder incidence globally (net drift = -0.24%, 95%CI: -0.29, -0.18), except for an increase in SDI regions (net drift = 0.07, 95%CI:0, 0.14). In high SDI regions, depressive disorder incidence increased among the younger and declined among the elder population, whereas the opposite trend was observed in middle and low-middle SDI regions. The depressive disorder incidence increased significantly among people aged 15 to 24 years after adjusting for age effects, decreased since 2000 after adjusting for period effects and increased rapidly in the birth cohort after 1990 in high SDI by adjusting for cohort effects. CONCLUSION: Globally, there was a declining trend of depressive disorder incidence in 1990-2019. Specifically, the incidence was declining globally in younger populations, while increasing in older populations. However, this trend differed depending on the SDI of the region.

Association between inflammatory biomarkers and mortality in individuals with type 2 diabetes: NHANES 2005-2018.

PURPOSE: This study aimed to examine independent association between inflammatory biomarkers and all-cause mortality as well as cardio-cerebrovascular disease (CCD) mortality among U.S. adults with diabetes. METHODS: A cohort of 6412 U.S. adults aged 20 or older was followed from the start until December 31, 2019. Statistical models such as Cox proportional hazards model (Cox) and Kaplan-Meier (K-M) survival curves were employed to investigate the associations between the inflammatory biomarkers and all-cause mortality and CCD mortality. RESULTS: After adjusting for confounding factors, the highest quartile of inflammatory biomarkers (NLR HR = 1.99; 95 % CI:1.54-2.57, MLR HR = 1.93; 95 % CI:1.46-2.54, SII HR = 1.49; 95 % CI:1.18-1.87, SIRI HR = 2.32; 95 % CI:1.81-2.96, nLPR HR = 2.05; 95 % CI:1.61-2.60, dNLR HR = 1.94; 95 % CI:1.51-2.49, AISI HR = 1.73; 95 % CI:1.4 1-2.12)) were positively associated with all-cause mortality compared to those in the lowest quartile. K-M survival curves indicated that participants with an inflammatory biomarker above a certain threshold had a higher risk of both all-cause mortality and CCD mortality (Log rank P < 0.05). CONCLUSION: Some biomarkers such as NLR, MLR, SII, AISI, SIRI, and dNLR, are significantly associated with all-cause mortality and CCD mortality among U.S. adults with diabetes. The risk of both outcomes increased when the biomarkers surpassed a specific threshold.

Network Pharmacology Combined with Machine Learning to Reveal the Action Mechanism of Licochalcone Intervention in Liver Cancer.

There are reports indicating that licochalcones can inhibit the proliferation, migration, and invasion of cancer cells by promoting the expression of autophagy-related proteins, inhibiting the expression of cell cycle proteins and angiogenic factors, and regulating autophagy and apoptosis. This study aims to reveal the potential mechanisms of licochalcone A (LCA), licochalcone B (LCB), licochalcone C (LCC), licochalcone D (LCD), licochalcone E (LCE), licochalcone F (LCF), and licochalcone G (LCG) inhibition in liver cancer through computer-aided screening strategies. By using machine learning clustering analysis to search for other structurally similar components in licorice, quantitative calculations were conducted to collect the structural commonalities of these components related to liver cancer and to identify key residues involved in the interactions between small molecules and key target proteins. Our research results show that the seven licochalcones molecules interfere with the cancer signaling pathway via the NF-κB signaling pathway, PDL1 expression and PD1 checkpoint pathway in cancer, and others. Glypallichalcone, Echinatin, and 3,4,3',4'-Tetrahydroxy-2-methoxychalcone in licorice also have similar structures to the seven licochalcones, which may indicate their similar effects. We also identified the key residues (including ASN364, GLY365, TRP366, and TYR485) involved in the interactions between ten flavonoids and the key target protein (nitric oxide synthase 2). In summary, we provide valuable insights into the molecular mechanisms of the anticancer effects of licorice flavonoids, providing new ideas for the design of small molecules for liver cancer drugs.

Low-Carbohydrate and Low-Fat Diet with Metabolic-Dysfunction-Associated Fatty Liver Disease.

BACKGROUND: This observational cross-sectional study was designed to explore the effects of a low-carbohydrate diet (LCD) and a low-fat diet (LFD) on metabolic-dysfunction-associated fatty liver disease (MAFLD). METHODS: This study involved 3961 adults. The associations between LCD/LFD scores and MAFLD were evaluated utilizing a multivariable logistic regression model. Additionally, a leave-one-out model was applied to assess the effect of isocaloric substitution of specific macronutrients. RESULTS: Participants within the highest tertile of healthy LCD scores (0.63; 95% confidence interval [CI], 0.45-0.89) or with a healthy LFD score (0.64; 95%CI, 0.48-0.86) faced a lower MAFLD risk. Furthermore, compared with tertile 1, individuals with unhealthy LFD scores in terile 2 or tertile 3 had 49% (95%CI, 1.17-1.90) and 77% (95%CI, 1.19-2.63) higher risk levels for MAFLD, respectively. CONCLUSIONS: Healthy LCD and healthy LFD are protective against MAFLD, while unhealthy LFD can increase the risk of MAFLD. Both the quantity and quality of macronutrients might have significant influences on MAFLD.

Association of perfluoroalkyl and polyfluoroalkyl substances with sex hormones in children and adolescents 6-19 Years of age.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have raised concerns regarding sex hormones homeostasis disruption in critical windows including childhood and adolescence, but epidemiological evidence is limited. We aimed to explore the associations of total testosterone (TT), estradiol (E2), and sex hormone binding globulin (SHBG) in children and adolescents with PFAS in 921 participants 6-19 years of age from NHANES 2013 to 2016. Multiple linear regression models and Bayesian Kernel Machine Regression (BKMR) models stratified by sex-age and sex-puberty-status groups were performed to explore the associations of the associations of individual or mixture of PFAS with sex hormone levels, respectively. Inverse associations were observed between n-PFOA and SHBG in female adolescents when the exposure was modeled as continuous (ß = -0.20, 95% CI -0.33, -0.07) or categorized variable (P for trend = 0.005). In children, inverse associations were observed by BKMR in 6-11-year-old girls of high concentration, and in boys of low concentration of the PFAS mixture with TT. A positive association of PFAS mixture with SHBG was observed in boys. PFOS and PFNA were identified as major contributors to the associations in girls and boys, respectively. Although the 95% credible intervals included the null in adolescents, suggestive negative associations of PFAS mixture with TT and SHBG levels in adolescents aged 12-19 years were found by BKMR. Results by sex-puberty status presented a similar pattern, where significantly inverse associations between PFAS mixture and E2 were observed in the pubertal. Our findings suggested the associations of either individual or mixture PFAS with decreased TT levels, and increased SHBG levels in U.S. children and adolescents, and with decreased E2 levels in pubertal individuals. The associations were evident in children.

Weighted gene co-expression network-based identification of genetic effect of mRNA vaccination and previous infection on SARS-CoV-2 infection.

To investigate the effect conferred by vaccination and previous infection against SARS-CoV-2 infection in molecular level, weighted gene co-expression network analysis was applied to screen vaccination, prior infection and Omicron infection-related gene modules in 46 Omicron outpatients and 8 controls, and CIBERSORT algorithm was used to infer the proportions of 22 subsets of immune cells. 15 modules were identified, where the brown module showed positive correlations with Omicron infection (r = 0.35, P = 0.01) and vaccination (r = 0.62, P = 1 × 10-6). Enrichment analysis revealed that LILRB2 was the unique gene shared by both phosphatase binding and MHC class I protein binding. Pathways including "B cell receptor signaling pathway" and "FcγR-mediated phagocytosis" were enriched in the vaccinated samples of the highly correlated LILRB2. LILRB2 was also identified as the second hub gene through PPI network, after LCP2. In conclusion, attenuated LILRB2 transcription in PBMC might highlight a novel target in overcoming immune evasion and improving vaccination strategies.

Spontaneous regression of a large sequestered lumbar disc herniation: a case report and literature review.

Lumbar disc herniation is a common disorder in adults that is accompanied by lower back and radicular pain. A 32-year-old man visited our clinic with 1-week history of persistent lower back pain and weakness in his right big toe. Magnetic resonance imaging (MRI) of his lumbar spine revealed herniated discs at L3/L4, L5/S1 and L4/L5, where a right-sided intraspinal mass lesion deep to the L4 vertebral body was causing compression of the nerve root. The patient underwent conservative treatment and reported no symptoms referrable to his back or leg 4 months later. Follow-up MRI showed no herniation of the nucleus pulposus at the L4/L5 level or lesion deep to the vertebral body of L4, whereas no changes had occurred to the status of the herniated L3/L4 and L5/S1 discs. The present case and a literature review show that a sequestered lumbar disc herniation can regress within a relatively short timeframe without surgery. The authors emphasise the utility of conservative therapy for patients who do not have a definitive surgical indication.

[Research on TCM periodical Tong su yi shi yue kan (Popular Medical Monthly), a magazinepublished in Peking in the Republican period].

The Popular Medical Monthly, a periodical inaugurated by the Aiyou Society in October, 1919, was the earliest TCM periodical published in Peking, the goal of which was to spread common medical knowledgeand hygienic ideas. It included discussion, translation, investigation, random talk, record, and corresponding, featuring popularizing medical and hygienic conception to the populace, upgrading people's knowledge on seasonal epidemic disases, etc.

Identification of synthetic peptides that inhibit lipopolysaccharide (LPS) binding to myeloid differentiation protein-2 (MD-2).

Many studies have suggested that the synergic effect of myeloid differential protein-2 (MD-2) on bacterial lipopolysaccharide (LPS) stimulation of toll-like receptor 4 (TLR4) may be a critical step during the LPS-TLR4 response signaling pathway. We performed a bioinformatic analysis on the MD-2 protein and identified the amino acid sequence NH2-FSKGKYKCV-COOH (K128-132) as a possible key sequence involved in the binding between MD-2 and LPS. We then screened a random phage display peptide library using this sequence as bait in order to identify antagonistic peptides. After 3 rounds of selection, 3 positive clones were identified. All 3 peptides were shown to inhibit, in a dose-dependent manner the production of tumor necrosis factor-α and interleukin-6 in human U937 and THP-1 cell lines as well as human peripheral blood monocytes stimulated by LPS. Only 2 of the 3 peptides were able to bind MD-2 directly as shown by sulfo-SBED biotin label transfer experiments. BALB/C mice were used to estimate the protection of these peptides from LPS challenge, and 2 of the 3 peptides (Lys-Thr-Val-Pro-Asp-Asn-His and Ile-Gly-Lys-Phe-Leu-Tyr-Arg) reduced mortality of the challenged mice from 100% to 53.8%. This study has demonstrated that interfering with the binding between MD-2 and LPS might be a potential therapeutic strategy for treating LPS-induced sepsis, and in doing so has identified 2 potential peptide candidates.

[Cloning and identification of NF-kappaB p50 Rel homology domain and detection of its autonomous reporter gene activity].

AIM: To clone NF-kappaB p50 Rel homology domain (RHD) gene and construct the "bait" vector in yeast two-hybrid system, and detect the yeast cell toxicity and autonomous reporter gene activity of target gene. METHODS: Total RNA was extracted from human peripheral blood mononuclear cells and NF-kappaB p50 RHD gene was amplified by RT-PCR, and cloned into pGBKT7. The recombinant plasmid was transformed into yeast AH109. The growth condition of the transformants was observed in the selected medium SD/-Trp. The reporter gene activity of target gene in the yeast cells was verified by filter blotting. RESULTS: Using restriction enzyme digestion analysis and PCR, the length of inserted gene was confirmed correct. Sequencing result indicated that the sequence of the inserted gene and its open reading frame were completely correct, and then the recombinant plasmid was named pGBKT7-p50. p50 RHD gene had neither autonomous reporter gene activity nor yeast cytotoxicity. CONCLUSION: As a bait plasmid, pGBKT7-p50 could be used in yeast two-hybrid system to screen and capture the polypeptides which interact with p50 RHD.

[Changes in human leukocyte antigen-DR expression on monocytes and its value of prediction on infection complication in trauma patients].

OBJECTIVE: To observe the changes of human leukocyte antigen DR (HLA-DR) expression in monocytes of trauma patients and its value of prediction on infection complications. METHODS: Fifty-four trauma patients were divided into three groups according to severity of injury: severe trauma group injury severity score (ISS) >or=25, moderate trauma group (16or=16) were divided into three groups according to infection or not: no infection group, localized infection group and systemic infection group. Blood samples were collected immediately after admission and serially at 8:30 to 9:00 a.m. on days 1, 2, 4, 6, 8, 14 after admission, and monocyte HLA-DR expression was determined with monoclonal staining and flow cytometry. RESULTS: The HLA-DR expression in monocytes was reduced in the trauma patients. The lowest levels of HLA-DR were recorded on day 2 after trauma. Subsequently HLA-DR expression in monocytes increased gradually. During the whole observation, the HLA-DR expression was significantly decreased in both severe trauma group and moderate trauma group versus control group, but no significant differences were found between severe trauma group and moderate trauma group, mild trauma group and control group, Immediately after trauma, HLA-DR expression in monocytes was significantly lower in the localized infection group than that in the patients without infection, and lasted until day 4 after trauma. The mean fluorescence intensity of HLA-DR expression in monocytes on the day 2 to 14 after trauma, the percentage of HLA-DR monocytes on the day 1 to 14 after trauma were significantly lower in the systemic infection group than those in the localized infection group. The level of HLA-DR expression in monocyte in the 2 died trauma patients was lowered till died. CONCLUSION: In severe trauma patients, the HLA-DR expression in monocytes is significantly decreased, and decreased levels of HLA-DR expression in monocytes might be the early indicators of an immune deviation associated with the development of infection complications and prognosis.

[Effect of severe thoracic trauma combined with endotoxin challenge on phagocytosis function of alveolar macrophages and pulmonary interstitial macrophages].

OBJECTIVE: To observe the difference of phagocytosis between alveolar macrophages and pulmonary interstitial macrophages, and to investigate their responses to severe thoracic trauma with or without lipopolysaccharide (LPS) challenge. METHODS: A rat model of severe thoracic trauma was reproduced by thoracic impact machine. The alveolar macrophages and interstitial macrophages were isolated before injury and at 2, 4, 8, 16, 24 hours after injury respectively. The dynamic changes of these macrophage phagocytosis were tested by malachite green colorimetry. RESULTS: Macrophage phagocytosis function was increased during the early stage after trauma (2 and 4 hours) and then decreased. The phagocytosis function of alveolar macrophages was stronger than that of interstitial macrophages in all time points before and after trauma. After challenge with LPS, no further significant effect on the alveolar macrophages was found, while LPS challenge could stimulate the phagocytosis of interstitial macrophages. CONCLUSION: Alveolar macrophages and pulmonary interstitial macrophages are functional heterogeneous, and their response to trauma and combined with endotoxin challenge are different. The results indicate that the two subgroups of macrophages play different roles in immune function disorder after trauma.

Relations of transcription expression of IL-2 with nuclear factor of activated T cells as well as changes of C-Fos and C-Jun after trauma.

OBJECTIVE: To observe the relations among expression of interleukin-2 (IL-2) in spleen lymphocytes, DNA binding activity of nuclear factor of activated T cells (NFAT) and expression of the partly family members C-Fos, C-Jun after trauma. METHODS: A murine closed trauma model was used, animals were sacrificed 6, 12 hours and 1, 4, 7, 10, 14 days, respectively after injury. Spleen lymphocytes were isolated from injured mice and stimulated with concanavalin-A. The culture supernatants were harvested and assayed for IL-2 activity. Total RNA was extracted from spleen lymphocytes and assayed for IL-2 mRNA. Nuclear protein was extracted, and the DNA binding activity of NFAT was measured using an electrophoretic mobility shift assay (EMSA), the expressions of C-Fos, C-Jun protein determined by Western blot analysis. RESULTS: The expressions of IL-2 activity and IL-2 mRNA in spleen lymphocytes were decreased in injured mice compared with those in control mice, and the most obvious decrease appeared on the 4th day after injury. The DNA binding activity of NFAT decreased gradually and reached the minimum that was only 41% of the control on the 4th day after injury, which was closely associated with the decline of IL-2 activity and IL-2 mRNA. An decrease in the expression of C-Fos on the 1st and 4th day after injury, trauma had no significant effect on the C-Jun expression. CONCLUSIONS: These results suggest that the inhibition of IL-2 expression is partly due to the impairment in the activation of NFAT in injured mice; and the decline in the DNA binding activity of NFAT is partly due to trauma block in the C-Fos expression.

Expression of positive and negative regulators of cell cycle during wound healing.

OBJECTIVE: To detect the expression of cell cycle positive regulators cyclin D(1), cyclin E, CDK(2), CDK(4) and negative regulators p21(cip1), p27(kip1), p16(ink4a) and p15(ink4b) during wound healing in rats. METHODS: Open wounds of full-thickness skin, diameter 1.8 cm, on rat backs were used as the wound model. Wound tissues were harvested on postwounding days 3, 5, 7, 9, 11, 14, 21 and 30. Ki67 expression in granulation tissue was detected by immunohistochemical assay. The patterns of the expression of cyclin D(1), cyclin E, CDK(2), CDK(4) and p21(cip1), p27(kip1), p16(ink4a), p15(ink4b) were detected by Western blot. RESULTS: Cell proliferation in granulation tissue took place predominantly within the first week after injury, with the proliferation peak occurring at postwounding day 5. There were no dramatic variations in the expression of cyclin D(1), CDK(2) and CDK(4) during wound healing. Up-regulated cyclin E was maintained from day 3 to 11 after injury, and then was down-regulated. No expression of p16(ink4a) and p15(ink4b) was found. p21(cip1) was expressed only from day 7 to 14, with peak expression observed on day 9. Constitutive p27(kip1) was expressed throughout wound healing with low levels in the proliferating period of day 3 to 5 and with increased levels in the post-mitotic and remodeling stage. The expression of p21(cip1) and p27(kip1) showed an inverse gradient to that of Ki67. CONCLUSION: p21(cip1) and p27(kip1) play a supervising role in preventing the hyperproliferative tendency in tissue repair.

[The role of C5a in adhesion properties of polymorphonuclear leukocyte to pulmonary vascular endothelial cells in burn patients with acute lung injury].

OBJECTIVE: To explore the postburn adhesion properties of polymorphonuclear leukocyte (PMN) onto pulmonary vascular endothelial cells (PVEC) in burn patients with acute lung injury (ALI), so as to determine the role of C5a on PVEC-PMN adhesion. METHODS: Microtubule sucking technique was employed to determine the PVEC-PMN adhesion. The myeloperoxidase (MPO) was also assayed to reflect the magnitude of PVEC-PMN adhesion. RESULTS: The magnitude of PVEC-PMN adhesion increased and the adhesion force increased along with an increase in rh-C5a concentration. Simultaneously, the MPO activity was increased, which could be inhibited by anti-C5aR McAb in a concentration 1:104. CONCLUSION: Both C5a and C5aR participated in PVEC-PMN adhesion, which might be important in the pathogenesis of ALI.