Gallic acid ameliorates endometrial hyperplasia through the inhibition of the PI3K/AKT pathway and the down-regulation of cyclin D1 expression.

BACKGROUND: Gallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. PURPOSE: The objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. METHODS: Initially, the induction of EH was achieved by administering estradiol to mice via continuous subcutaneous injection for a duration of 21 days. Concurrently, GA treatment was administered, and subsequently, the uterine tissue structure was assessed using hematoxylin and eosin (H&E) staining. Following this, the proliferation of human endometrial cells treated by GA was determined utilizing the CCK-8 method. Furthermore, network pharmacology and single-cell-RNA-seq data were employed to identify the target of GA action. In addition, we will employ immunofluorescence (IF), immunohistochemistry (IHC), flow cytometry, western blot and RT-qPCR methodologies to investigate the impact of GA on the expression level of cyclin D1, PI3K, p-PI3K, AKT, p-AKT. RESULTS: GA treatment ameliorated histopathological alterations in the uterus and suppress proliferation. Estradiol stimulation can activate the PI3K/AKT pathway, leading to up-regulation of cyclin D1 expression, whereas GA treatment results in down-regulation of its expression. CONCLUSIONS: The expression of cyclin D1 is down-regulated by GA through the inhibition of the PI3K/AKT pathway, effectively mitigating estradiol-induced EH in mice.

Mental and physical health changes around transitions into unpaid caregiving in the UK: a longitudinal, propensity score analysis.

BACKGROUND: The health of unpaid caregivers is poorer, on average, than in non-caregivers. There has been little focus on how health changes when becoming a caregiver and whether this varies by age, gender, and caregiving intensity. We aimed to investigate the mental and physical health changes involved with becoming a caregiver and whether these associations varied by gender, caregiving intensity, or age. METHODS: This study used data from the UK Household Longitudinal Study (2009-20) to examine mental and physical health changes around the transition to becoming a caregiver in adults aged 16 years and older. We included adults with information on care, complete covariates needed for matching, and at least one measure of health before or after becoming a caregiver (or matched non-caregiver). Health was measured via General Health Questionnaire-12 (GHQ-12, psychological distress) and 12-item Short Form Survey (SF-12, physical and mental functioning). We applied piecewise growth curve modelling with propensity score matching to model trajectories of mental and physical health for caregivers and matched non-caregivers. Analyses were stratified by age group, gender, and caregiving intensity. FINDINGS: Sample sizes varied from 3025 (GHQ-12 analyses in early adulthood) to 5785 (SF-12 analyses in early mid-adulthood). Psychological distress increased during transition to caregiving for all ages, particularly in those younger than 64 years, those providing care for 20 h or more per week, and for someone living within the household. Mental health functioning worsened during caregiving transition for those aged 30-64 years, those providing 20 h or more per week, and for those caring for someone within the household. Physical health functioning did not change but there was evidence of lower levels of functioning before caregiving. Changes in mental and physical health upon transition to caregiving did not differ by gender. INTERPRETATION: Our findings highlight the importance of early identification of and support for caregivers, including younger caregivers. This is important to break the cycle of caregiving and future care need. Health services staff, including general practitioners and hospital discharge teams, are well positioned for early identification of caregivers. We also encourage particular support for the mental health of caregivers and particularly those who become caregivers at a younger age. FUNDING: The UK Economic and Social Research Council.

An investigation of the mechanism of ZiyinDianji decoction in treating follicular dysplasia based on network pharmacology and molecular docking.

Follicular development disorder is a common gynaecological endocrine disease that can cause infertility, menstrual disorders, abortion, and other complications. ZiyinDianji decoction (ZYDJD) is a commonly used traditional Chinese medicine in clinical practice to promote follicular growth and development, but its pharmacological activity and mechanism of action are not clear. We combined network pharmacology with molecular docking and in vivo animal experiments to investigate the mechanism of ZYDJD in follicular development disorder. Cytoscape software was used for constructing ZYDJD-active component-target and PPI networks. GO biological process and KEGG pathway enrichment analyses were performed. The main components and key targets were selected for molecular docking. Finally, animal experiments were conducted for validation. The network pharmacology results showed that ZYDJD contained 83 active components and 159 core targets. The six most important active components were quercetin, luteolin, kaempferol, baicalein, isorhamnetin, and ß-sitosterol, and the most important disease targets were AKT1, TNF, IL-6, and P53. GO analysis mainly involved 470 cell biological processes, including effect on hormones, vascular morphogenesis, development, and cell proliferation. KEGG analysis involved cancer pathways, lipid metabolism pathways, and PI3K/AKT signalling pathways. Molecular docking showed good results, and animal experiments further verified that ZYDJD prevented cyclophosphamide from causing excessive activation of primordial follicles. ZYDJD maintained ovarian reserve and reproductive function by inhibiting the hyperphosphorylation of key molecules of the PI3K/Akt pathway, reducing FOXO3a, thereby ensuring the development of normal follicles. In conclusion, based on network pharmacology, molecular docking, and animal experiments, ZYDJD may act through the PI3K/Akt/FOXO3a pathway.

Integrating metabolomics, 16S rRNA sequencing, network pharmacology, and metorigin to explore the mechanism of Cinnamomi Cortex in treating chronic atrophic gastritis rats.

BACKGROUND: Cinnamomi cortex called as Rougui (RG) in Chinese was a widely used food-medicine homology. RG has the potential to treat chronic atrophic gastritis (CAG), a disease with widespread impact in the Chinese population. PURPOSE: This study aimed to explore its mechanism against CAG based on amalgamated strategies. METHODS: Network pharmacology was used to predict the potential effective components and the core targets of RG against CAG based on the comprehensive chemical characterization using UHPLC-Q/TOF MS (ultra high performance liquid chromatogramphy-quadrupole/time-of-flight mass spectrometry). The CAG animals model were further used to validate its pharmacodynamics, of which gut microbiota of caecal contents were analyzed by integrating metabolomics, 16S rRNA sequencing, Metorigin metabolite traceability analysis and molecular docking to explore its action mechanism. RESULTS: Network pharmacology firstly predicted the efficacy of RG was attributed to four effective components and seven targets. Metabolomics of caecal contents in CAG rats revealed primary bile acid biosynthesis was its targeted metabolic pathway associated with the metabolism of gut microbiota coupled with Metorigin traceability analysis. 16S rRNA sequencing showed that RG treated CAG by regulating the imbalance of gut microbiota. Molecular docking further confirmed that the effective components of RG could intervene with potential targets, metorigin analysis pathway, and key enzymes of gut microbiota metabolic pathways. CONCLUSION: Our results proved that RG exerted favorable effect on CAG. The four active ingredients (quercetin, kaempferol, oleic acid, and (-)-epicatechin) of RG were the key to exert drug effect, which could targeted the core target of CAG, primary bile acid biosynthesis and intestinal flora metabolic pathways.

Systemic Lupus Erythematosus Risk Probability Index: ready for routine use? Results from a Chinese cohort.

OBJECTIVES: To evaluate the performance of Systemic Lupus Erythematosus Risk Probability Index (SLERPI) in patients with SLE using a Chinese cohort. METHODS: The Chinese cohort included 352 patients with and 385 without SLE (control group). The clinical data of patients, including demographic data, clinical findings and serological profiles, were collected. Patients with an SLERPI score >7 were classified as SLE. The performance of the American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and European League Against Rheumatism (EULAR)/ACR-2019 criteria were used as references. RESULTS: Of these four classification criteria, SLERPI has the highest sensitivity (98.3% (95% CI 96.3% to 99.4%)), but lowest specificity (89.4% (95% CI 85.8% to 92.2%)). In the control group, patients eligible for the classification criteria for SLE were mainly those with primary Sjogren's syndrome (pSS) and undifferentiated connective tissue disease (UCTD), which adversely affected the specificity of the classification criteria. Moreover, significantly more patients with pSS and UCTD met SLERPI than those who met other classification criteria. After excluding patients with pSS and UCTD from the control group, the specificity and accuracy of SLERPI improved to 94.3% (95% CI 91.0% to 96.6%) and 96.5% (95% CI 95.0% to 97.9%), respectively, and both outperformed the EULAR/ACR-2019 criteria. The time to SLERPI classification was the same as their clinical time to diagnosis in 261 patients, earlier than the clinical diagnosis in 23 patients and later than the clinical diagnosis in 9 patients. A total of 280 patients had the same time to SLERPI classification as EULAR/ACR-2019, 8 patients had earlier than EULAR/ACR-2019 and 1 patient had later than EULAR/ACR-2019. CONCLUSION: SLERPI performed well in patients with SLE, particularly for the earlier diagnosis of SLE.

Bidirectional association between depressive symptoms and mild cognitive impairment over 20 years: Evidence from the Health and Retirement Study in the United States.

BACKGROUND: Research examining the association between depressive symptoms and mild cognitive impairment (MCI) has yielded conflicting results. This study aimed to examine the bidirectional association between depressive symptoms and MCI, and the extent to which this bidirectional association is moderated by gender and education. METHODS: Data come from the US Health and Retirement Study over a 20-year period (older adults aged ≥50 years). Competing-risks regression is employed to examine the association between baseline high-risk depressive symptoms and subsequent MCI (N = 9317), and baseline MCI and subsequent high-risk depressive symptoms (N = 9428). Interactions of baseline exposures with gender and education are tested. RESULTS: After full adjustment, baseline high-risk depressive symptoms were significantly associated with subsequent MCI (SHR = 1.20, 95%CI 1.08-1.34). Participants with baseline MCI are more likely to develop subsequent high-risk depressive symptoms than those without baseline MCI (SHR = 1.16, 95%CI 1.01-1.33). Although gender and education are risk factors for subsequent depression and MCI, neither moderates the bidirectional association. LIMITATIONS: Items used to construct the composite cognitive measure are limited; selection bias due to missing data; and residual confounding. CONCLUSIONS: Our study found a bidirectional association between depressive symptoms and MCI. High-risk depressive symptoms are related to a higher risk of subsequent MCI; and MCI predicts subsequent high-risk depression. Though neither gender nor education moderated the bidirectional association, public health interventions crafted to reduce the risk of depression and MCI should pivot attention to older women and those with less formal education.

ATHLOS Healthy Aging Scale score as the predictor of all-cause mortality in Poland and Czechia.

Background: The ATHLOS consortium (Aging Trajectories of Health-Longitudinal Opportunities and Synergies) used data from several aging cohorts to develop a novel scale measuring healthy aging comprehensively and globally (ATHLOS Healthy Aging Scale). In the present study, we assessed the predictive performance of the ATHLOS Healthy Aging Scale for all-cause mortality in middle-aged and older adults. Methods: Data from the Polish and Czech HAPIEE (Health Alcohol and Psychosocial factors In Eastern Europe) prospective cohorts were used. There were 10,728 Poles and 8,857 Czechs recruited. The ATHLOS Healthy Aging Scale score was calculated for all participants using data from the baseline examination carried out from 2002 to 2005. The follow-up for all-cause mortality was completed over 14 years. The associations between quintiles of the ATHLOS Healthy Aging Scale and all-cause mortality were estimated using Cox proportional hazards models. Results: A total of 9,922 Polish and 8,518 Czech participants contributed ATHLOS Healthy Aging Scale and mortality data with 1,828 and 1,700 deaths, respectively. After controlling for age, the ATHLOS Healthy Aging Scale score was strongly associated with mortality in a graded fashion for both genders and countries (hazard ratios for lowest vs. highest quintile were 2.98 and 1.96 for Czech and Polish women and 2.83 and 2.66 for Czech and Polish men, respectively). The associations were only modestly attenuated by controlling for education, economic activity, and smoking, and there was further modest attenuation after additional adjustment for self-rated health. Conclusion: The novel ATHLOS Healthy Aging Scale is a good predictor of all-cause mortality in Central European urban populations, suggesting that this comprehensive measure is a useful tool for the assessment of the future health trajectories of older persons.

The association between subjective cognitive decline and trajectories of objective cognitive decline: Do social relationships matter?

OBJECTIVES: We examine the association between subjective cognitive decline (SCD) and the trajectories of objective cognitive decline (OCD); and the extent to which this association is moderated by social relationships. METHODS: Data come from waves 10 (2010) through 14 (2018) of the Health and Retirement Study, a nationally representative panel survey of individuals aged 50 and above in the United States. OCD is measured using episodic memory, and overall cognition. SCD is assessed using a baseline measure of self-rated memory. Social relationships are measured by social network size and perceived positive and negative social support. Growth curve models estimate the longitudinal link between SCD and subsequent OCD trajectories and the interactions between SCD and social relationship variables on OCD. RESULTS: SCD is associated with subsequent OCD. A wider social network and lower perceived negative support are linked to slower decline in memory, and overall cognition. None of the social relationship variables, however, moderate the link between SCD and future OCD. CONCLUSION: Knowing that SCD is linked to subsequent OCD is useful because at SCD stage, deficits are more manageable relative to those at subsequent stages of OCD. Future work on SCD and OCD should consider additional dimensions of social relationships.

The associations of physical incapacity and wealth with remaining in paid employment after age 60 in five middle-income and high-income countries.

Previous studies on health and socioeconomic determinants of later-life labour force participation have mainly come from high-income European countries and the United States of America (USA). Findings vary between studies due to different measures of socioeconomic status and labour force outcomes. This study investigated longitudinal associations of physical incapacity and wealth with remaining in paid employment after age 60 in middle- and high-income countries. Using harmonised cohort data in the USA, England, Japan, Mexico and China (N=32,132), multilevel logistic regression was applied for main associations. The age-related probabilities of remaining in paid employment by physical incapacity and wealth were estimated using marginal effects. This study found that physical incapacity predicted lower odds of remaining in paid employment in each country. Wealth was associated with higher odds of remaining in paid employment in the USA, England, and Japan, but not in Mexico. Probabilities of remaining in paid employment were high in Mexico but low in China. The absolute difference in the probability of remaining in paid employment between the richest and the poorest groups was greater in the USA than that in any other country. In the USA, England and Japan, the inverse association between physical incapacity and remaining in paid employment could be partially compensated by wealth only when physical incapacity was not severe. National policies, including considering older adults' changing capacities for job placement and prioritising the provision of supportive services for socioeconomically disadvantaged older adults, developing pathways for informal workers to access social security and pension coverage, and encouraging employers to hire socioeconomically disadvantaged older workers and enhancing their employability, could be facilitated. Future studies, such as exploring health and socioeconomic determinants of remaining in part-time and full-time paid employment separately in more countries, and the moderating effects of relevant policies on these associations, are needed.

Diagnostic accuracy of the European League against rheumatism/American College of Rheumatology-2019 versus the Systemic Lupus International Collaborating Clinics-2012 versus the ACR-1997 classification criteria in adult systemic lupus erythematosus: A systematic review and meta-analysis.

Aim: To evaluate the diagnostic performance of the American College of Rheumatology (ACR)-1997, the Systemic Lupus International Collaborating Clinics (SLICC)-2012, and the European League against Rheumatism (EULAR)/ACR-2019 classification criteria in adult patients with systemic lupus erythematosus (SLE). Methods: PubMed, Embase, Web of Science and Cochrane Library databases were searched for literature comparing the three classification criteria of ACR-1997, SLICC-2012 and EULAR/ACR-2019, which took clinical diagnosis as reference. Meta-analysis was used to evaluate and compare the sensitivity, specificity and diagnostic odds ratio of ACR-1997, SLICC-2012 and EULAR/ACR-2019. To assess the early diagnosis capability of the classification criteria, subgroups of patients with disease duration < 3 years and < 1 year were selected for comparison of sensitivity and specificity based on the inclusion of the original study. The sensitivity and specificity of each item in three sets of classification criteria were evaluated. In addition, the clinical and immunological characteristics of patients who did not meet the three classification criteria were compared. Results: Nine original studies were included in the analysis, including 6404 SLE patients and 3996 controls. Results showed that the diagnostic odds ratios (95% confidence interval) of the SLICC-2012 [136.35 (114.94, 161.75)] and EULAR/ACR-2019 [187.47 (158.00, 222.42)] were higher than those of the ACR-1997 [67.53 (58.75, 77.63)]. Compared with ACR-1997[(0.86 (0.82, 0.89)], SLICC-2012[(0.96 (0.93, 0.97)] and EULAR/ACR-2019[(0.95 (0.92, 0.97)] had higher sensitivity. The specificity of the three classification criteria was similar: ACR-1997, SLICC-2012, and EULAR/ACR-2019 were 0.93 (0.89, 0.95), 0.86 (0.79, 0.91), and 0.91 (0.85, 0.95), respectively. The sensitivity of SLICC-2012 and EULAR/ACR-2019 were higher than that of ACR-1997 in early-course subgroups. Patients who did not meet ACR-1997 had more hypocomplementemia, patients who did not meet SLICC-2012 had more cutaneous lupus and photosensitivity, and patients who did not meet EULAR/ACR-2019 had more cutaneous lupus and leucopenia. Conclusions: SLICC-2012 and EULAR/ACR-2019 have better diagnostic ability than the ACR-1997, and the sensitivity of the former two criteria is also higher than that of the latter; Moreover, the SLICC-2012 and EULAR/ACR-2019 for patients in the early stages of disease performed equally excellent.

Comparing relationships between health-related behaviour clustering and episodic memory trajectories in the United States of America and England: a longitudinal study.

BACKGROUND: Health-related behaviours (HRBs) cluster within individuals. Evidence for the association between HRB clustering and cognitive functioning is limited. We aimed to examine and compare the associations between three HRB clusters: "multi-HRB cluster", "inactive cluster" and "(ex-)smoking cluster" (identified in previous work based on HRBs including smoking, alcohol consumption, physical activity and social activity) and episodic memory trajectories among men and women, separately, in the United States of America (USA) and England. METHODS: Data were from the waves 10-14 (2010-2018) of the Health and Retirement Study in the USA and the waves 5-9 (2010-2018) of the English Longitudinal Study of Ageing in England. We included 17,750 US and 8,491 English participants aged 50 years and over. The gender-specific HRB clustering was identified at the baseline wave in 2010, including the multi-HRB (multiple positive behaviours), inactive and ex-smoking clusters in both US and English women, the multi-HRB, inactive and smoking clusters in US men, and only the multi-HRB and inactive clusters in English men. Episodic memory was measured by a sum score of immediate and delayed word recall tests across waves. For within country associations, a quadratic growth curve model (age-cohort model, allowing for random intercepts and slopes) was applied to assess the gender-stratified associations between HRB clustering and episodic memory trajectories, considering a range of confounding factors. For between country comparisons, we combined country-specific data into one pooled dataset and generated a country variable (0 = USA and 1 = England), which allowed us to quantify between-country inequalities in the trajectories of episodic memory over age across the HRB clusters. This hypothesis was formally tested by examining a quadratic growth curve model with the inclusion of a three-way interaction term (age × HRB clustering × country). RESULTS: We found that within countries, US and English participants within the multi-HRB cluster had higher scores of episodic memory than their counterparts within the inactive and (ex-)smoking clusters. Between countries, among both men and women within each HRB cluster, faster declines in episodic memory were observed in England than in the USA (e.g., b England versus the USA for men: multi-HRB cluster = -0.05, 95%CI: -0.06, -0.03, b England versus the USA for women: ex-smoking cluster = -0.06, 95%CI: -0.07, -0.04). Additionally, the range of mean memory scores was larger in England than in the USA when comparing means between two cluster groups, including the range of means between inactive and multi-HRB cluster for men (b England versus the USA = -0.56, 95%CI: -0.85, -0.27), and between ex-smoking and multi-HRB cluster for women (b England versus the USA = -1.73, 95%CI: -1.97, -1.49). CONCLUSIONS: HRB clustering was associated with trajectories of episodic memory in both the USA and England. The effect of HRB clustering on episodic memory seemed larger in England than in the USA. Our study highlighted the importance of being aware of the interconnections between health behaviours for a better understanding of how these behaviours affect cognitive health. Governments, particularly in England, could pay more attention to the adverse effects of health behaviours on cognitive health in the ageing population.

Allergic Skin Rash Caused by Iguratimod: A Report of Two Cases.

Iguratimod has been used in the treatment of rheumatoid arthritis and Sjogren's syndrome (SS). Herein, we report two cases of skin allergic reactions caused by iguratimod in our hospital. Case 1 was a woman with SS who developed diffuse pruritus erythema after three weeks of combination therapy of hydroxychloroquine (HCQ) and iguratimod. When the patient was again prescribed iguratimod after the rash subsided, the pruritus erythema reappeared. Case 2 was a 23-year-old girl treated with prednisone, HCQ, and mycophenolate mofetil for systemic lupus erythematosus and SS. In the follow-up treatment, mycophenolate mofetil was replaced by iguratimod. On the 20th day of treatment, a pruritic erythematous maculopapular rash appeared. To the best of our knowledge, this is the first study to report the characteristics of an allergic rash caused by iguratimod. It is better to administer HCQ and iguratimod successively rather than simultaneously to a patient.

Educational gradients in all-cause mortality in two cohorts in the Czech Republic during the early stage of the postcommunist transition.

OBJECTIVES: We investigated whether social gradient in all-cause mortality in the Czech Republic changed during the postcommunist transition by comparing two cohorts, recruited before and after the political changes in 1989. METHODS: Participants (aged 25-64 years) in two population surveys (n=2530 in 1985, n=2294 in 1992) were followed up for mortality for 15 years (291 and 281 deaths, respectively). Education was classified into attainment categories and years of schooling (both continuous and in tertiles). Cox regression was used to estimate HR of death by educational indices in each cohort over a 15-year follow-up. RESULTS: All three educational variables were significantly associated with reduced risk of death in both cohorts when men and women were combined; for example, the adjusted HRs of death in the highest versus lowest tertile of years of schooling were 0.65 (95% CI 0.47 to 0.89) in 1985 and 0.67 (95% CI 0.48 to 0.93) in 1992. Adjustment for covariates attenuated the gradients. In sex-specific analysis, the gradient was more pronounced and statistically significant in men. There were no significant interactions between cohort and educational indices. CONCLUSIONS: The educational gradient in mortality did not differ between the two cohorts (1985 vs 1992), suggesting no major increase in educational inequality during the early stage of postcommunist transition. Further research is needed to understand trends in health inequalities during socioeconomic transitions.

Prevalence, awareness, treatment and control of hypertension, diabetes and hypercholesterolemia, and associated risk factors in the Czech Republic, Russia, Poland and Lithuania: a cross-sectional study.

BACKGROUND: Empirical evidence on the epidemiology of hypertension, diabetes and hypercholesterolemia is limited in many countries in Central and Eastern Europe. We aimed to estimate the prevalence, awareness, treatment and control of hypertension, diabetes and hypercholesterolemia in the Czech Republic, Russia, Poland and Lithuania, and to identify the risk factors for the three chronic conditions. METHODS: We analysed cross-sectional data from the HAPIEE study, including adults aged 45-69 years in the Czech Republic, Russia, Poland and Lithuania, collected between 2002 and 2008 (total sample N = 30,882). Among prevalent cases, we estimated awareness, treatment, and control of hypertension, diabetes and hypercholesterolemia by gender and country. Multivariate logistic regression was applied to identify associated risk factors. RESULTS: In each country among both men and women, we found high prevalence but low control of hypertension, diabetes, and hypercholesterolemia. Awareness rates of hypertension were the lowest in both men (61.40%) and women (69.21%) in the Czech Republic, while awareness rates of hypercholesterolemia were the highest in both men (46.51%) and women (51.20%) in Poland. Polish participants also had the highest rates of awareness (77.37% in men and 79.53% in women), treatment (71.99% in men and 74.87% in women) and control (30.98% in men and 38.08% in women) of diabetes. The common risk factors for the three chronic conditions were age, gender, education, obesity and alcohol consumption. CONCLUSIONS: Patterns of awareness, treatment and control rates of hypertension, diabetes and hypercholesterolemia differed by country. Efforts should be made in all four countries to control these conditions, including implementation of international guidelines in everyday practice to improve detection and effective management of these conditions.

Proprietary Medicines Containing Bupleurum chinense DC. (Chaihu) for Depression: Network Meta-Analysis and Network Pharmacology Prediction.

Background and Aims: The rapid development of society has resulted in great competitive pressures, leading to the increase in suicide rates as well as incidence and recurrence of depression in recent years. Proprietary Chinese medicines containing Bupleurum chinense DC. (Chaihu) are widely used in clinical practice. This study aimed at evaluating the efficacy and safety of oral proprietary Chinese medicines containing Chaihu for treating depression by network meta-analysis (NMA) and exploring the potential pharmacological mechanisms of the optimal drugs obtained based on NMA. Methods: This study searched for clinical randomized controlled trial studies (RCTs) about Chaihu-containing products alone or in combination with selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and cyclic antidepressants (CAS) for depression in eight databases. The search deadline is from data inception to April 2021. For efficacy assessment, the clinical response rate, the Hamilton Depression Scale-17 (HAMD-17), and adverse reactions were calculated. The methodological quality of the included studies was assessed for risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions, and the data were subjected to NMA via the Stata version 16.0 software. Subsequently, the optimal drug obtained from the NMA results, Danzhi Xiaoyao pill (DZXY), was used to conduct network pharmacology analysis. We searched databases to acquire bioactive and potential targets of DZXY and depression-related targets. The protein-protein interaction (PPI) network, component-target network, the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the STRING database, Cytoscape 3.9.0 software, and R version 4.1.2, respectively. Results: Thirty-seven RCTs, with a total of 3,263 patients, involving seven oral proprietary Chinese medicines containing Chaihu, were finally included. The results of the NMA demonstrated that the top four interventions with the best efficiency were Jiawei Xiaoyao + SSRI, DZXY + SNRI, Xiaoyao pill + SSRI, and Jieyu pill + SNRI; the top four interventions reducing HAMD score were DZXY + SNRI, Jiawei Xiaoyao, Jieyu pill, and Puyu pill + SNRI; the top four interventions with the least adverse effects were Jieyu pill, Anle pill + SSRI, DZXY + SNRI, and Puyu pill + SNRI. In the aspects above, DZXY + SNRI performed better than other treatments. After network meta-analysis, we conducted a network pharmacology-based strategy on the optimal drugs, DZXY, to provide the pharmacological basis for a conclusion. A total of 147 active compounds and 248 targets in DZXY were identified, of which 175 overlapping targets related to depression. Bioinformatics analysis revealed that MAPK3, JUN, MAPK14, MYC, MAPK1, etc. could become potential therapeutic targets. The MAPK signaling pathway might play an essential role in DZXY against depression. Conclusion: This is the very first systematic review and network meta-analysis evaluating different oral proprietary Chinese medicines containing Chaihu in depressive disorder. This study suggested that the combination of proprietary Chinese medicines containing Chaihu with antidepressants was generally better than antidepressant treatment. The incidence of adverse reactions with antidepressants alone was higher than that with proprietary Chinese medicines containing Chaihu alone or in combination with antidepressants. DZXY + SNRI showed significantly better results in efficacy, HAMD scores, and safety. The antidepressant effect of DZXY may be related to its regulation of neuroinflammation and apoptosis.

Iguratimod alleviates tubulo-interstitial injury in mice with lupus.

INTRODUCTION: Tubulo-interstitial injury is a poor prognostic factor for lupus nephritis (LN). Here, we tested whether iguratimod could inhibit tubulo-interstitial injury in LN. METHODS: MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney were evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor ß1 (TGF-ß1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3, and p-p38 MAPK, ß-catenin and TGF-ß type II receptor (TGFßRII) in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. RESULTS: Iguratimod reduced immune deposition along the tubular basement membrane, inhibited the tubulo-interstitial infiltration of inflammatory cells, and alleviated tubular injury in MRL/lpr mice. Moreover, Iguratimod eased the tubulo-interstitial deposition of collagen fibers, which was confirmed by decreased expression of COL-I. Furthermore, iguratimod suppressed the expression of FSP-1 and increased that of E-cadherin in renal tubular epithelial cells. In HK2 cells cultured with TGF-ß1, iguratimod treatment not only reversed cellular morphological changes, but also prevented E-cadherin downregulation and fibronectin upregulation. In addition, iguratimod inhibited phosphorylation of TGFßRII, Smad2/3 and p38 MAPK in HK2 cells treated with TGF-ß1, and also blocked nuclear translocation of ß-catenin. CONCLUSION: Iguratimod eased tubulo-interstitial lesions in LN, especially tubulo-interstitial fibrosis, and might have potential as a drug for inhibiting the progression of tubulo-interstitial fibrosis in LN.

CRISPR/Cas9-mediated targeted mutation of the E1 decreases photoperiod sensitivity, alters stem growth habits, and decreases branch number in soybean.

The distribution of elite soybean (Glycine max) cultivars is limited due to their highly sensitive to photoperiod, which affects the flowering time and plant architecture. The recent emergence of CRISPR/Cas9 technology has uncovered new opportunities for genetic manipulation of soybean. The major maturity gene E1 of soybean plays a critical role in soybean photoperiod response. Here, we performed CRISPR/Cas9-mediated targeted mutation of E1 gene in soybean cultivar Tianlong1 carrying the dominant E1 to investigate its precise function in photoperiod regulation, especially in plant architecture regulation. Four types of mutations in the E1 coding region were generated. No off-target effects were observed, and homozygous trans-clean mutants without T-DNA were obtained. The photoperiod sensitivity of e1 mutants decreased relative to the wild type plants; however, e1 mutants still responded to photoperiod. Further analysis revealed that the homologs of E1, E1-La, and E1-Lb, were up-regulated in the e1 mutants, indicating a genetic compensation response of E1 and its homologs. The e1 mutants exhibited significant changes in the architecture, including initiation of terminal flowering, formation of determinate stems, and decreased branch numbers. To identify E1-regulated genes related to plant architecture, transcriptome deep sequencing (RNA-seq) was used to compare the gene expression profiles in the stem tip of the wild-type soybean cultivar and the e1 mutants. The expression of shoot identity gene Dt1 was significantly decreased, while Dt2 was significantly upregulated. Also, a set of MADS-box genes was up-regulated in the stem tip of e1 mutants which might contribute to the determinate stem growth habit.