It is time to explore the impact of length of gestation and fetal health on the human lifespan.

A recently proposed principal law of lifespan (PLOSP) proposes to extend the whole human lifespan by elongating different life stages. As the preborn stage of a human being, gestation is the foundation for the healthy development of the human body. The antagonistic pleiotropy (AP) theory of aging states that there is a trade-off between early life fitness and late-life mortality. The question is whether slower development during the gestation period would be associated with a longer lifespan. Among all living creatures, the length of the gestation period is highly positively correlated to the length of the lifespan, although such a correlation is thought to be influenced by the body sizes of different species. While examining the relationship between lifespan length and body size within the same species, dogs exhibit a negative correlation between lifespans and body sizes, while there is no such correlation among domestic cats. For humans, most adverse gestational environments shorten the period of gestation, and their impacts are long-term. While many issues remain unsolved, various developmental features have been linked to the conditions during the gestation period. Given that the length of human pregnancies can vary randomly by as long as 5 weeks, it is worth investigating whether a slow steady healthy gestation over a longer period will be related to a longer and healthier lifespan. This article discusses the potential benefits, negative impacts, and challenges of the relative elongation of the gestation period.

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.

OBJECTIVES: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. METHODS: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. RESULTS: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1ß, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. CONCLUSION: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

Care patterns and Traditional Chinese Medicine constitution as factors of depression and anxiety in patients with systemic sclerosis: A cross-sectional study during the COVID-19 pandemic.

Objective: Care patterns and Traditional Chinese Medicine (TCM) constitution affects the emotion and health of patients with systemic sclerosis (SSc) while the prevalence of COVID-19 may aggravate such patients' emotion and health. We investigated the depression and anxiety levels of patients with SSc during the pandemic to identify the correlation between care patterns, TCM constitution, and patients' emotion. Materials and methods: This was a cross-sectional study. Patients with SSc and healthy individuals were surveyed using the patient health questionnaire-9, generalized anxiety disorder-7, and constitution in Chinese medicine questionnaire and a modified care pattern questionnaire. Factors correlated with depression and anxiety were screened using univariate and multivariate logistic regression analyses. Results: A total of 273 patients with SSc and 111 healthy individuals were included in the analysis. The proportion of patients with SSc who were depressed was 74.36%, who had anxiety was 51.65%, and who experienced disease progression during the pandemic was 36.99%. The proportion of income reduction in the online group (56.19%) was higher than that in the hospital group (33.33%) (P = 0.001). Qi-deficiency [adjusted odds ratio (OR) = 2.250] and Qi-stagnation (adjusted OR = 3.824) constitutions were significantly associated with depression. Remote work during the outbreak (adjusted OR = 1.920), decrease in income (adjusted OR = 3.556), and disease progression (P = 0.030) were associated with the occurrence of depression. Conclusion: Chinese patients with SSc have a high prevalence of depression and anxiety. The COVID-19 pandemic has changed the care patterns of Chinese patients with SSc, and work, income, disease progression, and change of medications were correlates of depression or anxiety in patients with SSc. Qi-stagnation and Qi-deficiency constitutions were associated with depression, and Qi-stagnation constitution was associated with anxiety in patients with SSc. Trial registration: http://www.chictr.org.cn/showproj.aspx?proj=62301, identifier ChiCTR2000038796.

Level of Estrogen in Females-The Different Impacts at Different Life Stages.

Historically, a high level of estrogen in women is regarded as the signature for a longer lifespan than men. Estrogen is known to be responsible for the development and regulation of the female reproductive system and secondary sex characteristics. Ovariectomy brings on numerous complications such as early menopause, heart disease, and osteoporosis. Thus, ovariectomy impacts the long-term health and lifespan of women. However, the level of estrogen at different life stages should be managed differently. Life quality can be measured in many ways, but mainly it relates to how an individual is doing in terms of being healthy, comfortable, and able to participate in or enjoy life experiences. First of all, ovariectomy not only reduces the level of estrogen but also destroys the reproductive metabolism and potentially other metabolism functions; it may also reduce the lifespan because of the overall impact, not necessary due to the low level of estrogen. Secondly, according to the principal law of the lifespan (PLOSP), the impacts of ovariectomy at different life stages will be different. The objective of this article is to provide readers with a new view of the research on estrogen. Based on the PLOSP, we recapture the estrogen levels at different life stages and explore potential alternative approaches to the manipulation of the levels of estrogen based on the biological features of the difference life stages. Thus, a low level of estrogen in the early life stage may make a woman live longer than a woman with a normal level of estrogen. However, a low estrogen level does not equal ovariectomy. Here, we explain the different impacts of the estrogen levels during different life stages; the effects on the lifespan of the manipulation of estrogen levels at different life stages; and the differences among the estrogen levels, ovariectomy effects, life stages, and lifespan. The personalized manipulation of estrogen levels and relevant growth factors according to the characterization of the life stages may be able to extend the heathy lifespan of women.

LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis.

Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low-density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis-related PF (SSc-PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low-density lipoprotein (LDL) increased in SSc-PF and IPF patients. The disrupted LDL-LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr-deficient (Ldlr-/-) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast-like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild-type mice. In vitro experiments revealed that apoptosis and TGF-ß1 production were induced by LDL, while fibroblast-like cell accumulation and ET-1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL-pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL-LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM-induced LDL elevation, apoptosis, fibroblast-like cell accumulation and mitigated PF in mice. Therefore, LDL-LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.

Exome-Wide Association Analysis Suggests LRP2BP as a Susceptibility Gene for Endothelial Injury in Systemic Sclerosis in the Han Chinese Population.

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 × 10-12) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 × 10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 × 10-8) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

The relationship between cerebrospinal fluid metastasis and gene mutations in non-small-cell lung cancer patients.

OBJECTIVE: The aim of this study was to use cerebrospinal fluid (CSF) cytology to give undiagnosed patients admitted to the hospital with severe neurological symptoms and without any anti-tumor treatment history a definitive diagnosis. Further, the aim was to explore the relationship between the frequency of gene mutations and mortality on the incidence of CSF metastasis in advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 30 patients diagnosed with NSCLC through CSF cytology were retrospectively analyzed. We analyzed 30 CSF metastasis patients and a control group of 20 advanced NSCLC patients without CSF metastasis. RESULTS: 30 patients were diagnosed with CSF metastasis using CSF cytology and immunocytopathology. The frequencies of EGFR mutations and ALK fusion in the CSF metastasis group were higher than they were in the non-CSF metastasis group (80% and 50% respectively, P<0.05). The incidence of CSF metastasis with gene mutations was higher than it was with wild-type genes (70.6% and 37.5%, P<0.05), OR 4.0 (95% CI 1.14~13.99). The median survival time of the CSF metastasis group was 4.8 months (95% CI 4.2~5.3). However, the median survival time in the non-CSF metastasis group was 9.2 months (95% CI 3.3~15.1). The mortality of the CSF metastasis group (n=13, 43.3%) was significantly higher than it was in the non-CSF metastasis group (n=6, 30%). CONCLUSIONS: CSF metastasis in NSCLC patients has a higher frequency of gene mutations and mortality. EGFR mutation and ALK fusion patients have a higher incidence of CSF metastasis. EGFR mutations and ALK fusion may promote CSF metastasis and may be a predictor of prognosis in NSCLC patients.

Involvement of Disabled-2 on skin fibrosis in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis. Our previous research found Disabled-2 (DAB2) expression was significantly downregulated by salvianolic acid B, a small molecular medicine which attenuated experimental skin fibrosis of SSc. These suggest that DAB2 plays an important role in SSc skin fibrosis, but the role of DAB2 in SSc remains unclear. OBJECTIVES: To investigate the role of DAB2 in SSc. METHODS: DAB2 expression level was detected in the skin and peripheral blood mononuclear cells of SSc patients. Bleomycin (BLM)-induced SSc mice and primary SSc skin fibroblasts were used to investigate the effect of DAB2 downregulation on fibrosis. RNA-seq transcriptome analysis was performed to underlie the mechanism of DAB2 in fibroblasts. RESULTS: DAB2 expression was enhanced in SSc lesion skin and was positively correlated with fibrotic genes, such as α-SMA and PAI-1. The in vivo study revealed that DAB2 downregulation alleviated skin fibrosis, alleviating skin thickness and reducing collagen deposition, and DAB2 knockdown ameliorated the inflammatory cell infiltration. The in vitro study showed that DAB2 knockdown reduced extracellular matrix genes and proteins expression. Moreover, Transcriptome analysis revealed TGF-ß and focal adhesion signaling pathways were the main downregulated pathways involved in DAB2 siRNA treated fibroblasts. CONCLUSIONS: Taken together, our results revealed that DAB2 was increased in SSc skin, and DAB2 downregulation inhibited BLM-induced mouse skin fibrosis and SSc skin fibroblasts activation. DAB2 played an important role in the pathogenesis of SSc and DAB2 modulation may represent a potential therapeutic method for SSc.

Increased expression of GAB1 promotes inflammation and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease mainly characterized by persistent inflammation and fibrosis. The receptor tyrosine kinase (RTK) signal pathway plays an important role in the process of SSc, and Grb2-associated binding protein (GAB) is crucial in activating RTK signalling. A previous study found elevated levels of GAB1 in bleomycin (BLM)-induced fibrotic lungs, but the effects of GAB1 in SSc remain unclear. Our aim was to investigate whether GAB1 was dysregulated and its potential role in SSc. Compared with healthy donors, we found GAB1 expression was 1.6-fold higher in peripheral blood mononuclear cells (PBMC), 2.5-fold higher in CD4 + T cells, and 2-fold higher in skin from of SSc patients (P < .01). At the same time, the levels of type one collagen (COLI) were also significantly increased (1.8-fold higher) in SSc skin. Additionally, BLM-induced SSc mice showed mRNA levels of Gab1 2-fold higher than saline-treated controls, and Gab1 expression correlated positively with collagen content. A further in vitro study showed silencing of GAB1 suppressed inflammatory gene expression in TNF-α induced fibroblasts. Additionally, GAB1 deficiency prominently inhibited cell proliferation and reduced COLI protein levels in TGF-ß induced fibroblasts. Taken together, these data suggest that GAB1 has a relatively high expression rate in SSc, and knockdown of GAB1 may attenuate SSc by stimulating inflammatory and fibrotic processes.

Anti-N-Methyl-D-Aspartic Acid Receptor 2 (Anti-NR2) Antibody in Neuropsychiatric Lupus Serum Damages the Blood-Brain Barrier and Enters the Brain.

BACKGROUND Brain microvessel endothelial cells constitute an important component in the blood-brain barrier. Cell-culture-based models of the blood-brain barrier (BBB) have been extensively applied in pharmacology, pathology and physiology. This study investigated effects of anti-N-methyl-D-aspartic acid receptor 2 (anti-NR2), N-methyl-D-aspartic acid (NMDA) receptor antibodies, NMDA receptor antagonists, and NMDA receptor agonists on brain microvessel endothelial cell models, and verified the effect of anti-NR2 antibody on the BBB as a receptor agonist. MATERIAL AND METHODS The primary brain microvessel endothelial cells were isolated and cultured, and an in vitro BBB model was established based on microvessel endothelial cells. Anti-NR2 antibody, glutamic acid, ifenprodil, and memantine were added in the BBB model to analyze changes in transepithelial electrical resistance (TEER) and to examine the permeability of the brain microvessel endothelial cell model. RESULTS The results showed that TEER values were significantly decreased by the addition of anti-NR2 antibody and glutamate, but were significantly increased by the addition of ifenprodil and memantine. TEER values showed no changes when treated by anti-NR2 antibody and ifenprodil, as well as anti-NR2 antibody and memantine. When dexamethasone was added, the TEER values increased by 23.8%, 39.4%, and 29.6% by treating with anti-NR2 antibody, positive cerebrospinal fluid, and positive serum, respectively. CONCLUSIONS Our findings show that anti-NR2 antibody in neuropsychiatric lupus serum can damage the BBB and enter the brain.

Impact analysis of autoantibody level and NR2 antibody level in neuropsychiatric SLE treated by methylprednisolone combined with MTX and DXM intrathecal injection.

The objective is to explore the clinical curative effects of methylprednisolone combined with MTX and DXM intrathecal injection in treating neuropsychiatric systemic lupus erythematosus (NPSLE) and its effects on autoantibody level and anti-N-methyl-D-aspartate receptor subtype NR2a/2b antibody (anti-NR2 antibody) level. Thirty six admitted NPSLE patients were treated by methylprednisolone combined with MTX and DXM intrathecal injection. Thirty six SLE patients without neuropsychiatric symptoms were selected as non-NPSLE group. Clinical indexes including SLE activity index, erythrocyte sedimentation rate (ESR), cerebrospinal fluid pressure (CSFP), cerebrospinal fluid protein were observed before and after treatment. Autoantibodies including anti-nuclear antibody (ANA), anti-double stranded DNA antibody (anti-dsDNA antibody), anti-extractable nuclear antigen antibody (ENA-Ab) were detected before and after treatment. Enzyme linked immunosorbent assay was used to detect NR2 antibody level before and after treatment in two groups. Upon treatment of methylprednisolone combined with MTX and DXM intrathecal injection, SLE activity index, ESR, CSFP, cerebrospinal fluid protein of 36 NPSLE patients were significantly decreased. Before treatment, positive rates of ANA, anti-dsDNA antibody, and anti-ENA antibody in both NPSLE group and non-NPSLE group had no significant difference. However, positive rate of anti-NR2 antibody in NPSLE group was significantly higher than that of non-NPSLE group. After treatment, positive rates of autoantibodies and anti-NR2 antibody in both NPSLE and non-NPSLE group were significantly decreased. Anti-NR2 antibody can be a screening index of NPSLE, and methylprednisolone combined with MTX and DXM intrathecal injection has significant curative effects and can effectively decrease autoantibody level and anti-NR2 antibody level.

Association study of TLR-9 polymorphisms and systemic lupus erythematosus in northern Chinese Han population.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. We performed a case-control study to investigate the effects of 4 SNPs in the TLR9 gene in the development of SLE in Northern Chinese population. METHODS: Four SNPs including rs187084, rs5743836, rs352139 and rs352140 were genotyped using the SNaPshot® method. A group of 430 SLE patients were compared to 424 normal controls. Data were analyzed by SPSS 17.0 and HaploView v 4.1 software. RESULTS: The frequency distributions of SNP rs351240 and haplotype H2 (TGCT) and H3 (CATT) were found to differ significantly between patient and control groups (p<0.05), while other SNPs and haplotypes showed no significant difference between the two cohorts (p>0.05). CONCLUSION: The results revealed that variations in the TLR9 gene are associated with SLE, indicating that TLR9 may play an important role in the pathogenesis of SLE in the northern Chinese Han population.

Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate.

OBJECTIVE: To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks. RESULTS: After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups. CONCLUSION: Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.