Aberrant promoter methylation of Wnt inhibitory factor-1 gene is a potential target for treating psoriasis.

Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a critical role in psoriasis, but how the Wnt pathway is regulated in psoriatic skin and whether it can be exploited for therapeutic benefits is unclear. By comparing biopsies from healthy and psoriatic skin, we found that Wnt inhibitory factor 1 (WIF1), an inhibitor of Wnt signaling, showed reduced expression at both mRNA and protein levels in psoriatic skin. We then quantified methylation of the WIF1 gene promoter by DNA methylation sequencing and found that the WIF1 promoter region was hypermethylated. We further showed that recombinant WIF1 injection ameliorates the imiquimod (IMQ) mouse model of psoriasis. We also revealed that treatment with the DNA methylation inhibitor, decitabine, inhibited proliferation of immortalized human keratinocytes (HaCaT) in a psoriasis-like inflammatory environment. Finally, we applied decitabine to the IMQ mouse model and demonstrated that treatment of mice with decitabine ameliorates the disease. Therefore, our study reveals that methylation of the WIF1 gene is associated with the pathogenesis of psoriasis, and suggests that pharmacological targeting of DNA methylation is a potential treatment strategy for psoriasis.

Effect of Different Types of Hypoglycemic Medications on Psoriasis: An Analysis of Current Evidence.

BACKGROUND: Psoriasis is a chronic recurrent inflammatory skin disease with a high risk of diabetes based on disease severity. OBJECTIVES: The aim of the study was to evaluate the efficacy of different hypoglycemic medications in patients with psoriasis. METHODS: A systematic review and meta-analysis of studies were conducted to evaluate the efficacy of hypoglycemic medications in patients with psoriasis. The primary outcome was of changes in the psoriasis area and severity index (PASI) score, and a 75% improvement in PASI from baseline (PASI75). Subgroup analysis was used to investigate associations among the types of hypoglycemic medicines, combination therapy, patient characteristics, course of treatment, and curative effect. RESULTS: We included 3,286 patients from 19 studies to explore the effects of hypoglycemic medications. Patients randomized to receive hypoglycemic medicines showed a more significant decrease in the PASI score (standard mean difference = -0.55, 95% confidence interval (CI): -0.87 to -0.23, p = 0.0007) and a higher PASI75 ratio (RR: 1.80, 95% CI: 1.20-2.71, p = 0.0046). Patients consuming thiazolidinediones (TZDs) were more likely to reach PASI75 than those consuming glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors. The combined use of hypoglycemic medicines had an add-on effect on the standard psoriasis treatment, and the proportion of PASI75 in the combination group was nearly four times that in the noncombination group (p = 0.0216). In addition, hypoglycemic medications can reduce body weight, waist circumference, triglyceride, total cholesterol, low-density lipoprotein, and systolic blood pressure. CONCLUSIONS: Certain hypoglycemic drugs, such as GLP-1 RAs and TZDs, are beneficial for treating psoriasis. Multidisciplinary collaboration is recommended for the management of systemic inflammation in patients with psoriasis and diabetes.

Optimization strategies for expression of a novel bifunctional anti-PD-L1/TGFBR2-ECD fusion protein.

The novel anti-PD-L1/TGFBR2-ECD fusion protein (BR102) comprises an anti-PD-L1 antibody (HS636) which is fused at the C terminus of the heavy chain to a TGF-ß1 receptor Ⅱ ectodomain (TGFBR2-ECD), and which can sequester the PD-1/PD-L1 pathway and TGF-ß bioactivity in the immunosuppressive tumor microenvironment. In the expression of TGFBR2-ECD wild-type fused protein (BR102-WT), a 50 kDa clipped species was confirmed to be induced by proteolytic cleavage at a "QKS" site located in the N-terminus of the ectodomain, which resulted in the formation of IgG-like clipping. The matrix metalloproteinase-9 was determined to be associated with BR102-WT digestion. In addition, it was observed that the N-glycosylation modifications of the fusion protein were tightly involved in regulating proteolytic activity and the levels of cleavage could be significantly suppressed by MMP-inhibitors. To avoid proteolytic degradation, eliminating protease-sensitive amino acid motifs and introducing potential glycosylation were performed. Three sensitive motifs were mutated, and the levels of clipping were strongly restrained. The mutant candidates exhibited similar binding affinities to hPD-L1 and hTGF-ß1 as well as highly purified BR102-WT2. Furthermore, the mutants displayed more significant proteolytic resistance than that of BR102-WT2 in the lysate incubation reaction and the plasma stability test. Moreover, the bifunctional candidate Mu3 showed an additive antitumor effect in MC38/hPD-L1 bearing models as compared to that of with anti-PD-L1 antibody alone. In conclusion, in this study, the protease-sensitive features of BR102-WT were well characterized and efficient optimization was performed. The candidate BR102-Mutants exhibited advanced druggability in drug stability and displayed desirable antitumor activity.

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. METHODS: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. RESULTS: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved. CONCLUSIONS: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

Shifts of growing-season precipitation peaks decrease soil respiration in a semiarid grassland.

Changing precipitation regimes could have profound influences on carbon (C) cycle in the biosphere. However, how soil C release from terrestrial ecosystems responds to changing seasonal distribution of precipitation remains unclear. A field experiment was conducted for 4 years (2013-2016) to examine the effects of altered precipitation distributions in the growing season on soil respiration in a temperate steppe in the Mongolian Plateau. Over the 4 years, both advanced and delayed precipitation peaks suppressed soil respiration, and the reductions mainly occurred in August. The decreased soil respiration could be primarily attributable to water stress and subsequently limited plant growth (community cover and belowground net primary productivity) and soil microbial activities in the middle growing season, suggesting that precipitation amount in the middle growing season is more important than that in the early, late, or whole growing seasons in regulating soil C release in grasslands. The observations of the additive effects of advanced and delayed precipitation peaks indicate semiarid grasslands will release less C through soil respiratory processes under the projected seasonal redistribution of precipitation in the future. Our findings highlight the potential role of intra-annual redistribution of precipitation in regulating ecosystem C cycling in arid and semiarid regions.

Association between polycystic ovary syndrome and the risk of stroke and all-cause mortality: insights from a meta-analysis.

Many epidemiologic literatures have investigated the link between PCOS and long-term stroke risk and all-cause mortality, but the results are surprisingly conflicting. A meta-analysis was performed to examine the link between polycystic ovary syndrome (PCOS) and the risk of stroke, death from any cause, and assessed whether BMI might explain a higher risk of stroke. We searched the PUBMED, EMBASE, and Cochrane Library databases with no restrictions. Nine Cohort studies were identified, involving a total of 237,647 subjects. Compared with those without PCOS, subjects with PCOS were significantly associated with a increased risk of developing stroke (OR = 1.36; 95% CI 1.09-1.70; p = .007). However, no significant association was observed between PCOS and all-cause death (OR = 1.21; 95% CI 0.88-1.66; p = .25). Moreover, after pooling the five studies with risk estimates adjusted for BMI, the association between PCOS and stroke was slightly attenuated, although the odds ratios did not reach statistical significance (OR = 1.24; 95% CI 0.98-1.59). In conclusion, PCOS is associated with significant increased risk for stroke, while there is no consistent evidence to indicate that PCOS influences all-cause death outcomes. Increased BMI is an important contributor to the relationship between PCOS and stroke risk. Further study is needed to clarify which subgroups of subjects with the PCOS are at higher risk for stroke and should focus on developing reliable device for risk stratification.

Inhibitory effect and mechanism of mesenchymal stem cells on liver cancer cells.

Mesenchymal stem cells (MSCs), with their capacity for self-renewal and differentiation into various cell types, are important seed cells for stem cell therapy. MSCs exhibit potent pathotropic migratory properties that make them attractive for use in tumor prevention and therapy. However, little is known about the underlying molecular mechanisms that link MSCs to the targeted tumor cells. This study investigated the inhibitory effect and mechanism of MSCs on human hepatoma HepG2 cells using co-culture and conditioned medium system and animal transplantation model. The HepG2 cells were co-cultured with MSCs or treated with conditional media derived from MSCs cultures in vitro. Results of methylthiazolyldiphenyl tetrazolium assay and flow cytometric assay showed that the proliferation and apoptosis of HepG2 cells decreased and increased, respectively. Reverse transcription polymerase chain reaction analysis showed that the expression levels of bcl-2, c-Myc, ß-catenin, and survivin were downregulated. The results of enzyme-linked immunosorbent assay and Western blot proved that MSCs secreted Dkk-1 to inhibit the expression of Wnt signaling pathway-related factors (bcl-2, c-Myc, ß-catenin, and survivin) in tumor cells, consequently inhibiting the proliferation and promoting the apoptosis of HepG2 cells. Animal transplantation experiment showed that tumor growth was significantly inhibited when HepG2 cells were co-injected with MSCs into nude mice. These results suggested that MSCs inhibited the growth and promoted the apoptosis of HepG2 cells in a dose-dependent manner. This study provided a new approach and experimental basis for cancer therapy. This study also proved that the Wnt signaling pathway may have a function in MSC-mediated tumor cell inhibition.

Daily habits, diseases, drugs and knee osteoarthritis: a two-sample Mendelian randomization analysis.

Background: The causal relationship between daily habits, diseases, drugs, and knee osteoarthritis (KOA) remains unclear. This study utilized a two-sample Mendelian randomization (MR) method to investigate the causal links between these factors and KOA, providing new insights for KOA prevention. Methods: SNPs strongly associated with exposure factors (daily habits, diseases, drugs) were extracted from publicly available genome-wide association study (GWAS) as instrumental variables (IVs). We then selected GWAS of KOA as the outcome, conducting a two-sample MR analysis. Results: Our findings revealed significant causal relationships between several factors and KOA. There was a notable association with time spent watching TV (OR = 4.038; 95% CI: 1.859-8.770; P = 4.192E-04), frequency of friend/family visits (OR = 0.415; 95% CI: 0.219-0.788; P = 7.174E-03), smoking history (OR = 0.781; 95% CI: 0.663-0.921; P = 3.235E-03), gastroesophageal reflux disease (GERD) (OR = 1.519; 95% CI: 1.244-1.856; P = 4.183E-05), hypercholesterolemia (OR = 0.498; 95% CI: 0.290-0.855; P = 0.011), hypothyroidism (OR = 1.048; 95% CI: 1.013-1.084; P = 6.645E-03), use of antithrombotic agents (OR = 0.892; 95% CI: 0.816-0.976; P = 0.013), statin medication (OR = 0.956; 95% CI: 0.916-0.998; P = 0.041), and thyroid preparations (OR = 1.042; 95% CI: 1.014-1.071; P = 2.974E-03) with KOA. Specifically, KOA was positively associated with longer time spent watching TV, GERD, hypothyroidism and thyroid preparations, however showed a negative correlation with more frequent visits from friends or family, smoking history, hypercholesterolemia, antithrombotic agents and statin medication. Sensitivity analysis indicated no significant pleiotropy in these studies (P > 0.05). Conclusion: This comprehensive study underscores the significance of modifying certain habits to mitigate the risk of KOA. Additionally, the elevated risk of KOA among individuals with GERD, hypothyroidism, and those using thyroid preparations warrants attention. These results would be beneficial for clinical research and nursing education.

Association of hypertension with the triglyceride-glucose index and its associated indices in the Chinese population: A 6-year prospective cohort study.

The authors aim to assess the correlation between hypertension and the triglyceride-glucose (TyG) index and its associated indices, and to compare their abilities to identify hypertension. Four thousand eight hundred and sixty-six non-hypertensive participants were enrolled from the China National Health Survey in 2009. The data on new-onset hypertension were gathered in both 2011 and 2015. The TyG index and its associated indices were derived from the fasting triglyceride, blood glucose levels, and anthropometric parameters. Multivariate logistic regression analyses and receiver operating characteristic curve analysis were used. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the new-onset hypertension for the TyG-waist-to-height ratio (TyG-WHtR), TyG-waist circumference (TyG-WC), TyG-waist-to-hip ratio (TyG-WHR), TyG-body mass index (TyG-BMI), and TyG index were 1.379 (1.230-1.546), 1.002 (1.001-1.003), 1.156 (1.069-1.251), 1.007 (1.005-1.009), and 1.187 (1.051-1.341), respectively. In addition, comparing the lowest quartile (Q1) group with the highest quartile (Q4), the adjusted OR and 95% CI for the new-onset hypertension were found to be 1.86 (1.48-2.35), 1.93 (1.53-2.43), 1.71 (1.36-2.16), 2.00 (1.60-2.50), and 1.49 (1.19-1.88) for TyG-WHtR, TyG-WC, TyG-WHR, TyG-BMI, and TyG index, respectively, among all participants. The TyG-WHtR had the largest area under the curve (AUC) for hypertension (AUC, 0.628; 95% CI, 0.614-0.641) in all participants. Stratified analysis also indicated that the TyG-WHtR exhibited the greatest AUC in both males (AUC, 0.608; 95% CI, 0.587-0.629) and females (AUC, 0.648; 95% CI, 0.629-0.666). In conclusions, the TyG index and its associated indices were positively associated with hypertension. Among these indices, TyG-WHtR was the most valuable indicator for predicting hypertension.

Intraprocedural Cortisol Measurement Increases Adrenal Vein Cannulation Success Rate in Primary Aldosteronism: A Systematic Review and Meta-analysis.

BACKGROUND: This study aimed to explore the effectiveness of intraprocedural cortisol measurement (IPCM) for the technical success rates of bilateral adrenal vein, right adrenal vein (RAV), and left adrenal vein (LAV) cannulation during adrenal vein sampling (AVS). METHODS: Systematic searches of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were performed from database inception to May 10, 2023, without any restrictions. We estimated the overall effect estimates of outcomes using the Mantel-Haenszel random-effects model. We conducted subgroup analyses, meta-regression, and sensitivity analysis to explore the possible sources of between-study heterogeneity. RESULTS: In total, 3,485 patients from 11 studies (three prospective and eight retrospective) were enrolled. Bilateral selectivity in patients who underwent IPCM during AVS was significantly higher than that in patients who underwent a routine AVS procedure (84% vs. 64%, RR 1.42, 95% confidence interval [CI]: 1.27-1.59, P < 0.01), with significant heterogeneity (I2 = 68%). A 42% relative risk reduction in the failure rate of bilateral adrenal vein cannulation was found in the IPCM group. Moreover, pooled analysis showed a significant increase in the success rates of RAV cannulation (84% vs. 72%, RR 1.21, 95% CI 1.12-1.31, P < 0.01, I2 = 33%) and LAV cannulation (89% vs. 84%, RR 1.05, 95% CI 1.02-1.08, P < 0.01, I2 = 4%) when IPCM was implemented during the AVS procedure compared to the routine AVS procedure. CONCLUSIONS: An IPCM-based strategy during AVS appears to have a significant beneficial effect on improving the success rate of bilateral cannulation, RAV cannulation and LAV cannulation.

A controlled trial of percutaneous adrenal arterial embolization for hypertension in patients with idiopathic hyperaldosteronism.

Our prior study has suggested that percutaneous superselective adrenal arterial embolization (SAAE) with ethanol reduces blood pressure in patients with primary aldosteronism. This study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with idiopathic hyperaldosteronism. In this prospective, randomized, controlled trial, we randomly assigned patients with idiopathic hyperaldosteronism in a 1:1 ratio to undergo SAAE (n = 29) or receive MRA (n = 30) treatment. The primary endpoint was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The secondary endpoints included changes in office blood pressure, home blood pressure, correction of aldosterone-to-renin ratio, and adverse events at 6 months. The mean change in 24-h ambulatory systolic blood pressure from baseline to 6-month follow-up was significantly different between the two groups (-8.4 mmHg; 95% confidence interval, -15.2 to -2.1 mmHg; P < 0.01). Office, home, and ambulatory blood pressure reduction at 6 months was more pronounced in the SAAE group than the MRA group (all P < 0.05). Aldosterone-to-renin ratio was lower in the SAAE group than the MRA group at 1 and 3 months (both P < 0.01), while it had no difference between the two groups at 6 months. None of the patients experienced serious adverse events in the perioperative and 6-month follow-up periods. SAAE, as a hormonal debulking procedure, is superior to MRA in blood pressure control and correction of biochemical abnormalities in patients with idiopathic hyperaldosteronism.

Predictive value of neutrophil-to-lymphocyte ratio in coronary chronic total occlusion patients.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) has been reported as a novel predictor for atherosclerosis and cardiovascular outcomes. This study aimed to determine the effects of NLR on long-term clinical outcomes of chronic total occlusion (CTO) patients. METHODS: A total of 670 patients with CTO who met the inclusion criteria were included at the end of the follow-up period. Patients were divided into tertiles according to their baseline NLR levels at admission: low (n = 223), intermediate (n = 223), and high (n = 224). The incidence of major adverse cardiac events (MACEs) during the follow-up period, including all-cause death, nonfatal myocardial infarction (MI), or ischemia-driven revascularization, were compared among the three groups. RESULTS: Major adverse cardiac events were observed in 27 patients (12.1%) in the low tertile, 40 (17.9%) in the intermediate tertile, and 61 (27.2%) in the high NLR tertile (P < 0.001). Kaplan-Meier analysis demonstrated a significantly higher incidence of MACE, ischemia-driven coronary revascularization, non-fatal MI, and mortality in patients within the high tertile than those in the low and intermediate groups (all P < 0.001). Multivariable COX regression analysis showed that the high tertile of baseline NLR level showed a strong association with the risk of MACE (hazard ratio [HR] = 2.21; 95% confidence interval [CI]: 1.21-4.03; P = 0.009), ischemia-driven coronary revascularization (HR = 3.19; 95% CI: 1.56-6.52; P = 0.001), MI (HR = 2.61; 95% CI: 1.35-5.03; P = 0.043) and mortality (HR = 3.78; 95% CI: 1.65-8.77; P = 0.001). CONCLUSION: Our findings suggest that NLR is an inexpensive and readily available biomarker that can independently predict cardiovascular risk in patients with CTO.

Global prevalence of obesity in patients with psoriasis: An analysis in the past two decades.

BACKGROUND: Obesity is the risk factor for psoriasis. Therefore, we conducted a comprehensive review and meta-analysis to determine the prevalence of obesity in patients with psoriasis. METHODS: We examined four databases from their inception to October 2023 and used the Agency for Healthcare Research and Quality and the Newcastle-Ottawa Scale to assess the quality of observational studies. Data analysis was conducted by R language. Meta-regression, sensitivity and subgroup analyses were used to evaluate inter-study heterogeneity. Egger's test and funnel plots were used to evaluate publication bias. RESULTS: The global prevalence of psoriasis and obesity comorbidity was 25% (95% confidence interval [CI]: 0.21-0.30). Furthermore, the co-morbidity rate was 18% (95% CI: 0.11-0.24) in children and adolescents, and 35% (95% CI: 0.30-0.39) in adults. The gender-specific prevalence rates were 23% (95% CI: 0.16-0.32) in men and 38% (95% CI: 0.20-0.61) in women. Africa had the highest prevalence (60%, 95% CI: 0.21-0.99), followed by Asia (40%, 95% CI: 0.28-0.51), while Europe and North America had similar prevalence rates at 34% (95% CI: 0.27-0.41) and 31% (95% CI: 0.27-0.38), respectively. Regarding psoriasis severity, obesity prevalence was higher in moderate psoriasis (36%, 95% CI: 0.20-0.64) and lower in mild psoriasis (27%, 95% CI: 0.16-0.46). The prevalence of obesity in the patients with severe psoriasis was 30% (95% CI: 0.20-0.45). CONCLUSION: This study underscores the importance of identifying and treating obesity in patients with psoriasis to mitigate disease progression. However, more high-quality observational studies are required to elucidate their global prevalence and comorbid associations.

Inflammatory and Immunomodulatory Effects of Tripterygium wilfordii Multiglycoside in Mouse Models of Psoriasis Keratinocytes.

OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ+TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45+ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS: TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.

Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production.

Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.

Unilateral chemical ablation of the adrenal gland lowers blood pressure and alleviates target organ damage in spontaneously hypertensive rats.

Adrenal gland hormones play a critical role in the development and maintenance of hypertension. Adrenal ablation has been used to treat primary aldosteronism but not essential hypertension. The present study aimed to investigate the effectiveness and safety of unilateral adrenal gland ablation in treating spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of anhydrous ethanol or a sham procedure. Blood pressure was monitored by both tail-cuff plethysmography and telemetry until 6 months after the procedure. Adrenal ablation significantly lowered systolic and diastolic blood pressure of the SHR (P < 0.05 or P < 0.01) but not WKY from 4 to 24 weeks after the procedure. Adrenal ablation substantially damaged adrenal cortex and medulla with fibrosis in SHR and WKY rats. The ablation procedure remarkably reduced the levels of renin, angiotensin II, aldosterone, cortisol, noradrenaline, and epinephrine in SHR (all P < 0.05) but not in WKY. Hypokalemia in SHR was significantly improved by adrenal ablation (P < 0.05), while the serum sodium levels were not affected by adrenal ablation in either SHR or WKY rats. Additionally, adrenal ablation improved cardiac, renal, and vascular remodeling and function measured 3 months after the procedure in SHR. In conclusion, the present study shows that ethanol ablation of adrenal gland can effectively lower blood pressure and prevent target organ damage in SHR. These findings suggest that unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were subjected to unilateral adrenal ablation with injection of ethanol or a sham procedure. Blood pressure was monitored for 24 weeks. RESULTS: Adrenal ablation significantly lowered systolic and diastolic blood pressure of SHR but not WKY from 4 to 24 weeks after the procedure. CONCLUSION: Unilateral debulking of the adrenal gland using ethanol ablation is a promising therapeutic strategy for treating hypertension.

Efficacy and safety of biological agents to treat patients with palmoplantar pustulosis: A systematic scoping review.

BACKGROUND: Palmoplantar pustulosis (PPP), a chronic, recurrent pustular dermatosis associated with erythema, scales, and sterile pustules on the palms and soles, is commonly encountered in dermatology clinics. Whether PPP is a variant of psoriasis or a distinct condition is still debated. Although biological agents have been successfully used to treat moderate-to-severe psoriasis, existing literature on PPP is limited to case reports or small case series. The lack of well-documented clinical studies makes it difficult to select the ideal treatment for this condition. This review aims to discuss the efficacy and safety of biological agents in PPP treatment based on randomized controlled trials with the hope of inspiring dermatologist clinicians to propose new therapeutic approaches. OBJECTIVES: This review aims to obtain high-level evidence to assess the efficacy and safety of biological agents in the treatment of patients with PPP. METHODS: We searched the PubMed, Embase, and Cochrane databases up to May 18, 2023, for high-quality randomized controlled trials that reported at least one adverse event after PPP treatment with biological agents in patients > 18 years of age. RevMan 5.3 software was used for the meta-analysis. RESULTS: Nine trials involving 799 participants were included in the analysis. We used ppPASI 75 as the primary efficacy measure. Anti-IL-23 and anti-IL-17A agents afforded 4.14-fold and 1.95-fold better outcomes than placebo treatment at weeks 16 and 12, respectively (P-value = 0.009, RR = 4.14, 95% confidence interval [CI; 1.43-11.98]; P-value = 0.02, RR = 1.95, 95% CI [1.11-3.42]). Moreover, anti-IL-23 agents at a dose of 100 mg were more effective than at 200 mg, indicating that 100 mg may be the best dose for anti-IL-23 agents. Next, we investigated the safety of biological agents for PPP treatment. The incidence of total adverse events (AEs) was 1.25 times higher for biological agents than for controls, indicating a good safety profile (RR = 1.25, P-value ＜ 0.00001, 95% CI [1.13, 1.37]). Additionally, we divided the common AEs into 16 categories and found that anti-IL-23 agents were more likely to induce infections. In conclusion, we evaluated safety and efficacy in a comprehensive comparison and found that anti-IL-23 agents conferred good clinical efficacy with a low incidence of AEs and could be recommended with caution. LIMITATIONS: Only a few relevant, high-quality, randomized controlled trials were included in the study. CONCLUSION: This study showed that biological agents can be used to treat patients with PPP with good efficacy; however, AEs cannot be ignored. Multi-center, high-quality clinical studies with large sample sizes are needed to further evaluate the effects and safety of biological agents in PPP treatment.

A novel monospecific tetravalent IgG1-(scFv)2 version shown enhanced neutralizing and Fc-mediated effector functions against SARS-CoV-2.

Neutralizing monoclonal antibodies (nMABs) have been proved to be effective therapeutics in treating coronavirus disease (COVID-19). To enhance the potency of nMAB 553-15, we generated a novel monospecific tetravalent IgG1-(scFv)2 version. This was achieved by covalently fusing two forms of 553-15-derived single chain variable fragments (scFv) to the C-terminus of the hIgG1 (human Immunoglobulin G1) Fc fragment. We found that the Fc-fused VL-linker-VH format achieved similar binding affinity and neutralizing behavior as 553-15. The tetravalent versions were constructed by fusing the scFv domains to the C-terminus of nMAB 553-15. As a result, the tetravalent version 55,315-VLVH exhibited significantly higher binding activity to target spike protein variants and enhanced neutralization against VOCs (variants of concern) pseudovirus compared to 553-15. We also measured the Fc effector responses of candidates using wild-type Spike-expressing CHOK1 cells. The 55,315-VLVH enhanced the function of ADCP (antibody-dependent cellular phagocytosis) but had similar IL-6 release levels compared to the bivalent 553-15. It seemed that the novel tetravalent version avoids the pro-inflammatory effect induced by macrophage activation. However, the 55,315-VLVH displayed slightly increased potency in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), which might contribute to higher systemic inflammation. Further investigation is necessary to determine whether the tetravalent version is beneficial to balance efficiency and safety against COVID-19.

Transmembrane protein 117 knockdown protects against angiotensin-II-induced cardiac hypertrophy.

Mitochondrial dysfunction plays a critical role in the pathogenesis of pathological cardiac hypertrophy. Transmembrane protein 117 modulate mitochondrial membrane potential that may be involved in the regulation of oxidative stress and mitochondrial function. However, its role in the development of angiotensin II (Ang-II)-induced cardiac hypertrophy is unclear. Cardiac-specific TMEM117-knockout and control mice were subjected to cardiac hypertrophy induced by Ang-II infusion. Small-interfering RNAs against TMEM117 or adenovirus-based plasmids encoding TMEM117 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) before Ang-II stimulation. We found that TMEM117 was upregulated in hypertrophic hearts and cardiomyocytes and TMEM117 deficiency attenuated Ang-II-induced cardiac hypertrophy in vivo. Consistently, the in vitro data demonstrated that Ang-II-induced cardiomyocyte hypertrophy significantly alleviated by TMEM117 knockdown. Conversely, overexpression of TMEM117 exacerbated cardiac hypertrophy and dysfunction. An Ang II-induced increase in cardiac (cardiomyocyte) oxidative stress was alleviated by cardiac-specific knockout (knockdown) of TMEM117 and was worsened by TMEM117 supplementation (overexpression). In addition, TMEM117 knockout decreased endoplasmic reticulum stress induced by Ang-II, which was reversed by TMEM117 supplementation. Furthermore, TMEM117 deficiency mitigated mitochondrial injury in hypertrophic hearts and cardiomyocyte, which was abolished by TMEM117 supplementation (overexpression). Taken together, these findings suggest that upregulation of TMEM117 contributes to the development of cardiac hypertrophy and the downregulation of TMEM117 may be a new therapeutic strategy for the prevention and treatment of cardiac hypertrophy.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.