IL-22, a vital cytokine in autoimmune diseases.

Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.

The Concentration of Lactoferrin in Breast Milk Correlates with Maternal Body Mass Index and Parity.

Background: Lactoferrin (LF) is a multifunctional glycoprotein found in human milk and body fluids, which has been shown to play a vital role in regulating the immunity and supporting the intestinal health of infants. Aim: This study evaluated the association between maternal/parturient factors and LF concentration in the breast milk of Chinese mothers. Methods: 207 breast milk samples were collected from healthy mothers with in the first year of lactation. Maternal and parturient information was collected for these participants through questionnaires. The content of lactoferrin in breast milk was detected by liquid chromatography, and macronutrient concentration in breast milk was measured by human milk analyzer in only 109 samples. Results: Our findings demonstrated that the LF content was much higher within the first month of lactation than it was after that period (p < 0.05). When compared with normal and lean mothers, the LF content of obese mothers was considerably higher (p < 0.05). The parity and LF content showed a favorable correlation. The proportion of LF to total protein tended to decrease as lactation progressed. Protein, fat, dry matter, and energy content were significantly positively correlated with LF content (p < 0.001). Conclusion: Early breast milk tends to have a higher level of LF, and the change of LF concentration in breast milk is associated with the parity and body mass index of the mother.

Enhancement of LC3-associated efferocytosis for the alleviation of intestinal inflammation.

LC3-associated phagocytosis (LAP) is an instrumental machinery for the clearance of extracellular particles including apoptotic cells for the alleviation of inflammation. While pharmacological approaches to modulate LAP for inflammation regulation have been poorly explored, in our study we identified a novel compound, columbamine (COL), which can trigger LAP and enhance efferocytosis in an animal model of colitis to attenuate inflammation. We found that COL directly binds to and biasedly activates FPR2 (formyl peptide receptor 2) to promote efferocytosis and alleviate colitis. Biochemically, COL induces an interaction between RAC1 and the PIK3C3/VPS34-RUBCN/RUBICON complex, stimulating LC3-associated efferocytosis. These findings provide a novel interpretation of the potential roles of LAP in regulating inflammatory bowel disease (IBD), reveal the relationship between G protein-coupled receptors (GPCRs) and LAP, and highlight the role of RAC1 in regulating the PIK3C3/VPS34-RUBCN complex in LAP.

Molecular Modulators and Receptors of Selective Autophagy: Disease Implication and Identification Strategies.

Autophagy is a highly conserved physiological process that maintains cellular homeostasis by recycling cellular contents. Selective autophagy is based on the specificity of cargo recognition and has been implicated in various human diseases, including neurodegenerative diseases and cancer. Selective autophagy receptors and modulators play key roles in this process. Identifying these receptors and modulators and their roles is critical for understanding the machinery and physiological function of selective autophagy and providing therapeutic value for diseases. Using modern researching tools and novel screening technologies, an increasing number of selective autophagy receptors and modulators have been identified. A variety of Strategies and approaches, including protein-protein interactions (PPIs)-based identification and genome-wide screening, have been used to identify selective autophagy receptors and modulators. Understanding the strengths and challenges of these approaches not only promotes the discovery of even more such receptors and modulators but also provides a useful reference for the identification of regulatory proteins or genes involved in other cellular mechanisms. In this review, we summarize the functions, disease association, and identification strategies of selective autophagy receptors and modulators.

Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.

Risk factors for mortality among lung cancer patients with covid-19 infection: A systematic review and meta-analysis.

BACKGROUND: Lung cancer patients with coronavirus disease 2019 (COVID-19) infection experience high mortality rates. The study aims to determine the risk factors for mortality in lung cancer patients with COVID-19 infection. MATERIALS AND METHODS: Followed the PRISMA reporting guidelines, PubMed, Embase, and Web of Science were systematically searched to February 20, 2023, for studies of lung cancer patients with COVID-19 infection. The main outcome of interest was the risk factor for mortality. We also compared the mortality rate of those patients among different continents. A pooled risk ratio (RR) with 95% CI was presented as the result of this meta-analysis. RESULTS: Meta-analysis of 33 studies involving 5018 patients showed that pooled mortality rate of lung cancer in COVID-19 patients was 0.31 (95% CI: 0.25-0.36). Subgroup analysis based on the continents showed significant difference of the mortality rate was observed between Asia and the rest of world (χ2 = 98.96, P < 0.01). Older age (SMD: 0.24, 95% CI: 0.09-0.40, P < 0.01), advanced lung cancer (RR: 1.14, 95% CI: 1.04-1.26, P < 0.01), coexisting comorbidities such as hypertension (RR: 1.17, 95% CI: 1.01-1.35, P = 0.04) and cardiovascular disease (RR: 1.40, 95% CI: 1.03-1.91, P = 0.03) were associated with higher risk of mortality rate in those patients. CONCLUSIONS: Findings of this meta-analysis confirms an increased risk of mortality in lung cancer patients with COVID-19 infection, whose risk factors for these patients appear to be exacerbated by older age, advanced-stage lung cancer, and comorbidities such as hypertension and cardiovascular disease.

Lamellar Wood Sponge with Vertically Aligned Channels for Highly Efficient and Salt-Resistant Solar Desalination.

Solar-assisted interfacial evaporation is a promising approach for purifying and desalinating water. As a sustainable biomass material, wood has attracted increasing interest as an innovative substrate for solar desalination, owing to its intrinsic porous structure, high hydrophilicity, and low thermal conductivity. However, developing wood-based solar evaporators with high evaporation rates and excellent salt resistance still remains a significant challenge, owing to the absence of large pores with high interconnectivity in natural wood. Herein, by converting the honeycombed structure of natural wood into a lamellar architecture via structural engineering, we develop a flexible wood sponge with vertically aligned channels for efficient and salt-resistant solar desalination after surface coating with carbon nanotubes (CNTs). The special lamellar structure with an interlayer distance of 50-300 µm provides the wood sponge with faster water transport, lower thermal conductivity, and water evaporation enthalpy, thus achieving higher evaporation performances in comparison with the cellular structure of natural wood. Noteworthy, the vertically aligned channels of the wood sponge facilitate sufficient fluid convection and diffusion and enable efficient salt exchanges between the heating interface and the underlying bulk water, thus preventing salt accumulation on the surface. Benefiting from the distinctive lamellar structure, the developed wood-sponge evaporator exhibits exceptional salt resistance even in a hypersaline brine (20 wt %) during continuous 7-day desalination under 1 sun irradiation, with a high evaporation rate (1.38-1.43 kg m-2 h-1), outperforming most previously reported wood-based evaporators. The lamellar wood sponge may provide a promising strategy for desalinating high-salinity brines in an efficient manner.

Association between composite dietary antioxidant index and hypertension: insights from NHANES.

AIM: The association between composite dietary antioxidant index (CDAI) and hypertension remains unknown. Our study was to investigate the association of CDAI with hypertension in general adults. METHODS: A total of 21 526 participants were enrolled from the National Health and Nutrition Examination Surveys (NHANES). The CDAI was calculated from the intake of six dietary antioxidants. Multivariable logistic regressions were performed to explore the associations between CDAI and the prevalence of hypertension. Non-linear correlations were explored using restricted cubic splines. And the inflection point was determined by the two-piecewise linear regression. RESULTS: In the multivariate logistic regression model with full adjustment for confounding variables, the odds ratio (95% confidence interval) of CDAI associating with hypertension was 0.98 (0.97-1.00; P = .016). Besides, compared to the lowest quartile, the highest quartile of CDAI was associated with a lower risk of hypertension (0.81 [0.70-0.94]; P = .006). Furthermore, a linear association was found by restricted cubic spline, with 3.4 being the turning point. CONCLUSION: Our study highlighted a negative linear association between CDAI and hypertension in general adults.

G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth.

Introduction: Melanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear. Methods: We established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR. Results: GPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity. Discussion: GPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.

Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.

Association of low-density lipoprotein-cholesterol with all-cause and cause-specific mortality.

AIMS: To explore the association between low-density lipoprotein-cholesterol (LDL-C) and all-cause and cause-specific mortality based on a prospective cohort study. METHODS: Among 10850 individuals enrolled from National Health and Nutrition Examination Survey (NHANES) 1999-2014, 1355 (12.5%) died after an average follow-up of 5.7 years. Cox proportional regression models were used to determine the association between LDL-C with the risk of mortality. RESULTS: The level of LDL-C was L-shaped associated with the risk of all-cause mortality, namely a low level was related to an increased mortality risk. The level of LDL-C associated with the lowest risk of all-cause mortality was 124 mg/dL (3.2 mmol/L) in the overall population, and 134 mg/dL (3.4 mmol/L) in individuals not receiving lipid lowering treatment. Compared with participants with LDL-C of 110-134 mg/dL (2.8-3.5 mmol/L), the multivariable adjusted hazard ratio was 1.18 (95% confidence interval 1.01 to 1.38) for individuals with the lowest quartile for all-cause mortality. In participants with coronary heart diseases, the conclusion was similar but the critical point was lower. CONCLUSIONS: We found that low levels of LDL-C increased the risk of all-cause mortality, and the lowest risk of all-cause mortality for LDL-C concentration was 124 mg/dL (3.2 mmol/L). Our results provide a reasonable range of LDL-C when to initiate a statin therapy in clinical practice.

Modeling multivariate cyber risks: deep learning dating extreme value theory.

Modeling cyber risks has been an important but challenging task in the domain of cyber security, which is mainly caused by the high dimensionality and heavy tails of risk patterns. Those obstacles have hindered the development of statistical modeling of the multivariate cyber risks. In this work, we propose a novel approach for modeling the multivariate cyber risks which relies on the deep learning and extreme value theory. The proposed model not only enjoys the high accurate point predictions via deep learning but also can provide the satisfactory high quantile predictions via extreme value theory. Both the simulation and empirical studies show that the proposed approach can model the multivariate cyber risks very well and provide satisfactory prediction performances.

Mineralocorticoid receptor agonist aldosterone rescues hippocampal neural stem cell proliferation defects and improves postoperative cognitive function in aged mice.

OBJECTIVES: Hippocampal neurogenesis is closely related to learning and memory, and hippocampal neurogenesis disorders are involved in the development of many neurodegenerative diseases. Mineralocorticoid receptor (MR) plays a vital role in regulating stress response, neuroendocrine and cognitive functions, and is involved in regulating the integrity and stability of neural networks. However, the potential role of MR in the pathogenesis of postoperative cognitive dysfunction (POCD) is unclear. Therefore, this study evaluated the effect and mechanism of MR activation on postoperative hippocampal neurogenesis and cognitive function in aged mice. METHODS: 18-month-old male Kunming mice were randomly divided into Control group (C group), Surgery group (S group), Surgery+ Aldosterone group (S+Aldo group), Surgery + Wortmannin group (S+Wort group), Surgery + Aldosterone + Wortmannin group (S+Aldo+Wort group). Laparotomy was used to establish an animal model of postoperative cognitive dysfunction. After surgery, mice were intraperitoneally injected with aldosterone (100 ug/kg,150 ug/kg,200 ug/kg) and / or wortmannin (1 mg/kg); One day before the sacrifice, mice were injected intraperitoneally with BrdU (100 mg / kg / time, 3 times in total). Mice were subjected to Morris water maze and field tests at 1, 3, 7, and 14 days after surgery. Immunofluorescence was used to detect the number of BrdU +, Nestin +, BrdU/Nestin + positive cells in the hippocampal dentate gyrus of mice at 1, 3, 7 and 14 days after surgery. Western-blot was used to detect PI3K/Akt/GSK-3ß signaling pathway related proteins Akt, p-Akt, GSK-3ß, P-GSK-3ß expression. RESULTS: Stress impairs the performance of aged mice in water maze and open field tests, reduces the number of BrdU/Nestin+ cells in the hippocampal dentate gyrus, and inhibits the phosphorylation of Akt and GSK-3ß proteins in the hippocampus. Aldosterone treatment promotes P-Akt, P-GSK-3ß protein expression and hippocampal neural stem cell proliferation, and improves postoperative cognitive dysfunction. However, wortmannin treatment significantly reversed these effects of aldosterone. CONCLUSIONS: The mineralocorticoid receptor agonist aldosterone promotes the proliferation of hippocampal neural stem cells and improves cognitive dysfunction in aged mice after surgery, and the mechanism may be related to activation of PI3K/Akt/GSK-3ß signaling.

Epidemiological Characteristics and Factors Associated with Cure of Leprosy in Chongqing, China, from 1949 to 2019.

Chongqing is one of the focuses of leprosy control in China. Although leprosy control in Chongqing has achieved remarkable results over the years, there are also some problems, such as recurrent epidemics and insufficient early detection in some areas. The aim of this study was to analyze the epidemiological characteristics of leprosy in Chongqing, from 1949 to 2019 and explore the potential factors sociated with cure of leprosy to provide a basis for improving leprosy prevention and treatment strategies in Chongqing. Epidemiological indicators such as incidence and prevalence rates were used to evaluate the prevalence of leprosy. The epidemiological characteristics and control situation of leprosy in patients were analyzed using demographic characteristics, diagnosis, and treatment. Survival analysis was conducted to explore factors associated with the cure of leprosy. From 1949 to 2019, 3,703 cases of leprosy were registered in Chongqing. The incidence of leprosy in the city peaked at 0.853/105 in 1960 and remained below 0.100/105 after 2003. The number of high incidence areas decreased significantly, but they were mainly concentrated in the northeast and southeast regions. The early detection rate increased yearly from 1949 to 2019, and the rate of grade 2 disability ranged from 38.2% to 21.7%, with a fluctuating downward trend after 1960. Male, young age, employment as a farmer, delayed diagnosis, and multibacillary leprosy were risk factors for leprosy cure. Chongqing should continue to strengthen leprosy monitoring to improve the early detection of leprosy and focus on sociated risk factors to carry out multiple strategies.

Emerging role of different DNA methyltransferases in the pathogenesis of cancer.

DNA methylation is one of the most essential epigenetic mechanisms to regulate gene expression. DNA methyltransferases (DNMTs) play a vital role in DNA methylation in the genome. In mammals, DNMTs act with some elements to regulate the dynamic DNA methylation patterns of embryonic and adult cells. Conversely, the aberrant function of DNMTs is frequently the hallmark in judging cancer, including total hypomethylation and partial hypermethylation of tumor suppressor genes (TSGs), which improve the malignancy of tumors, aggravate the ailment for patients, and significantly exacerbate the difficulty of cancer therapy. Since DNA methylation is reversible, currently, DNMTs are viewed as an important epigenetic target for drug development. However, the impression of DNMTs on cancers is still controversial, and therapeutic methods targeting DNMTs remain under exploration. This review mainly summarizes the relationship between the main DNMTs and cancers as well as regulatory mechanisms and clinical applications of DNMTs in cancer and highlights several forthcoming strategies for targeting DNMTs.

Clinical characteristics and outcomes of lung cancer patients with COVID-19: A systematic review and meta-analysis protocol.

BACKGROUND: COVID-19 is spreading rapidly worldwide, and the population is generally susceptible to SARS-CoV-2, especially those with cancer. Hence, our study aims to design a protocol for a systematic review and meta-analysis of the clinical characteristics and prognoses of lung cancer patients with COVID-19. METHODS: The protocol is prepared following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The literature will be searched in Embase, Pubmed, the Cochrane Library, LitCovid, and CNKI for potentially eligible articles. The quality of the articles will be used in the Newcastle-Ottawa Quality Assessment Scale (NOS) and Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis will be performed through RevMan 5 software. This review protocol has been registered in PROSPERO (CRD42022306866). DISCUSSION: To clarify whether COVID-19 affects the clinical symptoms and prognoses of lung cancer patients. Further study is needed to establish the best evidence-based for the management of lung cancer patients with COVID-19. CONCLUSION: The definitive conclusion will be important to physicians effectively manage lung cancer patients with COVID-19.