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Objective To evaluate the therapeutic effect of evodiamine (Evo) on atopic dermatitis (AD) in rat models by regulating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element binding protein (CREB) signaling pathway. Methods A rat model of AD was established by administration of multiple doses of 2,4-dinitrochlorobenzene (DNCB).The animals were randomly divided into AD group, Evo-low-dose (Evo-L, 5 mg/kg) group, Evo-high-dose (Evo-H, 10 mg/kg) group, Evo-H+H-89 (5 mg/kg) group and dexamethasone (0.1 mg/kg) group. Normal rats were used as the control group and then the degree of skin damage of rats in each group was scored. Abdominal blood was taken to detect the levels of interleukin-4 (IL-4), cAMP, and tumor necrosis factor-α(TNF-α) in serum; Skin lesion tissue was collected to detect pathological change, counting of mast cells, PKA/CREB related protein expression and expression of IL-4 and TNF-α mRNA in the tissue. Results Compared with control group, the level of cAMP in serum, the expression of p-PKA/PKA, and p-CREB/CREB in skin lesions of AD group were reduced, the severity score of skin lesions, level of IL-4 and TNF-α, epidermal thickness, number of mast cells and mRNA expression of IL-4 and TNF-α in skin lesion tissues were all significantly increased (P＜0.05). Compared with AD group, the level of cAMP in serum, the expression of p-PKA/PKA, and p-CREB/CREB in skin lesions in Evo-L group, Evo-H group, and dexamethasone group were increased, the severity score of skin lesions, level of IL-4 and TNF-α, epidermal thickness, number of mast cells, and mRNA expression of IL-4 and TNF-α in skin lesion tissues all reduced (P＜0.05). Compared with the Evo-H group, the level of cAMP in serum, the expression of p-PKA/PKA, and p-CREB/CREB in skin lesions in Evo-H+H-89 group was reduced and the severity score of skin lesion, level of IL-4 and TNF-α, epidermal thickness, number of mast cells, and mRNA expression of IL-4 and TNF-α in skin lesion tissues significantly increased(P＜0.05). Conclusions Evo inhibits inflammatory response and pathological damage through regulation of cAMP/PKA/CREB signaling pathway in AD rat models.

Objective To investigate the molecular mechanism of polysaccharides from Atractylodes macrocephala koidz.(PAM) to treat severe pneumonia. Methods Sixty male SD rats were randomly divided into control group, model group (inoculation of Klebsiella pneumonia by tracheal puncture), positive control group (levofloxacin, 18 mg/kg), PAM low-dose group (50 mg/kg) and PAM high-dose group (200 mg/kg) with 12 in each. After occurrence of severe pneumonia, the rats were orally administered the medicine once daily for 7 day. The lung tissue underwent histopathological examination using HE staining microscopy to find the pathological alterations and evaluate the extent of injury. Wet/dry ratio of lung tissue was measured by weighing method. The leukocytes and neutrophils counts in peripheral blood were determined by hematology analyzer. The level of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and IL-6 in serum and bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The expression of proteins related to the Toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88)/nuclear factor-κB(NF-κB) signaling pathway in lung tissues was detected using Western blot analysis. Results Compared with the control group, lung injury score and wet/dry ratio, the number of leukocytes and neutrophils in peripheral blood, the level of TNF-α, IL-1β and IL-6 in serum and in BALF,protein expression of TLR4 and MyD88 and the phosphorylation level of NF-κB p56 in lung tissues from model group were all significantly increased(P＜0.05). The lung injury of rats in each levofloxacin treatment group exhibited significant improvement compared to the model group. Among them, the number of leukocytes and neutrophils in peripheral blood of rats in PAM high-dose group decreased significantly(P＜0.05); The level of TNF-α, IL-1β and IL-6 in serum and BALF, the protein expression of TLR4 and MyD88 and the phosphorylation level of NF-κB p56 in lung tissue were significantly decreased(P＜0.05). Conclusions The administration of PAM exerts a specific protective effect against Klebsiella pneumoniae-induced pneumonia in rats, potentially suppress inflammatory response through modulation of the TLR4/MyD88/NF-κB signaling pathway.

Abstract The inflammation and coagulopathy during coronavirus disease (COVID-19) impairs the efficiency of the current stroke treatments. Remote ischaemic conditioning (RIC) has shown potential in recent years to protect the brain and other organs against pathological conditions. This study aimed to evaluate the efficiency of RIC in brain infarct size using TTC staining and lung injury reduction by H&E staining during the hyper-inflammatory response in rats. The inflammation and coagulopathy were assessed by sedimentation rate, haematocrit, systemic oxidative stress and clotting time. Moreover, we observed changes in the cytokine profile. The results of the first part of the experiment showed that the inflammation and lung injury are fully developed after 24 h of intratracheal LPS administration. At this time, we induced focal brain ischaemia and examined the effect of RIC pre- and post-treatment. Our results showed that RIPre-C reduced the infarct size by about 23%, while RIPost-C by about 30%. The lung injury was also reduced following both treatments. Moreover, RIC modulated systemic inflammation. The level of chemokines CINC-1, LIX and RANTES decreased after 24 h of post-ischaemic reperfusion in treated animals compared to non-treated. The RIC-mediated decrease of inflammation was reflected in improved sedimentation rate and hematocrit, as well as reduced systemic oxidative stress. The results of this work showed neuroprotective and lung protective effects of RIC with a decrease in inflammation response. On the basis of our results, we assume that immunomodulation through the chemokines CINC-1, LIX, and RANTES play a role in RIC-mediated protection.

Gallbladder cancer (GBC) starts in the epithelial tissue (lining of the bile duct and gallbladder). It is a type of aggressive cancer called adenocarcinoma that can spread to other tissues. Among all cases of biliary tract cancer, 50% is from GBC. It is a deadly cancer with a survival rate of 17.6% between 2007 and 2013. GBC is rarely found in the Western world, but it is commonly found in South Asia. In Southeast Asian countries, GBC plays a significant role in cancer-related morbidity and mortality. GBC incidence exhibits marked regional variability, a rare condition in the western population but having a higher frequency in India, especially the Indo-Gangetic belt and some northeast districts excluding Nagaland. This might be attributed to the differences in environmental factors and genetic predisposition modulating carcinogenesis. In GBC, only 10% of cases are identified in the early stages. The low rate of early detection is due to the lack of screening techniques and the aggressive characteristics of the tumor. Various risk factors are associated with GBC, for example, chronic cholecystitis with or without gallstones, obesity, exposure to heavy metals such as lead and arsenic, bacterial infection, congenital biliary cysts, and abnormal pancreaticobiliary duct junction. The risk factors can cause chronic gallbladder mucosa irritation, leading to dysplasia and neoplasia. GBC can form metaplasia to dysplasia in a time span of 5–15 years, then to carcinoma in situ, and finally to invasive cancer. Dysbiosis is responsible for various diseases, including cancer. Multiple triggers can cause dysbiosis, for example, environmental changes, inflammation, infection, medications, dietary changes, or genetic predisposition. Various researches show that Helicobacter pylori, human papillomavirus, Hepatitis B virus, and Hepatitis C virus microbial species can cause cancer. They are the major species responsible for 90% of infection-associated cancers. Various studies demonstrate that the strains of Salmonella and Helicobacter colonize are linked to developing GBC. While the mechanisms linking gut microbiota to GBC are not fully understood, several studies have suggested a potential association. According to a study, certain gut microbiomes, such as Fusobacterium nucleatum, found glut in GBC tissues, compared to adjacent normal tissues. By evaluating gut microbiome dysbiosis, we can see the potential link between gut microbiome dysbiosis and GBC; it may provide valuable insights into the development and progression of GBC. It could lead to the identification of new diagnostic markers and the development of novel therapeutic strategies. In GBC, the evaluation of gut microbiome dysbiosis (involving evaluating the composition, diversity, and functional capacity of the gut microbiome in patients) has emerged as a promising method for understanding the molecular mechanisms and identifying biomarkers for early prevention and detection of GBC and also investigating the possibility of any link between the gut microbiome and host immune response. In conclusion, evaluating gut microbiome dysbiosis in GBC is a promising direction for identifying potential early detection and prevention biomarkers. Additional investigation is therefore needed to determine the role of gut microbiome dysbiosis in the development and progression of GBC and to identify reliable biomarkers for clinical use.

Background and aim: Muscular atrophy is one of the most common age-related conditions characterized by the deterioration of skeletal muscle structures and impaired functions. It is associated with cellular senescence and chronic inflammation, which impair the function of muscle stem cells. Bazi Bushen (BZBS) is a patent compound Chinese medicine that has been shown to have anti-aging effects in various animal models. In this study, we investigated the effects and mechanisms of BZBS on muscular atrophy in naturally aged mice. Experimental procedure: A muscular atrophy model of naturally aged mice (18 months) was employed with administration of BZBS (2 g/kg/d, 1 g/kg/d) and nicotinamide mononucleotide (NMN, 200 mg/kg/d). After six months of drug administration, muscle weight loss, muscle function and muscle histopathology were measured to evaluate the therapeutic effect of BZBS. The expression of cellular senescence, inflammatory and satellite cell-related factors were used to assess the effects of BZBS in inhibiting cellular senescence, reducing inflammation and improving muscle atrophy. Results and conclusion: Compared with age matched natural aging mice, we found that BZBS improved muscle strength, mass, and morphology by reducing senescent cells, inflammatory cytokines, and intermyofiber fibrosis in aged muscle tissues. We also found that BZBS prevented the reduction of Pax7 positive stem cells and stimulated the activation and differentiation into myocytes. Our results suggest that BZBS might be a promising intervention in senile muscular atrophy.

Objective To employ next-generation sequencing (NGS) to analyze differentially expressed mRNAs in the gingival tissue of hypertensive rats with or without periodontitis to provide a theoretical basis for the prevention and treatment of hypertension with periodontitis. Methods After obtaining approval from the Animal Experiment Ethics Committee, a hypertensive rat model was established by administering high-salt feed containing 8%（w/w） NaCl, and a periodontitis rat model was established by ligating the first molar of the mandibular region using 3-0 sterile silk thread. Rat models of the normal control (N), hypertension (H), and hypertension with periodontitis (PH) groups were established. The blood pressure, heart rate, alveolar bone resorption, and number of osteoclasts in the alveolar bone were measured, before harvesting the gingival tissues from the three groups for NGS to analyze the expression of significantly different genes. Gene ontology (GO) enrichment analysis was performed for all significantly differentially expressed genes between the H and PH groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. Key genes were screened by protein-protein interaction (PPI) networks, and the key gene expression in each group was verified using immunohistochemistry (IHC). The expression of key genes in the systemic circulation of each group was analyzed using enzyme-linked immunosorbent assay (ELISA). Results At the end of the experiment (11th week), the blood pressure was higher in both the H and PH groups than that in the N group (PPPP

Pulmonary arterial hypertension (PAH) is a severe and progressive pulmonary vascular disease mainly characterized by a continuous increase in pulmonary vascular resistance and rise of pulmonary artery pressure caused by pulmonary arteriolar lesions, ultimately resulting in right heart failure and even death. Pulmonary vascular remodeling is a characteristic pathological change of PAH, and its mechanism involves gene susceptibility, imbalance of vasoactive substances, abnormal energy metabolism and other potential factors. Recent studies have found that inflammatory reaction plays a crucial role in the mechanism of pulmonary vascular remodeling. Inflammatory cells are found to infiltrate and accumulate around the pulmonary vessels of PAH patients and of animal models. In addition, significantly high level of cytokines and auto-antibodies were also found in peripheral blood, which is closely related to poor prognosis of PAH. This article reviews the research progress about the potential role of inflammatory cells in the vascular remodeling of PAH and provides new ideas for developing of safe and effective treatment methods for PAH.

Objective To investigate the effect of artesunate (ART) on neuroinflammation in depressed mice by regulating the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) pathway. Methods Mice were divided into model group, control group, low-dose ART group, high-dose ART group, fluoxetine group, and high-dose ART+RocA (cGAS-STING pathway activator) group. Sugar solution consumption experiment and forced swimming experiment were applied to evaluate the depressive behavior of mice; HE staining microscopy was applied to detect pathological changes in hippocampal tissue; ELISA method was applied to detect the level of interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), serotonin(5-HT) and dopamine (DA); TUNEL staining microscopy was applied to detect neuronal apoptosis; Western blot was applied to detect Bcl-2 associated X protein (Bax), p53, cGAS, and STING proteins. Results Compared to the control group, the mice in the model group exhibited neuronal pustule degeneration, the sugar water consumption rate, level of 5-HT and DA decreased, the rest time of forced swimming increased. The level of IL-6 and TNF-α, neuronal apoptosis rate, expression of Bax, p53, cGAS, and STING proteins all elevated (P＜0.05); Compared with model group, the damage to hippocampus neurons in the ART low-dose group, ART high-dose group and fluoxetine group neuronal pustular degeneration was alleviated, while sugar water consumption rate, 5-HT, and DA levels increased, the rest time of forced swimming reduced, the level of IL-6 and TNF-α, neuronal apoptosis rate and the expression of Bax, p53, cGAS, and STING proteins reduced (P＜0.05); RocA reversed the improvement effect of high-dose ART on depression in mice. Conclusions ART inhibits neuroinflammation and neuronal apoptosis in depressed mice, and up-regulates amine neurotransmitters expression. The mechanism is potentially related to the blocking of cGAS-STING pathway.

The aim of the study is to study the morphological changes in tissue in the laparostomy area when it is closed with a xenopericardial plate under conditions of an active purulent-inflammatory process. Material and methods. Analysis of data from patients at the Penza regional clinical hospital named after. N.N. Burdenko, with diseases of the abdominal organs, complicated by diffuse purulent peritonitis. During treatment, xenopericardial plates with perforations in a checkerboard pattern were used (hole diameter 0.5 cm). Disinfection of the material was carried out with a sterile solution of furacilin. Using the standard hematoxylin and eosin staining protocol, as well as alternative staining methods according to Van Gieson and Weigert, light-optical examination of stained sections was carried out at a magnification of 40–400 times. Results. In 8 out of 9 patients participating in the study, a favorable course of the inflammatory process was observed; on the 21st day after laparotomy, the symptoms of peritonitis were eliminated, the surgical wound was sutured. In one case, progression of local and general signs of peritonitis was observed within two weeks. After replacing the xenopericardial plate, the course of changes in the surgical wound was favorable. On day 21, the laparotomy wound was also sutured. Repeated examination of the biomaterial one year and two months after implantation of the xenopericardial plate into the anterior abdominal wall did not reveal signs of inflammation. Conclusions. The xenopericardium performed well in conditions of purulent inflammation and in most cases was not subject to melting. In the long term, biointegration of the xenopericardium into its own connective tissue occurred.

Abstract Although thrombocytopenia on admission to the ICU is associated with increased in-hospital mortality in septic patients, the role of longitudinally measured platelet counts, which are dynamically changing, is unclear. We aimed to identify patterns of dynamic platelet count trajectories and evaluate their association with outcomes and thrombocytopenia in septic patients. We tested the longitudinal platelet trajectory patterns of sepsis patients within the first four days of ICU admission in the MIMIC-IV database and their association with 28-day mortality, and independently validated our findings in the eICU-CRD database. Statistical methods used included multivariate regression, propensity score analysis, doubly robust estimation, gradient boosting model, and inverse probability weighting to ensure the robustness of our findings. A total of 22,866 septic patients were included in our study. The trajectory analysis categorizes patients into ascending (AS), stable (ST), or descending (DS) patterns. The risk of 28-day mortality was increased in the DS patients (OR = 2.464, 95%CI 1.895–3.203, p

Abstract Impaired wound healing in diabetic individuals creates huge social and financial burdens for both diabetic patients and the health system. Unfortunately, the current treatment has not resulted in consistently lower amputation rates. Quinoxalines are heterocyclic compounds with multiple important pharmacological properties. Their effect on wound healing have not been closely studied. In the current work, the wound healing effect of 3-hydrazinylquinoxaline-2-thiol hydrogel is tested topically in a full-thickness excision wound in streptozotocin-induced type 1 diabetic rats. We examined the wound closure rate, expression of inflammatory factors, growth factors in addition to the histological analysis. The results revealed a significant acceleration in wound closure in the treated group compared with the control experimental animals. Histological data demonstrated enhanced re-epithelialization and collagen disposition. The healing effect was additionally evaluated by the inhibition of the inflammatory response of interleukin (IL)—1β interleukin (IL)—6, tumor necrosis factor (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) with a marked improvement of the transforming growth factor beta (TGFβ-1), antioxidant markers and collagen-1. In silico study indicated a favorable drug-like properties and toxicity profile. The present work showed that 3-hydrazinylquinoxaline-2-thiol holds great potential for the treatment of diabetic wounds.

Abstract Microglia are resident immune cells in the central nervous system, including the retina that surveil the environment for damage and infection. Following retinal damage, microglia undergo morphological changes, migrate to the site of damage, and express and secrete pro-inflammatory signals. In the zebrafish retina, inflammation induces the reprogramming and proliferation of Müller glia and the regeneration of neurons following damage or injury. Immunosuppression or pharmacological ablation of microglia reduce or abolish Müller glia proliferation. We evaluated the retinal architecture and retinal regeneration in adult zebrafish irf8 mutants, which have significantly depleted numbers of microglia. We show that irf8 mutants have normal retinal structure at 3 months post fertilization (mpf) and 6 mpf but fewer cone photoreceptors by 10 mpf. Surprisingly, light-induced photoreceptor ablation induced Müller glia proliferation in irf8 mutants and cone and rod photoreceptor regeneration. Light-damaged retinas from both wild-type and irf8 mutants show upregulated expression of mmp-9, il8, and tnfβ pro-inflammatory cytokines. Our data demonstrate that adult zebrafish irf8 mutants can regenerate normally following acute retinal injury. These findings suggest that microglia may not be essential for retinal regeneration in zebrafish and that other mechanisms can compensate for the reduction in microglia numbers.

Objective: This study aimed to investigate the comparison of the Erythrocyte Sedimentation Rate (ESR) levels in patients with type 1 diabetes mellitus (T1DM) rather than the standard ESR rate as the reference. Materials and Methods: In this analytical cross-sectional study 80 individuals with T1DM under 14 years of age were selected from Diabetes Research Center from 2021-2022. Sampling was done by available methods. Demographic information such as age, gender, HbA1c, and ESR level was recorded. The collected data were entered into SPSS v.22 software. Pearson correlation was used for association and t-test was used for comparing means. A significance level of P < 0.05 was considered. Results: thirty three (41.2%) were male and 47 (58.8%) were female. The mean (±SD) age was 9.50 (± 0.414) years. The mean (±SD) ESR in the studied samples was 11.60(±6.475), which had a significant difference with the ESR value of 10 (P= 0.031). Moreover, the ESR of both groups of studied boys -and girls was significantly higher than the standard upper limit of the society (P= 0.0001). Additionally, ESR had a statistical relationship with HbA1c (P= 0.016) and no significant relationship with age (P= 0.730). Conclusion: ESR levels in children with T1D were significantly elevated, indicating systemic inflammation. ESR also showed a statistical relationship with HbA1c levels, suggesting its potential as a valuable marker for disease activity and management in T1D patients.

Abstract Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC–MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.

Abstract Plasma levels of endocannabinoids (eCBs) are very dynamic and variable in different circumstances and pathologies. The aim of the study was to determine the levels of the main eCBs and N-acylethanolamines (NAEs) in COVID-19 patients during the acute and post-acute phase of SARS-CoV-2 infection. Samples collected before December 31, 2020 were used for the determination of circulating eCB levels by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The association between plasma eCB measurements and biochemical and hematological parameters, as well as serum IL-6 levels, was evaluated. Samples of 64 individuals were analysed, n = 18 healthy donors, n = 30 acute, and n = 16 post-acute patients. Plasma levels of 2-arachidonoylglycerol (2-AG), were significantly elevated in COVID-19 patients when compared to healthy individuals. Plasma N-palmitoylethanolamide (PEA) and N-arachidonoylethanolamide (AEA) levels were found to be decreased in post-acute patient samples. These results suggest that 2-AG plays an important role in the inflammatory cascade in COVID-19 disease; in addition, eCBs might be involved in the post-acute pathogenesis of COVID-19. This study provides evidence of altered levels of circulating eCBs as a consequence of SARS-CoV-2 infection.

Abstract General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.

Abstract Background Gestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes. Methods GAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays). Results GAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p

Abstract Background Around 10% of people with HIV (PWH) exhibit a low-level viremia (LLV) under antiretroviral therapy (ART). However, its origin and clinical significance are largely unknown, particularly at viremias between 50 and 200 copies/mL and under modern ART based on integrase strand transfer inhibitors (INSTIs). Our aim was to characterize their poor immune response against HIV in comparison to individuals with suppressed viremia (SV) and non-HIV controls (NHC). Methods Transversal observational study in 81 matched participants: 27 PWH with LLV, 27 PWH with SV, and 27 NHC. Activation (CD25, HLA-DR, and CD38) and senescence [CD57, PD1, and HAVCR2 (TIM3)] were characterized in peripheral T-cell subsets by spectral flow cytometry. 45 soluble biomarkers of systemic inflammation were evaluated by immunoassays. Differences in cell frequencies and plasma biomarkers among groups were evaluated by a generalized additive model for location, scale, and shape (GAMLSS) and generalized linear model (GLM) respectively, adjusted by age, sex at birth, and ART regimen. Results The median age was 53 years and 77.8% were male. Compared to NHC, PWH showed a lower CD4+/CD8+ ratio and increased activation, senescence, and inflammation, highlighting IL-13 in LLV. In addition, LLV showed a downtrend in the frequency of CD8+ naive and effector memory (EM) type 1 compared to SV, along with higher activation and senescence in CD4+ and CD8+ EM and terminally differentiated effector memory RA+ (TEMRA) subpopulations. No significant differences in systemic inflammation were observed between PWH groups. Conclusion LLV between 50 and 200 copies/mL leads to reduced cytotoxic activity and T-cell dysfunction that could affect cytokine production, being unable to control and eliminate infected cells. The increase in senescence markers suggests a progressive loss of immunological memory and a reduction in the proliferative capacity of immune cells. This accelerated immune aging could lead to an increased risk of developing future comorbidities. These findings strongly advocate for heightened surveillance of these PWH to promptly identify potential future complications.

Abstract Cathepsin C (CTSC) is a lysosomal cysteine protease constitutively expressed at high levels in the lung, kidney, liver, and spleen. It plays a key role in the activation of serine proteases in cytotoxic T cells, natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase, proteinase 3) underscoring its pivotal significance in immune and inflammatory defenses. Here, we comprehensively review the structural attributes, synthesis, and function of CTSC, with a focus on its variants implicated in the etiopathology of several syndromes associated with neutrophil serine proteases, including Papillon–Lefevre syndrome (PLS), Haim–Munk Syndrome (HMS), and aggressive periodontitis (AP). These syndromes are characterized by palmoplantar hyperkeratosis, and early-onset periodontitis (severe gum disease) resulting in premature tooth loss. Due to the critical role played by CTSC in these and several other conditions it is being explored as a potential therapeutic target for autoimmune and inflammatory disorders. The review also discusses in depth the gene variants of CTSC, and in particular their postulated association with chronic obstructive pulmonary disease (COPD), COVID-19, various cancers, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, sudden cardiac death (SCD), atherosclerotic vascular disease, and neuroinflammatory disease. Finally, the therapeutic potential of CTSC across a range of human diseases is discussed.

Varicose vein disease of the lower extremities is an inflammatory disorder with abnormal structure and functional activity of the venous valves, venous walls and cells, as well as with abnormal activity of the infiltrating leukocytes. The abnormally changed varicose vein are characterized by increased venous pressure, blood accumulation and congestion, ischemia, and metabolic and energy turnover derangement, which result in clinical manifestations of complications, such as pain, edema and formation of trophic ulcers. For many years, flavonoids have been used to treat varicose veins. The most effective flavonoids used in varicose vein disease and its complications, are hesperidin and diosmin, as well as their combinations. The review sets forth the state-of-the-art knowledge on the universal inflammatory processes playing a leading role in the pathophysiology of many cardiovascular disorders, including venous ones. In the recent years, it has been found that one of the main causes of inflammation is the formation of intracellular protein complexes (inflammasomes), which both produce a set of proinflammatory cytokines and are responsible for their excretion from the cells. In addition, inflammasomes control the development of regulated necrosis (pyroptosis) that takes part in the process of ulceration. The inflammasome activity can be modified by various mechanisms, of which the gene independent synthesis of the inflammasomal proteins has been recognized as the leading one. It has been shown that flavonoids inhibit the activation of a key factor NF-kappa B and suppress the synthesis of proteins, including NOD-like receptor protein 3 (NLRP3) inflammasome components, decrease the expression of NLRP3 receptor, protein ASC and caspase 1, as well as diminish interleukin 1 beta, interleukin 6 and tumor necrosis factor-alpha expression. Thus, this is the explanation of positive effects observed with the use of hesperidin, diosmin and their combination in clinical practice.

Objective(s): Evaluating the effect of fresh Oleaster leaf extract (OLE) and purified oleuropein (OLR) on ethanol-induced gastric ulcers in rats. HPLC analysis demonstrates the presence of various polyphenol compounds such as ligstroside, luteolin derivative, oleuropein, and comselogoside. Materials and Methods: Gastric ulcer was induced by administration of ethanol by the gastric gavage route. The olive leaf extract was analyzed by HPLC-PDA-ESI-MS, and OLR was purified. These two compounds were given 2 hr before gastric ulcer induction by ethanol.Results: This study verified that OLE and purified OLR protect from ethanol-induced gastric ulceration and damage, evidenced by the significant decrease in gastric ulcer urea (by 74 and 58% respectively) and stomach mucus content (by 169 and 87% respectively). In addition, the ulcer index (UI) and curative index (CI) levels in the stomach of the rats treated with this supplement were also suppressed by 55 and 46%, respectively. OLE and OLR also decreased the gastric myeloperoxidase (MPO) activity and ameliorated the Nitric oxide (NO) content. OLE and OL also ingestion suppressed gastric tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6) rates. Macroscopic and histological findings revealed that OLE and OLR protect from gastric hemorrhage, severe disruption of the gastric mucosa, and neutrophil infiltration.Conclusion: Overall, the findings demonstrate that OLE and OLR have both promising potential with regard to the inhibition of gastric hemorrhage and lesions.

Objective(s): Acute pancreatitis (AP) is an abrupt inflammatory condition characterized by a storm of inflammatory cytokines leading to high morbidity and mortality. The current study aimed to examine the efficacy of Ginkgo biloba extract EGb 761 (GBE) in the treatment of L-arginine-induced AP and its associated lung injury. Materials and Methods: Forty rats were randomly assigned into four groups. The normal group received only saline intraperitoneally while the other groups received two intraperitoneal L-arginine injections (250 mg/100 g b.wt) separated by a 1-hour interval to provoke AP. GBE (200 and 400 mg/kg/day, PO) was administered for 2 weeks post-induction of pancreatitis. Sera and pancreatic tissues were isolated.Results: The outcome of the present study revealed that GBE ameliorated the elevated levels of serum amylase, lipase, and pancreatic inflammatory mediators viz., tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase P38 (MAPK-P38), c-Jun N-terminal kinase 1 (JNK1), and nuclear factor-kappa B (NF-κB). Moreover, GBE restored the pancreatic gene expression of Toll-like receptor 4 (TLR4) and prostatic acid phosphatase-2 (PAP-2). Pancreatic and lung histopathological examinations confirmed the aforementioned parameters. Conclusion: GBE interfered with the mechanistic pathway of L-arginine-induced acute pancreatic and its associated lung injury. Due to its anti-inflammatory properties, GBE can be used as a novel therapeutic candidate for the treatment of AP through down-regulating TLR-4/MAPK-p38/JNK and MAPK- p38/NF-κB signaling cascades.

Objective(s): Hyperglycemia, a prevalent metabolic condition observed in diabetes, leads to oxidative damage, inflammatory responses, and other consequences. Natural compounds alleviate the adverse impacts of diabetes. We aimed to explore the effects of alpha-pinene (AP) as a monoterpene on oxidative damage and inflammation caused by high glucose (HG) in the human hepatocellular liver carcinoma (HepG2) cell line. Materials and Methods: The HepG2 cells were subjected to non or HG concentration (50 mM) and treated with or without AP (8, 16, and 32 μg/ml) for 48 hr. The effect of treatments on cellular viability, malondialdehyde (MDA), glutathione (GSH), and activity of anti-oxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), was determined. The gene expression levels of nuclear factor-κβ (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and dipeptidyl peptidase-4 (DPP-4) were estimated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: HG exposure significantly increased cell death, MDA formation, and depletion of GSH content and GPx, CAT, and SOD activity (P

Interest in naturally occurring phytochemicals has been on the increase, they are believed to reduce the risk of brain disorders. Hispidulin (HN) is a phenolic flavonoid compound with various pharmacological and biological effects on the central nervous system. It belongs to the flavone class of flavonoids. It can be found in different plant materials, especially fruits and vegetables. The literature used in this review was collected from credible scientific databases including ScienceDirect, Scopus, PubMed, Google Scholar, and Hindawi without time restriction, using relevant keywords, such as HN, brain, central nervous system, flavonoids, and flavones. HN was discovered to possess pro-apoptotic properties, act as an antioxidant, inhibit cytokine production and toll-like receptor 4 expression, as well as impede nuclear factor kappa beta and mitogen-activated protein kinase B. HN was also found to inhibit lipid peroxidation in vitro and reduce brain edema in mice. These pharmacological potentials suggest that HN is a promising candidate for neuroprotection in CNS disorders like depression and epilepsy. This review provides an update on the scientific literature concerning how these activities could help provide various forms of neuroprotection in the CNS. Additional experimental data on the effects of HN in models of neurological disorders and neuroprotection should be explored further. Based on the current study, HN is a promising candidate for neuroprotection of the CNS.

Abstract A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.

Abstract Systemic inflammatory response index (SIRI) has been proven to be associated with the prognosis of coronary artery disease and many other diseases. However, the relationship between SIRI and acute traumatic spinal cord injury (tSCI) has rarely been evaluated. The study aims to assess the prognostic value of SIRI for clinical outcomes in individuals with acute tSCI. A total of 190 patients admitted within eight hours after tSCI between January 2021 and April 2023 were enrolled in our study. Logistic regression analysis was used to analyze the association between SIRI and American Spinal Injury Association Impairment Scale (AIS) grade at admission and discharge, as well as neurological improvement in tSCI patients, and receiver operating characteristic (ROC) analysis was performed to assess the discriminative ability of SIRI in predicting AIS grade at discharge. After adjusting for confounding factors, SIRI positively correlated with the AIS grade (A to C) at admission and discharge, and negatively correlated with neurological improvement. The area under the curve values in ROC analysis was 0.725 (95% CI 0.647, 0.803). The study suggests that SIRI is significantly associated with an increased risk of poor clinical outcome at discharge in tSCI patients and has a certain discriminative value.

Abstract Endometriosis is a common condition that affects 5% to 10% of women during their reproductive years, although the aetiology and pathophysiology are still unknown. This study aimed to create an endometriosis model in rats to investigate the efficacy of natural and synthetic medications in treating endometriosis. An in vivo endometriotic model was established using a surgical induction method and the endocrine-disrupting drug diethylstilbestrol (DES). In brief, the experiment is categorised into three different groups. Each group contains five rats. The first group had no surgery, while in the in the second group of rats (n = 5), two small tissue grafts were fixed at the right and left walls of the abdomen. But in the in the third group of rats (n = 5), two small pieces of tissue have been grafted on the right and left abdomen walls by surgically along with DES treatments. Noninvasive photoacoustic imaging (PAI) was employed in the study to measure factors such as haemoglobin levels, oxygen saturation, and the size of endometriotic lesions. Histopathological analysis was carried out utilising staining techniques such as Hematoxylin and Eosin, Masson's Trichrome, and Periodic Acid Schiff, as well as immunohistochemistry with marker antibodies. Molecular markers in uterine tissue were examined using Western blots and real-time PCR. The developed endometriosis rat model showed a significant increase in the expression of anti-apoptotic Bcl-2, angiogenic marker VEGF and pro-inflammatory (COX-2 and IL-6) protein markers. In contrast to the control group, the treatment group had considerably lower Caspase-3 expression levels. Photoacoustic imaging (PAI) data demonstrated a constant increase in lesion size, as well as a decrease in oxygen saturation levels. The findings suggest that the in vivo endometriosis rat model may accurately assess the efficacy of natural or synthetic endometriosis treatments. This model may help in the improvement of disease understanding and the development of targeted therapeutic drugs.

Abstract Background The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. Methods Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis. Results Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men. Conclusions Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases.

Abstract A comprehensive understanding of the intricate cellular and molecular changes governing the complex interactions between cells within acne lesions is currently lacking. Herein, we analyzed early papules from six subjects with active acne vulgaris, utilizing single-cell and high-resolution spatial RNA sequencing. We observed significant changes in signaling pathways across seven different cell types when comparing lesional skin samples (LSS) to healthy skin samples (HSS). Using CellChat, we constructed an atlas of signaling pathways for the HSS, identifying key signal distributions and cell-specific genes within individual clusters. Further, our comparative analysis revealed changes in 49 signaling pathways across all cell clusters in the LSS— 4 exhibited decreased activity, whereas 45 were upregulated, suggesting that acne significantly alters cellular dynamics. We identified ten molecules, including GRN, IL-13RA1 and SDC1 that were consistently altered in all donors. Subsequently, we focused on the function of GRN and IL-13RA1 in TREM2 macrophages and keratinocytes as these cells participate in inflammation and hyperkeratinization in the early stages of acne development. We evaluated their function in TREM2 macrophages and the HaCaT cell line. We found that GRN increased the expression of proinflammatory cytokines and chemokines, including IL-18, CCL5, and CXCL2 in TREM2 macrophages. Additionally, the activation of IL-13RA1 by IL-13 in HaCaT cells promoted the dysregulation of genes associated with hyperkeratinization, including KRT17, KRT16, and FLG. These findings suggest that modulating the GRN-SORT1 and IL-13-IL-13RA1 signaling pathways could be a promising approach for developing new acne treatments.

Abstract Bacterial testicular inflammation is one of the important causes of male infertility. Using plant-derived compounds to overcome the side effects of antibiotics is an alternative treatment strategy for many diseases. Schizandrin B (SchB) is a bioactive compound of herbal medicine Schisandra chinensis which has multiple pharmacological effects. However its effect and the mechanism against testicular inflammation are unknown. Here we tackled these questions using models of lipopolysaccharide (LPS)-induced mice and -Sertoli cells (SCs). Histologically, SchB ameliorated the LPS-induced damages of the seminiferous epithelium and blood-testicular barrier, and reduced the production of pro-inflammatory mediators in mouse testes. Furthermore, SchB decreased the levels of pro-inflammatory mediators and inhibited the nuclear factor kB (NF-κB) and MAPK (especially JNK) signaling pathway phosphorylation in LPS-induced mSCs. The bioinformatics analysis based on receptor prediction and the molecular docking was further conducted. We targeted androgen receptor (AR) and illustrated that AR might bind with SchB in its function. Further experiments indicate that the AR expression was upregulated by LPS stimulation, while SchB treatment reversed this phenomenon; similarly, the expression of the JNK-related proteins and apoptotic-related protein were also reversed after AR activator treatment. Together, SchB mitigates LPS-induced inflammation and apoptosis by inhibiting the AR-JNK pathway.

Abstract Acute pancreatitis (AP) is a common disease caused by a variety of causes. Is uric acid associated with the onset of AP? The objective of this study was to assess whether uric acid concentration in AP patients was higher than that in healthy population, and whether there were associations between uric acid concentration and serological indicators related to AP. A total of 205 AP patients were included in this study. Two hundred and five people who underwent physical examination in our hospital were randomly selected as controls. We analyzed whether there was difference in uric acid concentrations between the two groups. If the difference was statistically significant, the correlations between uric acid concentration and serological indicators in AP patients was further analyzed. There was significant difference in uric acid concentration (P

Abstract Background Invasive Aspergillosis is a fungal infection caused by Aspergillus species, typically posing life-threatening risks to immunocompromised individuals. While occurrences in immunocompetent hosts are rare, a recent case report documented fulminant pulmonary aspergillosis in an immunocompetent patient during autopsy. Here, we present a case of invasive aspergillosis in an immunocompetent woman, manifesting with disseminated lesions. Case presentation A 29-year-old Asian woman presented to our hospital in March 2022, reporting chest pain and shortness of breath persisting for two months. Upon examination, she appeared thin and unwell, with no notable abnormalities otherwise. Radiographic imaging revealed an ill-defined lesion in her left lung. Subsequent bronchoscopy and lavage were performed, followed by initiation of empirical antibiotic therapy. Lavage results were negative for gram staining, culture, and ZN staining for AFB, but revealed numerous septate hyphae on fungal smear. Histopathological examination indicated chronic granulomatous inflammation with septal fungal hyphae, indicative of aspergillosis. Subsequent culture confirmed Aspergillus species, prompting initiation of voriconazole therapy. Remarkably, the patient exhibited significant improvement, with weight gain and restored appetite observed within a short period. Within 2 months of treatment, her symptoms resolved, and she resumed near-normal daily activities. Conclusion This case highlights the diagnosis of aspergillosis in an immunocompetent individual presenting with disseminated nodular lesions across the lungs, mediastinum, and abdomen. Clinicians should maintain a high index of suspicion for aspergillosis in cases of non-resolving pneumonia and disseminated nodular lesions, even in patients lacking traditional predisposing factors.

Abstract Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.

Abstract Background ERAP2 is an aminopeptidase involved in antigen processing and presentation, and harbor genetic variants linked to several inflammatory diseases such as Inflammatory Bowel Disease (IBD). The lack of an ERAP2 gene homologue in mice has hampered functional studies, and most human studies have focused on cells of hematopoietic origin. Using an IBD biobank as vantage point, this study explores how genetic variation in ERAP2 affects gene expression in human-derived epithelial organoids upon proinflammatory stimulation. Methods An IBD patient cohort was genotyped with regards to two single nucleotide polymorphisms (SNP) (rs2910686/rs2248374) associated with ERAP2 expression levels, and we examined the correlation between colon gene expression and genotype, specifically aiming to establish a relationship with ERAP2 expression proficiency. Human-derived colon organoids (colonoids) with known ERAP2 genotype were established and used to explore differences in whole genome gene expression between ERAP2-deficient (n = 4) and -proficient (n = 4) donors upon pro-inflammatory encounter. Results When taking rs2910686 genotype into account, ERAP2 gene expression is upregulated in the inflamed colon of IBD patients. Colonoids upregulate ERAP2 upon IFNɣ stimulation, and ERAP2 expression proficiency is dependent on rs2910686 genotype. Colonoid genotyping confirms that mechanisms independent of the frequently studied SNP rs2248374 can cause ERAP2-deficiency. A total of 586 genes involved in various molecular mechanisms are differentially expressed between ERAP2 proficient- and deficient colonoids upon proinflammatory stimulation, including genes encoding proteins with the following molecular function: catalytic activity (AOC1, CPE, ANPEP and MEP1A), regulator activity (TNFSF9, MDK, GDF15, ILR6A, LGALS3 and FLNA), transmembrane transporter activity (SLC40A1 and SLC5A1), and extracellular matrix structural constituents (FGL2, HMCN2, and MUC17). Conclusions ERAP2 is upregulated in the inflamed IBD colon mucosa, and expression proficiency is highly correlated with genotype of rs2910686. While the SNP rs2248374 is commonly used to determine ERAP2 expressional proficiency, our data confirms that mechanisms independent of this SNP can lead to ERAP2 deficiency. Our data demonstrates that epithelial ERAP2 presence affects the inflammatory response in colonoids, suggesting a pleiotropic role of ERAP2 beyond MHC class I antigen processing.

Abstract Background Inflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored. Method We retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC. Results Our results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram. Conclusion The inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.

Introduction: Ankylosing Spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton, peripheral joints, and extra-articular structures. Typically, the condition starts in the second or third decade. Lower back pain lasting longer than three months, morning stiffness lasting more than 30 minutes, relieved by daily activities, are signs of disease onset. Aim: To establish a correlation between disease severity score Ankylosing Spondylitis Disease Activity Score (ASDAS) and Magnetic Resonance Imaging (MRI) scoring in patients with AS. Materials and Methods: This cross-sectional study was conducted on 66 patients attending the Medicine Emergency/Outpatient Department (OPD)/ward of ESIPGIMSR and ESI Hospital, Basaidarapur, New Delhi, India, who were diagonsed with AS based on the modified New York Criteria. Clinical assessments included ASDAS based on Erythrocyte Sedimentation Rate (ESR) and C-reactive Protein (CRP), while MRI disease activity scores were determined using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scoring. The sample size was calculated with a coefficient limit of 10% and a confidence level of 95%. Data analysis was performed using Statistical Packages for Social Sciences (SPSS) version 21.0, a widely used statistical computing and graphics tool. Pearson’s correlation coefficients were computed to explore relationships between variables, including age, disease duration, ASDAS-ESR, and MRI changes. Results: In present study, a total of 66 patients were included, out of which 51 (77.3%) were males and 15 (22.7%) were females. The age group of patients included in present study was 33 years to 44 years with a mean of 37.96 years. In present study, the disease duration ranged from a minimum of two years to a maximum of 10 years with a mean of 5.4 years. The mean ASDAS CRP was 3.687 (minimum-2.80, maximum-4.60), and the disease activity as assessed by MRI score (SPARCC) had a minimum value of 8.85 and a maximum value of 26.2 with a mean of 16.359. In present study, the X-ray grading of sacroiliitis revealed that 19.7% of the subjects were classified as Grade-2, 60.6% as Grade-3, and 19.7% as Grade-4. Conclusion: The clinical disease activity index may not always reflect active inflammation, which is detectable by MRI. Incorporating MRI into diagnostic and treatment strategies for AS is crucial for the accurate assessment of disease severity and better patient outcomes.

Introduction: Plantar fasciitis is the most common cause of heel and foot pain, leading individuals to use compensatory techniques to alleviate their pain, resulting in an antalgic gait. These compensations alter the feeling of joint position and muscle activation, making it challenging to maintain an upright posture within the base of support. According to Mulligan's concept, rigid tape allows painful or restricted movements with quick pain relief and increased range of motion while correcting positional faults and reducing tensile tension on the fascia, thereby decreasing inflammation and microscopic tears. Currently, there is a scarcity of data studying the effect of Mulligan’s calcaneal taping on dynamic balance. Aim: To evaluate the effect of Mulligan’s calcaneal taping on dynamic balance and functional performance in subjects with plantar fasciitis. Materials and Methods: The study was a prospective cohort study conducted at D.Y. Patil Hospital and Research Centre, Navi Mumbai, Maharashtra, India. It began in March 2023 and concluded in March 2024, spanning one year. Thirty-six subjects were randomly divided into group A (n=18) and group B (n=18). Subjects experiencing pain for more than six weeks, aged between 18-60 years, with a positive Windlass test, plantar medial heel pain, and abnormal foot posture index (between +6 to +9) were included in the study. The experimental group received Mulligan’s calcaneal taping along with conventional physiotherapy exercises, while the control group received only conventional physiotherapy exercises. Pre-post assessments were conducted using the star excursion balance test for dynamic balance assessment and the Foot Function Index (FFI) for functional performance. Results: Statistically significant differences were found among the medial (p-value=0.0212), posteromedial (p-value=0.0199), and posterior (p-value=0.0091) directions of the star excursion balance test. Both groups did not show statistically significant differences in the FFI score. However, with effect size, there was good clinical significance for the FFI score and all directions of the star excursion balance test except the posterolateral direction. Conclusion: Mulligan calcaneal taping has been shown to be more effective in improving dynamic balance in subjects with plantar fasciitis.

Background Cerebral infarction is a disorder of blood supply to the local brain tissue area caused by various causes. Tongnao Decoction is approved and used in Jiangsu Province Hospital of Chinese Medicine for the treatment of cerebral infarction. However, the specific mechanisms underlying its action remain unclear. Objective To explain the mechanism of Tongnao Decoction in the treatment of cerebral infarction through network pharmacology and clinical trails. Methods From January 2019 to June 2020, a total of 199 patients with cerebral infarction admitted to Jiangsu Province Hospital of Chinese Medicine were included in the clinical study. and divided into the control group (97 cases) and experimental group (102 cases) according to the method of random number table. Both groups received standardized treatment for stable cerebral infarction, and the experimental group was treated with Tongnao Decoction. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the degree of functional impairment caused by stroke, and the modified Rankin Scale (mRS) was used to assess the recovery of neurological function for both groups before treatment and at 2 weeks of treatment. The chemical compounds of Tongnao Decoction were screened from TCMSP and literature, and those with bioavailability (OB) ≥30% and drug-like properties (DL) ≥0.18 requirements were selected to find the active ingredient of the prescription. OMIM and GeneCards databases were used to analyze the molecular targets of Tongnao Decoction for the treatment of cerebral infarction. After screening the common targets, Cytoscape software, String database were used to plot the network of compounds and target proteins, construct protein-protein interaction (PPI) network, gene ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, respectively. Molecular docking experiments were finally performed to identify the main active ingredients of Tongnao Decoction for the treatment of cerebral infarction. Results After treatment, the scores of NIHSS and mRS in the experimental group were lower than those in the control group (P

As a crucial component of the cardiac autonomic nervous system, the cardiac vagus nerve plays a significant role in the management of chronic heart failure. In recent years, several studies have found that vagus nerve stimulation protects cardiac function and delays the progression of chronic heart failure by reducing the expression of inflammatory factors and related proteins, apoptosis-related proteins, and improving myocardial function and ventricular remodeling. However, there are limited reports related to the mechanism of inflammation and apoptosis of the vagus nerve in chronic heart failure. Hence, this article reviews the anatomy of the cardiac vagus nerve, potential treatment mechanisms, practical parameters of vagus nerve stimulation, and the recent applications and clinical progress of vagus nerve stimulation in inflammation and apoptosis mechanisms in chronic heart failure, in order to provide a reference for the future related research.

Objective(s): Skin aging is a degenerative process that can be induced by UV irradiation. UV radiation can produce reactive oxidate stress which causes premature aging. This study aims to examine the antiaging potential of secretome gel (SC) from human Wharton Jelly Mesenchymal Stem Cells (hWJ-MSCs) in a UVB-induced mice model. Materials and Methods: The secretome was obtained from hWJ-MSCs and made in gel form. Male mice were radiated by UVB for 15 min twice daily for 14 days. The gel was topically applied to the mice’s dorsal skin. Two treatments of secretome gel: secretome 1 is applied once and secretome 2 is applied twice daily after UVB radiation. TGF-β1, IL-10, and IL-18 gene expression was determined using RT-PCR. Hematoxylin Eosin staining was used to observe the inflammation and collagen density of skin tissue. An immunohistochemistry assay was used to analyze the protein expression of P53, COL4A1, MMP-2, and MMP-13. The data were statistically analyzed using the ANOVA test followed by the Tukey post hoc test (P

Background and purpose: Osteoporosis is one of the main public health concerns worldwide, which imposes a significant economic burden on the healthcare system. Chronic inflammation might play a role as one of the possible risk factors for osteoporosis and fractures. Also, previous studies have reported that dietary factors are effective in controlling and modulating inflammation. Recently, an index was designed to determine the dietary inflammatory potential (DIP), which estimates the inflammatory potential of diet on a continuous spectrum from anti-inflammatory to pro-inflammatory. There are limited studies investigating the relationship between dietary inflammatory potential (DIP) and the risk of osteoporosis in the Middle East. The present study aimed to explore the relationship between DIP and the risk of osteoporosis in a large population of Iranian adult women. Materials and methods: This study was conducted cross-sectionally using the basic data of the Tabari Cohort Study (TCS). Dietary information of study participants, which included 5417 adult women aged 35-70 living in Mazandaran, was collected using a validated semi-quantitative 119-item food frequency questionnaire. Dietary inflammatory potential was calculated using the method proposed by Shivappa et al. Data on osteoporosis was collected using the self-report method. Information on other variables was collected using standard questionnaires. A binary logistic regression test was used to assess the relationship between DIP and osteoporosis in crude and adjusted models. Results: The mean ± standard deviation of the age of the study participants was 49.20±9.14 years. The prevalence of osteoporosis in the participants was 9.8% (n=529). The mean±standard deviation dietary inflammatory potential of the study participants was 2.29±0.36. Individuals who were in the highest quartile of the DIP score were older and had higher physical activity than those in the lowest quartile of the DIP score (P

Src-homology region 2 domain-containing phosphatase 1 (SHP-1) is considered an anti-inflammatory factor, but its role in chronic obstructive pulmonary disease (COPD) remains unknown. Herein, overexpression of SHP-1 was utilized to explore the functions of SHP-1 in COPD models established by stimulating 16HBE cells with cigarette smoke extracts (CSE) in vitro. SHP-1 was downregulated in both COPD patients and CES-treated 16HBE cells. SHP-1 overexpression reinforced cell viability and significantly prevented CSE-induced cell apoptosis in 16HBE cells. Furthermore, SHP-1 overexpression greatly reversed the CSE-induced migration, epithelial–mesenchymal transition (EMT), and pro-inflammatory factor production in 16HBE cells. In addition, CSE activated the P65 and PI3K/AKT pathways in 16HBE cells, which was also reversed by SHP-1 overexpression. Our findings indicated that SHP-1 alleviated CSE-induced EMT and inflammation in 16HBE cells, suggesting that SHP-1 regulated the development of COPD, and these functions may be linked to the inhibition of the PI3K/AKT pathway.

Abstract Inflammation is an important factor in Alzheimer’s disease (AD). An NMR measurement in plasma, glycoprotein acetyls (GlycA), captures the overall level of protein production and glycosylation implicated in systemic inflammation. With its additional advantage of reducing biological variability, GlycA might be useful in monitoring the relationship between peripheral inflammation and brain changes relevant to AD. However, the associations between GlycA and these brain changes have not been fully evaluated. Here, we performed Spearman’s correlation analyses to evaluate these associations cross-sectionally and determined whether GlycA can inform AD-relevant longitudinal measurements among participants in the Alzheimer’s Disease Neuroimaging Initiative (n = 1506), with additional linear models and stratification analyses to evaluate the influences of sex or diagnosis status and confirm findings from Spearman’s correlation analyses. We found that GlycA was elevated in AD patients compared to cognitively normal participants. GlycA correlated negatively with multiple concurrent regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD. Baseline GlycA level was associated with executive function decline at 3–9 year follow-up in participants diagnosed with LMCI at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. Results here indicated that GlycA is an inflammatory biomarker relevant to AD pathogenesis and that the stage of LMCI might be relevant to inflammation-related intervention.

Abstract Prostaglandin E2 (PGE2) is a major contributor to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of nociceptive axons is incompletely understood. We developed and characterized a microfluidic cell culture model to investigate sensitisation of the axons of dorsal root ganglia neurons. We show that application of PGE2 to fluidically isolated axons leads to sensitisation of their responses to depolarising stimuli. Interestingly the application of PGE2 to the DRG axons elicited a direct and persistent spiking activity propagated to the soma. Both the persistent activity and the membrane depolarisation in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Further investigated into the mechanisms of the spiking activity showed that the PGE2 evoked depolarisation was inhibited by Nav1.8 sodium channel blockers but was refractory to the application of TTX or zatebradine. Interestingly, the depolarisation of axons was blocked by blocking ANO1 channels with T16Ainh-A01. We further show that PGE2-elicited axonal responses are altered by the changes in chloride gradient within the axons following treatment with bumetanide a Na-K-2Cl cotransporter NKCC1 inhibitor, but not by VU01240551 an inhibitor of potassium-chloride transporter KCC2. Our data demonstrate a novel role for PGE2/EP4/cAMP pathway which culminates in a sustained depolarisation of sensory axons mediated by a chloride current through ANO1 channels. Therefore, using a microfluidic culture model, we provide evidence for a potential dual function of PGE2 in inflammatory pain: it sensitises depolarisation-evoked responses in nociceptive axons and directly triggers action potentials by activating ANO1 and Nav1.8 channels.

Abstract Insufficient sleep duration may lead to a series of immune dysfunctions. One of the factors influencing this effect could be physical activity (PA). The study aimed to assess the impact of deprivation of sleep (DS) on selected inflammatory parameters. Seventy-seven participants completed the protocol consisting of polysomnography (PSG) conducted in a sleep laboratory and DS, monitored with an actigraph. PA was assessed with actigraphy, which categorized participants as active or inactive. White blood cells (WBC) values negatively correlated with sleep efficiency based on sleep diaries and PSG parameters (total sleep time, sleep efficiency, and REM duration), but regression analysis showed that WBC depends only on the sleep diary parameter. Granulocytes (GRA) positively correlated with REM latency, and negatively with sleep efficiency. After DS, all participants exhibited an elevated GRA count. The number of WBC and GRA increased also in the active group; inactive participants showed no changes in inflammatory parameters. The overall number of WBC depends primarily on the quality of sleep over a period of several days. Under the influence of sleep deprivation, the number of GRA increases, but the number of leukocytes depends on the level of physical activity during DS.

Abstract Short-chain fatty acids (SCFAs) have been proposed to have anti-inflammatory effects and improve immune homeostasis. We aimed to examine the effects of SCFAs on skin phenotype, systemic inflammation, and gut microbiota in mice with psoriasis-like inflammation. Imiquimod (IMQ)-treated C57BL/6 mice served as the study model. We conducted a metagenomic association study of IMQ-mice treated with SCFAs or anti-IL-17 antibody using whole-genome shotgun sequencing. The associations among SCFA supplements, skin thickness, circulating inflammatory profiles, and fecal microbiota profiles were investigated. The microbiome study was performed using pipelines for phylogenetic analysis, functional gene analysis, and pathway analysis. In IMQ-treated mice, there were increases in skin thickness and splenic weight, as well as unique fecal microbial profiles. SCFAs ameliorated IMQ-induced skin thickening, splenic weight gain, and serum IL-17F levels, with results that were comparable with those receiving anti-IL-17 treatment. IMQ-treated mice receiving SCFAs had greater microbial diversity than mice treated with IMQ alone. SCFAs and anti-IL17 treatment were associated with alteration of gut microbiota, with increased prevalences of Oscillospiraceae and Lachnopiraceae and decreased prevalences of Muribaculaceae and Bacteroides, which have been predicted to be associated with increased glycan degradation, phenylalanine metabolism, and xylene degradation. SCFAs may mitigate IMQ-induced skin thickening and IL-17F levels and alter fecal microbiota profiles in IMQ-treated mice.

Abstract Stroke, the second leading cause of death and disability, causes massive cell death in the brain followed by secondary inflammatory injury initiated by disease associated molecular patterns released from dead cells. Nonetheless, the evidence regarding the causal relationship between inflammatory cytokines and stroke subtypes is obscure. To leverage large scale genetic association data to investigate the interplay between circulating cytokines and stroke, we adopted a two-sample bi-directional Mendelian randomization (MR) analysis. Firstly, we performed a forward MR analysis to examine the associations of genetically determined 31 cytokines with 6 stroke subtypes. Secondly, we conducted a reverse MR analysis to check the associations of 6 stroke subtypes with 31 cytokines. In the forward MR analysis, genetic evidence suggests that 21 cytokines were significantly associated with certain stroke subtype risk with |β| ranging from 1.90 × 10−4 to 0.74. In the reverse MR analysis, our results found that five stroke subtypes (intracerebral hemorrhage (ICH), large artery atherosclerosis ischemic stroke (LAAS), lacunar stroke (LS), cardioembolic ischemic stroke (CEI), small-vessel ischemic stroke (SV)) caused significantly changes in 16 cytokines with |β| ranging from 1.08 × 10−4 to 0.69. In particular, those five stroke subtypes were statistically significantly associated with C-reactive protein (CRP). In addition, ICH, LAAS, LS and SV were significantly correlated with vascular endothelial growth factor (VEGF), while LAAS, LS, CEI and SV were significantly related to fibroblast growth factor (FGF). Moreover, integrated bi-directional MR analysis, these factors (IL-3Rα, IL-6R, IL-6Rα, IL-1Ra, insulin-like growth factor-1(IGF-1), IL-12Rβ2) can be used as predictors of some specific stroke subtypes. As well as, IL-16 and C–C motif chemokine receptor 7 (CCR7) can be used as prognostic factors of stroke. Our findings prognostic identify potential pharmacological opportunities, including perturbation of circulating cytokines for both predicting stroke risk and post stroke treatment effects. As we conducted a comprehensive search and analysis of stroke subtype and cytokines in the existing publicly available GWAS database, the results have good population-generalizability.

Abstract Background High-altitude cerebral edema (HACE) is considered an end-stage acute mountain sickness (AMS) that typically occurs in people after rapid ascent to 2500 m or more. While hypoxia is a fundamental feature of the pathophysiological mechanism of HACE, emerging evidence suggests that inflammation serves as a key risk factor in the occurrence and development of this disease. However, little is known about the molecular mechanism underlying their crosstalk. Methods A mouse HACE model was established by combination treatment with hypobaric hypoxia exposure and lipopolysaccharides (LPS) stimulation. Lactylated-proteomic analysis of microglia was performed to reveal the global profile of protein lactylation. Molecular modeling was applied to evaluate the 3-D modeling structures. A combination of experimental approaches, including western blotting, quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and RNA interference, were used to explore the underlying molecular mechanisms. Results We found that hypoxia exposure increased the lactate concentration and lactylation in mouse HACE model. Moreover, hypoxia aggravated the microglial neuroinflammatory response in a lactate-dependent manner. Global profiling of protein lactylation has shown that a large quantity of lysine-lactylated proteins are induced by hypoxia and preferentially occur in protein complexes, such as the NuRD complex, ribosome biogenesis complex, spliceosome complex, and DNA replication complex. The molecular modeling data indicated that lactylation could affect the 3-D theoretical structure and increase the solvent accessible surface area of HDAC1, MTA1 and Gatad2b, the core members of the NuRD complex. Further analysis by knockdown or selectively inhibition indicated that the NuRD complex is involved in hypoxia-mediated aggravation of inflammation. Conclusions These results revealed a comprehensive profile of protein lactylation in microglia and suggested that protein lysine lactylation plays an important role in the regulation of protein function and subsequently contributes to the neuroinflammatory response under hypoxic conditions.

Abstract Background Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls. Methods We performed a case–control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels. Results Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks. Conclusion and interpretation Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and has become one of the leading causes of blindness and visual impairment in diabetes patients. The pathogenesis of DR is multifaceted, involving inflammation, oxidative stress, neurovascular abnormalities, and other factors that present potential targets for disease management interventions. Currently, anti-vascular endothelial growth factor (VEGF) drugs serve as the primary treatment for advanced stages of DR when irreversible neurovascular damage and visual impairment have occurred. Additionally, some patients show poor or no response to anti-VEGF treatment. There is a lack of early intervention options for the initial phases of the disease. Therefore, there is an urgent need to develop novel local or systemic therapies based on the underlying mechanisms of DR to enable early prevention and treatment with the aim of preserving patients′ vision. Medications targeting various pathways including anti-inflammatory agents (corticosteroids and nonsteroidal anti-inflammatory drugs), neurotrophic and neuroprotective drugs, drugs modulating biochemical pathways, antioxidant phytochemicals, and gene therapy can complement each other in terms of therapeutic effects to benefit a larger number of individuals affected by DR. This article reviews previous research reports on the pathogenesis, drug treatment methods, and potential therapeutic targets associated with DR in order to provide guidance for clinical practice.