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Polycystic ovary syndrome (PCOS) is a metabolic-reproductive-endocrine disorder that, while having a genetic component, is known to have a complex multifactorial etiology. As PCOS is a diagnosis of exclusion, standardized criteria have been developed for its diagnosis. The general consensus is that hyperandrogenism is the primary feature of PCOS and is associated with an array of physiological dysfunctions; excess androgens, for example, have been correlated with cytokine hypersecretion, adipocyte proliferation, and signaling pathway dysregulation. Another key feature of PCOS is insulin resistance, resulting in aberrant glucose and fatty acid metabolism. Additionally, the immune system plays a key role in PCOS. Hyperandrogenism stimulates some immune cells while it inhibits others, thereby disrupting the normal balance of immune cells and creating a state of chronic inflammation. This low-grade inflammation could contribute to infertility since it induces ovarian dysfunction. This dysregulated immune response in PCOS exhibits autoimmunity characteristics that require further investigation. This review paper examines the relationship between androgens and the immune response and how their malfunction contributes to PCOS. [ABSTRACT FROM AUTHOR]

It is widely acknowledged that gastric cancer seriously affects the quality of life and survival of patients. The correlation between the microbiota and gastric cancer has attracted extensive attention in recent years, nonetheless the specific mechanism of its impact on gastric cancer remain largely unclear. Recent studies have shown that in addition to its role in the host's inflammatory and immune response, the microbiota can also affect the occurrence and development of gastric cancer by affecting the expression of miRNAs. This paper brings together all currently available data on miRNAs, microbiota and gastric cancer, and preliminarily describes the relationship among them. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Omicron variant impacts populations with its rapid contagiousness, and part of patients suffered from persistent symptoms termed as long COVID. The molecular and immune mechanisms of this currently dominant global variant leading to long COVID remain unclear, due to long COVID heterogeneity across populations. Methods: We recruited 66 participants in total, 22 out of 66 were healthy control without COVID-19 infection history, and 22 complaining about long COVID symptoms 6 months after first infection of Omicron, referred as long COVID (LC) Group. The left ones were defined as non-long COVID (NLC) Group. We profiled them via plasma neutralizing antibody titer, SARS-CoV-2 viral load, transcriptomic and proteomics screening, and machine learning. Results: No serum residual SARS-CoV-2 was observed in the participants 6 months post COVID-19 infection. No significant difference in neutralizing antibody titers was found between the long COVID (LC) Group and the non-long COVID (NLC) Group. Transcriptomic and proteomic profiling allow the stratification of long COVID into neutrophil function upregulated (NU-LC) and downregulated types (ND-LC). The NU-LC, identifiable through a refined set of 5 blood gene markers (ABCA13, CEACAM6, CRISP3, CTSG and BPI), displays evidence of relatively higher neutrophil counts and function of degranulation than the ND-LC at 6 months after infection, while recovered at 12 months post COVID-19. Conclusion: The transcriptomic and proteomic profiling revealed heterogeneity among long COVID patients. We discovered a subgroup of long COVID population characterized by neutrophil activation, which might associate with the development of psychiatric symptoms and indicate a higher inflammatory state. Meanwhile, a cluster of 5 genes was manually curated as the most potent discriminators of NU-LC from long COVID population. This study can serve as a foundational exploration of the heterogeneity in the pathogenesis of long COVID and assist in therapeutic targeting and detailed epidemiological investigation of long COVID. [ABSTRACT FROM AUTHOR]

Background and purpose: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. Methods: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. Results: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. Conclusion: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. Methods: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. Results: Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1β (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. Conclusions: Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions. [ABSTRACT FROM AUTHOR]

Background: Acne, a chronic inflammatory disease impacting the pilosebaceous unit, is influenced significantly by inflammation and oxidative stress, and is commonly associated with obesity. Similarly, obesity is also associated with increased inflammation and oxidation. The role of diet in acne remains inconclusive, but the very low-calorie ketogenic diet (VLCKD), known for weight loss and generating anti-inflammatory ketone bodies, presents promising potential. Despite this, the effects of VLCKD on acne remain underexplored. This study aimed to investigate the efficacy of a 45-day active phase of VLCKD in reducing the clinical severity of acne in young women with treatment-naïve moderate acne and grade I obesity. Methods: Thirty-one women with treatment-naïve moderate acne, grade I obesity (BMI 30.03–34.65 kg/m2), aged 18–30 years, meeting inclusion/exclusion criteria, and consenting to adhere to VLCKD were recruited. Baseline and post-intervention assessments included anthropometric measurements, body composition, phase angle (PhA), trimethylamine N-oxide (TMAO) levels, and reactive oxygen metabolite derivatives (dROMs) as markers of inflammation, dysbiosis, and oxidative stress, respectively. A comprehensive dermatological examination, incorporating the Global Acne Grading System (GAGS) and the Dermatology Life Quality Index (DLQI), was conducted for all women. Results: VLCKD resulted in general improvements in anthropometric and body composition parameters. Significantly, there were significant reductions in both the GAGS score (Δ%: − 31.46 ± 9.53, p < 0.001) and the DLQI score (Δ%: − 45.44 ± 24.02, p < 0.001) after the intervention. These improvements coincided with significant decreases in TMAO (p < 0.001) and dROMs (p < 0.001) levels and a significant increase in PhA (Δ%: + 8.60 ± 7.40, p < 0.001). Changes in the GAGS score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjusting for Δ% FM. Changes in the DLQI score positively correlated with changes in dROMs (p < 0.001) and negatively with PhA (p < 0.001) even after adjustment for Δ% FM. Conclusion: Given the side effects of drugs used for acne, there is an increasing need for safe, tolerable, and low-cost treatments that can be used for acne disease. The 45-day active phase of VLCKD demonstrated notable improvements in acne severity, and these improvements seemed to be attributable to the known antioxidant and anti-inflammatory effects of VLCKD. [ABSTRACT FROM AUTHOR]

Widespread pain and inflammation Discussion of endothelial dysfunction and vascular damage in ME/CFS and Long COVID generally focuses on how leakages from dysfunctional blood vessels lead to reduced blood flow, which has many consequences, including reduced oxygenation of muscles and reduced cerebral brain flow. To the Editor, In their hypothesis paper, Wirth, Scheibenbogen, and Paul describe how endothelial dysfunction could produce a wide range of neurological symptoms in people with ME/CFS [[1]]. [Extracted from the article]

Background Relative hypovolemia is frequently found in early stages of severe sepsis and septic shock and prompt and aggressive fluid therapy has become standard of care improving tissue perfusion and patient outcome. This paper investigates the role of the nitric oxide pathway on beneficial microcirculatory effects of fluid resuscitation. Methods After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were fluid resuscitated and then sequentially treated with L-Nω-Nitroarginine and L-Arginine hydrochloride (LPS/FR/LNNA group). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables including venular leukocyte rolling and adhesion. Macro-hemodynamic, biochemical and hematological parameters as well as survival rate were also evaluated. Endotoxemic hamsters treated with fluid therapy alone (LPS/FR group) and non-treated animals (LPS group) served as controls. Results Fluid resuscitation was effective in reducing lipopolysaccharide-induced microcirculatory changes. After 3 hours of lipopolysaccharide administration, non-fluid resuscitated animals (LPS group) had the lowest functional capillary density (1% from baseline for LPS group vs. 19% for LPS/FR one; p <0.05). At the same time point, arteriolar mean internal diameter was significantly wider in LPS/FR group than in LPS one (100% vs. 50% from baseline). Fluid resuscitation also reduced leukocyte-endothelium interactions and sequestration (p <0.05 for LPS vs. LPS/FR group) and increased survival (median survival time: 2 and 5.5 days for LPS and LPS/FR groups, respectively; p <0.05). Nitric oxide synthase inhibition prevented these protective effects, while L-Arginine administration markedly restored many of them. Conclusion Our results suggest that the underlying mechanism of fluid therapy is the restoration of nitric oxide bioavailability, because inhibition of NOS prevented many of its beneficial effects. Nevertheless, further investigations are required in experimental models closer to conditions of human sepsis to confirm these results. [ABSTRACT FROM AUTHOR]

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor-infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases. [ABSTRACT FROM AUTHOR]

Background: The complex interplay between health, lifestyle and genetics represents a critical area of research for understanding and promoting human well-being. Importantly, genetics plays a key role in determining individual susceptibility to disease and response to lifestyle. The aim of the present study was to identify genetic factors related to the metabolic/inflammatory profile of adolescents providing new insights into the individual predisposition to the different effects of the substances from the environment. Methods: Association analysis of genetic variants and biochemical parameters was performed in a total of 77 healthy adolescents recruited in the context of the DIMENU study. Results: Polymorphisms of 3-hydroxy-3-methylglutaril coenzyme A reductase (HMGCR; rs142563098), C-reactive protein gene (CRP; rs1417938, rs1130864), cholesteryl ester transfer protein (CETP; rs5030708), interleukin (IL)—10 (IL-10; rs3024509) genes were significantly associated (p < 0.05) with various serum metabolic parameters. Of particular interest were also the correlations between the HMGCRpolymorphism (rs3846663) and tumor necrosis factor (TNF)-α levels, as well Fatty-acid desaturase (FADS) polymorphism (rs7481842) and IL-10 level opening a new link between lipidic metabolism genes and inflammation. Conclusion: In this study, we highlighted associations between single nucleotide polymorphisms (SNPs) and serum levels of metabolic and inflammatory parameters in healthy young individuals, suggesting the importance of genetic profiling in the prevention and management of chronic disease. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is considered as a risk factor for cardiovascular diseases and atherosclerosis. However, the relationship between periodontitis and stroke is rarely studied. Therefore, we aimed to explore the relationship between periodontitis and stroke. Methods: Statistical analysis was performed using the complex sampling design. We analyzed data on 6,460 participants, representing 92,856,028 American citizens aged 30 years or older, who had valid data on periodontitis and stroke from the National Health and Nutrition Examination Survey 2009–2014. We used clinical attachment level and probing pocket depth precisely to determine periodontitis and it is the first time to use such a precise method for exploring the relationship between periodontitis and stroke. Results: 39.9% of participants had periodontitis and 2.1% of participants had a record of stroke diagnosis. Stroke was associated with severity levels of periodontitis (p for trend = 0.018). The odds ratio for stroke was significantly elevated in the severe periodontitis and moderate periodontitis participants compared to participants without periodontitis (OR for severe periodontitis: 2.55, 95% CI 1.25–5.21; OR for moderate periodontitis: 1.71, 95% CI 1.17–2.50). After adjusting for race/ethnicity and sex, the association remained significant (p for trend = 0.009). After further adjusting for BMI, hypercholesterolemia, diabetes, alcohol consumption and physical activity, the association still existed (p for trend = 0.027). The association was significant consistently after further adjusting for age (p for trend = 0.033). Conclusions: In this nationally representative study, we found an association between periodontitis and stroke. The risk of stroke in participants with severe periodontitis and moderate periodontitis was 2.55 times and 1.71times as high as those without periodontitis. Dental health management may be of benefit to stroke prevention. [ABSTRACT FROM AUTHOR]

Background: Vibrational spectroscopy can be a valuable tool to monitor the markers of cardiovascular diseases. In the present work, we explored the vibrational spectroscopy characteristics of the cardiac tissue in an experimental model of heart failure with preserved ejection fraction (HFpEF). The goal was to detect early cardiac chemical modifications associated with the development of HFpEF. Methods: We used the Fourier-transform infrared (FTIR) and Raman micro-spectroscopic techniques to provide complementary and objective tools for the histological assessment of heart tissues from an animal model of HFpEF. A new sampling technique was adopted (tissue print on a CaF2 disk) to characterize the extracellular matrix. Results: Several spectroscopic markers (lipids, carbohydrates, and glutamate bands) were recognized in the cardiac ventricles due to the comorbidities associated with the pathology, such as obesity and diabetes. Besides, abnormal collagen cross-linking and a decrease in tryptophan content were observed and related to the stiffening of ventricles and to the inflammatory state which is a favourable condition for HFpEF. Conclusions: By the analyses of tissues and tissue prints, FTIR and Raman techniques were shown to be highly sensitive and selective in detecting changes in the chemistry of the heart in experimental HFpEF and its related comorbidities. Vibrational spectroscopy is a new approach that can identify novel biomarkers for early detection of HFpEF. [ABSTRACT FROM AUTHOR]