Search Results (56,743)

The gut microbiota plays a crucial role in modulating the immune response during COVID-19, with several studies reporting significant alterations in specific bacterial genera, including Akkermansia, Bacteroides, Bifidobacterium, Faecalibacterium, Lactobacillus, Oscillospira, and Ruminococcus. These genera are symbionts of the gut microbiota and contribute to host health. However, comparing results across studies is challenging due to differences in analysis methods and reference databases. We screened 16S rRNA raw datasets available in public databases on COVID-19, focusing on the V3–V4 region of the bacterial genome. In total, seven studies were included. All samples underwent the same bioinformatics pipeline, evaluating the differential abundance of these seven bacterial genera at each level of severity. The reanalysis identified significant changes in differential abundance. Bifidobacterium emerged as a potential biomarker of disease severity and a therapeutic target. Bacteroides presented a complex pattern, possibly related to disease-associated inflammation or opportunistic pathogen growth. Lactobacillus showed significant changes in abundance across the COVID-19 stages. On the other hand, Akkermansia and Faecalibacterium did not show significant differences, while Oscillospira and Ruminococcus produced statistically significant results but with limited relevance to COVID-19 severity. Our findings reveal new insights into the differential abundance of key bacterial genera in COVID-19, particularly Bifidobacterium and Bacteroides. Full article

Background: Glioblastoma IDH-wildtype (GBM IDH-wt) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping its tumor microenvironment (TME) regulate tumor progression and treatment response. The aim of this study was to characterize the main immunosuppressive elements of the GBM IDH-wt TME. Methods: Immunohistochemistry for CD3, CD4, CD8, CD163, programmed death ligand 1 (PD-L1) and programmed death 1 (PD1) was performed on surgical tumor specimens from patients diagnosed with GBM IDH-wt, according to the CNS WHO 2021 criteria. The impact of categorical variables on time-dependent outcomes such as overall survival (OS) and progression-free survival (PFS) has been estimated through the Kaplan–Meier method. Results: We included 30 patients (19 males and 11 females), median age of 59.8 years (range 40.2–69.1 years). All patients underwent surgery followed by temozolomide concurrent with and adjuvant to radiotherapy. MGMT was methylated in 14 patients (47%) and unmethylated in 16 patients (53%). The overall absolute percentages of CD4+ lymphocytes, both intratumoral and perivascular, were significantly more represented than CD8+ lymphocytes in the TME (p = 0.02). A low density of CD4+ lymphocytes (≤10%) was found to be a favorable prognostic factor for GBM outcome (p = 0.02). Patients with MGMT methylated and unmethylated tumors exhibited a distinct TME composition, with a significant higher number of perivascular CD8+ lymphocytes (p = 0.002), intratumoral CD8+ lymphocytes (p = 0.0024) and perivascular CD4+ lymphocytes (p = 0.014) in MGMT unmethylated tumors. PD-L1 expression in tumor cell surface was observed in four tumors (13.3%), and PD1 expression in infiltrating T lymphocytes was observed in nine (30%) tumors, with predominantly perivascular distribution. Conclusions: MGMT methylated and unmethylated tumors exhibit different immune profiles, likely reflecting the different biology of these tumors. The expression of PD-L1 in GBM IDH-wt patients is confined to a small subpopulation. While we found a significant association between low CD4+ lymphocyte density (≤10%) and survival, given the small numbers of our cohort, the prognostic value of CD4+ lymphocyte density will need to be validated in large-scale studies. Full article

Tick-borne encephalitis (TBE) is a vaccine-preventable viral infection that poses significant public health challenges, particularly in regions where tick-borne diseases are endemic. This case report describes a 2-year-old boy with confirmed abortive TBEV infection following a tick bite during travel to Switzerland. The patient developed fever and mild symptoms but did not exhibit central nervous system involvement. The case underscores the importance of raising awareness among healthcare providers and travelers from non-endemic areas, such as Serbia, about TBE risk and the potential benefits of preventive vaccination. Strategic immunization campaigns could mitigate the public health impact of travel-related TBE. Full article

Tea polyphenols (TP) and probiotics (PB) have been recognized for their ability to improve lipid metabolism and regulate immune function. However, their specific impact on lipid metabolism in laying hens has not been thoroughly elucidated. Therefore, this study sought to examine the effect of TP and Bacillus subtilis on lipid metabolism in laying hens through transcriptome and metabolome analyses. Two hundred Hy-line Brown layers were randomly allocated into four groups with supplemental dietary TP and PB alone and their combination for 8 weeks. Each treatment had 10 replicates of five birds. Supplementation with a TP and PB combination (TP-PB) increased redness (a*) (p < 0.05) compared to the control basal diet (CT). Dietary TP-PB decreased egg yolk and serum total cholesterol (TC) concentrations (p < 0.05) without affecting the content of total bile acid (TBA). The combined use of TP and PB significantly improved hepatic fatty acid synthetase (FAS) activity (p < 0.05) and reduced liver fat particles. Dietary TP-PB primarily influenced the transcript levels of genes involved in fat metabolic pathways. In particular, TP-PB supplementation reduced lipid storage by activating the Notch signaling pathway. Furthermore, the addition of TP-PB in the diet modulated the abundance of metabolic biomarkers associated with bile secretion and valine, leucine, and isoleucine degradation. An interaction network of mRNAs and metabolites was constructed associated with lipid metabolism, such as deoxycholic acid, TAG (14:3–14:3–20:5), PDK4, and HES4. Overall, these findings emphasized the potential health advantages of the TP and PB combination as a possible functional feed supplement in livestock nutrition. Full article

Summary: Anti PD1/PD-L1 agents, including pembrolizumab, have revolutionized the oncological treatment of different types of cancer, including non-small cell lung cancer. The most frequent complications associated with this type of treatment are mild and are located at the thyroid, pulmonary or hepatic level. Sarcoid like reaction and mesenteric panniculitis secondary to pembrolizumab treatment are two very rare adverse effects. We present the case of a patient with these complications. Purpose: the treatment of metastatic non-small cell lung cancer has undergone a major change in the last 10 years, largely due to the advent of immunotherapy. Anti PD1 agents such as pembrolizumab have increased the median survival of these patients from 13 to 26 months. Most frequent immunorelated side effects are hypothyroidism, pneumonitis or elevated liver enzymes. However, there are other adverse effects, including sarcoid-like reaction and mesenteric panniculitis, which should be known by the professionals involved in the diagnosis and treatment of this type of patient. We present the case of a 62-year-old man with a history of unresectable and non-irradiable stage IIIB epidermoid lung carcinoma with a PD-L1 expression of 30% in whom pembrolizumab was discontinued after 4 cycles due to immunorelated arthritis. One year later he consulted for severe abdominal pain. A PET-CT scan was performed, showing hilar lymphadenopathy and inflammation of abdominal mesenteric fat. A biopsy of lesions in both areas showed non-necrotizing granulomatous lymphadenitis in hilar adenopathy and patchy fibrosis of mesenteric fat. The picture was classified as sarcoidosis-like reaction and mesenteric panniculitis secondary to pembrolizumab. Anti-PD1 agents cause hyperactivation of the immune system through T-cell proliferation. Sarcoid-like reaction is a very rare complication that can mask progressive tumor disease. Awareness of immunorelated complications by oncologists, internists, and radiologists is important for an appropriate diagnostic approach and targeted test ordering. Full article

Sepsis is a life-threatening disease caused by the overwhelming response to pathogen infections. Currently, treatment options for sepsis are limited to broad-spectrum antibiotics and supportive care. However, the growing resistance of pathogens to common antibiotics complicates treatment efforts. Excessive immune response (i.e., cytokine storm) can persist even after the infection is cleared. This overactive inflammatory response can severely damage multiple organ systems. Given these challenges, managing the excessive immune response is critical in controlling sepsis progression. Therefore, Mesenchymal stem cells (MSCs), with their immunomodulatory and antibacterial properties, have emerged as a promising option for adjunctive therapy in treating sepsis. Moreover, MSCs exhibit a favorable safety profile, as they are eventually eliminated by the host’s immune system within several months post-administration, resulting in minimal side effects and have not been linked to common antibiotic therapy drawbacks (i.e., antibiotic resistance). This review explores the potential of MSCs as a personalized therapy for sepsis treatment, clarifying their mechanisms of action and providing up-to-date technological advancements to enhance their protective efficacy for patients suffering from sepsis and its consequences. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism. The genetic defect in WD affects the ATP7B gene, which encodes the ATP7B transmembrane protein, which is essential for maintaining normal copper homeostasis in the body. It is primarily expressed in the liver and acts by incorporating copper into ceruloplasmin (Cp), the major copper transport protein in the blood. In conditions of excess copper, ATP7B transports it to bile for excretion. Mutations in ATP7B lead to impaired ATP7B function, resulting in copper accumulation in hepatocytes leading to their damage. The toxic “free”—unbound to Cp—copper released from hepatocytes then accumulates in various organs, contributing to their damage and clinical manifestations of WD, including hepatic, neurological, hematological, renal, musculoskeletal, ophthalmological, psychiatric, and other effects. While most clinical manifestations of WD correspond to identifiable organic or cellular damage, the pathophysiology underlying its psychiatric manifestations remains less clearly understood. A search for relevant articles was conducted in PubMed/Medline, Science Direct, Scopus, Willy Online Library, and Google Scholar, combining free text and MeSH terms using a wide range of synonyms and related terms, including “Wilson’s disease”, “hepatolenticular degeneration”, “psychiatric manifestations”, “molecular mechanisms”, “pathomechanism”, and others, as well as their combinations. Psychiatric symptoms of WD include cognitive disorders, personality and behavioral disorders, mood disorders, psychosis, and other mental disorders. They are not strictly related to the location of brain damage, therefore, the question arises whether these symptoms are caused by WD or are simply a coincidence or a reaction to the diagnosis of a genetic disease. Hypotheses regarding the etiology of psychiatric symptoms of WD suggest a variety of molecular mechanisms, including copper-induced CNS toxicity, oxidative stress, mitochondrial dysfunction, mitophagy, cuproptosis, ferroptosis, dysregulation of neurotransmission, deficiencies of neurotrophic factors, or immune dysregulation. New studies on the expression of noncoding RNA in WD are beginning to shed light on potential molecular pathways involved in psychiatric symptomatology. However, current evidence is still insufficient to definitively establish the cause of psychiatric symptoms in WD. It is possible that the etiology of psychiatric symptoms varies among individuals, with multiple biological and psychological mechanisms contributing to them simultaneously. Future studies with larger samples and comprehensive analyses are necessary to elucidate the mechanisms underlying the psychiatric manifestations of WD and to optimize diagnostics and therapeutic approaches. Full article

A 9-week experiment investigated the effects of dietary cobalt levels on the growth performance, antioxidant capacity, and immunity of largemouth bass. Six feed groups were designed and each group received different cobalt levels, including 0.129 mg/kg (control group), 0.192 mg/kg, 0.201 mg/kg, 0.233 mg/kg, 0.277 mg/kg, and 0.316 mg/kg. The results show that the control group (0.129 mg/kg diet) had the lowest final body weight (FBW), weight gain rate (WGR), and specific growth rate (SGR), and the highest feed conversion ratio (FCR), when compared to the cobalt supplementation groups. Dietary cobalt levels of 0.192 mg/kg increased the body protein content and decreased the body moisture content. Regarding antioxidant capacity, the highest catalase (CAT) activity was found in the 0.277 mg/kg dietary cobalt group, while the malondialdehyde (MDA) content was significantly diminished; the total antioxidant capacity (T-AOC) content and glutathione peroxidase (GSH-Px) activity exhibited the highest values in the 0.192 mg/kg and 0.233 mg/kg dietary cobalt groups, respectively. Regarding gene expression, compared with the control group, the mRNA expression of sod was upregulated in the 0.192 mg/kg, 0.233 mg/kg, and 0.277 mg/kg dietary cobalt groups, while the mRNA expression of gpx was diminished when dietary cobalt levels were below 0.233 mg/kg. In addition, the highest il-10 and tgf-β mRNA expression levels were observed in the 0.201 mg/kg and 0.233 mg/kg dietary cobalt groups, respectively. According to the quadratic regression analysis based on the SGR and FCR, the optimal requirement was 0.24 and 0.26 mg/kg of dietary cobalt, respectively. Full article

Polyunsaturated fatty acids such as arachidonic acid are indispensable components of innate immune signaling. Plasmalogens are glycerophospholipids with a vinyl ether bond in the sn-1 position of the glycerol backbone instead of the more common sn-1 ester bond present in “classical” glycerophospholipids. This kind of phospholipid is particularly rich in polyunsaturated fatty acids, especially arachidonic acid. In addition to or independently of the role of plasmalogens as major providers of free arachidonic acid for eicosanoid synthesis, plasmalogens also perform a varied number of functions. Membrane plasmalogen levels may determine parameters of the plasma membrane, such as fluidity and the formation of microdomains that are necessary for efficient signal transduction leading to optimal phagocytosis by macrophages. Also, plasmalogens may be instrumental for the execution of ferroptosis. This is a nonapoptotic form of cell death that is associated with oxidative stress. This review discusses recent data suggesting that, beyond their involvement in the cellular metabolism of arachidonic acid, the cells maintain stable pools of plasmalogens rich in polyunsaturated fatty acids for executing specific responses. Full article

Background: The early exposure of nutrients during pubertal mammary gland development may reduce the risk of developing breast cancer later in life. Anticancer n-3 polyunsaturated fatty acids (n-3 PUFA) are shown to modulate pubertal mammary gland development; however, the mechanisms of action remain unclear. Prior work focused on effects at the whole tissue level, and little is known at the cellular level, such as at the level of mammary epithelial cells (MECs), which are implicated in cancer development. Methods: This pilot study examined the effects of lifelong n-3 PUFA exposure on the transcriptome by RNA-Seq in the isolated MECs of pubertal (6–8-week-old) female fat-1 transgenic mice capable of de novo n-3 PUFA synthesis. edgeR and DESeq2 were used separately for the differential expression analysis of RNA sequencing data followed by the Benjamani–Hochberg procedure for multiple testing correction. Results: Nine genes were found concordant and significantly different (p ≤ 0.05) by both the DESeq2 and edgeR methods. These genes were associated with multiple pathways, suggesting that n-3 PUFA stimulates estrogen-related signaling (Mlltl0, Galr3, and Nrip1) and a glycolytic profile (Soga1, Pdpr, and Uso1) while offering protective effects for immune and DNA damage responses (Glpd1, Garre1, and Rpa1) in MECs during puberty. Conclusions: This pilot study highlights the utility of RNA-Seq to better understanding the mechanistic effects of specific nutrients such as n-3 PUFA in a cell-specific manner. Thus, further studies are warranted to investigate the cell-specific mechanisms by which n-3 PUFA influences pubertal mammary gland development and breast cancer risk later in life. Full article

Oncolytic virotherapy is a promising approach for cancer treatment. However, when introduced into the body, the virus provokes the production of virus-neutralizing antibodies, which can reduce its antitumor effect. To shield viruses from the immune system, aptamers that can cover the membrane of the viral particle are used. Aptamers that specifically bind to the JX-594 strain of the vaccinia virus were developed earlier. However, the parameters for binding to the recombinant virus VV-GMCSF-Lact, developed based on the LIVP strain of the vaccinia virus, may differ due its different repertoire of antigenic determinants on its membrane compared to JX-594. In this work, the spatial atomic structures of aptamers to JX-594 and bifunctional aptamers were determined using molecular modeling. The efficiency of viral particles binding to the aptamers (EC50), as well as the cytotoxicity and stability of the aptamers were studied. The synergistic effect of the VV-GMCSF-Lact combination with the aptamers in the presence of serum was investigated using human glioblastoma cells. This proposed approach allowed us to conduct a preliminary screening of sequences using in silico modeling and experimental methods, and identified potential candidates that are capable of shielding VV-GMCSF-Lact from virus-neutralizing antibodies. Full article

It is estimated that nearly all individuals have been infected with herpesviruses, with herpes simplex virus type 1 (HSV-1) representing the most prevalent virus. In most cases, HSV-1 causes non-life-threatening skin damage in adults. However, in patients with compromised immune systems, it can cause serious diseases, including death. The situation is further complicated by the emergence of strains that are resistant to both traditional and novel antiviral drugs. It is, therefore, imperative that new methods of combating HSV-1 and other herpesviruses be developed without delay. CRISPR/Cas systems may prove an effective means of controlling herpesvirus infections. This review presents the current understanding of the underlying molecular mechanisms of HSV-1 infection and discusses four potential applications of CRISPR/Cas systems in the fight against HSV-1 infections. These include the search for viral and cellular genes that may serve as effective targets, the optimization of anti-HSV-1 activity of CRISPR/Cas systems in vivo, the development of CRISPR/Cas-based HSV-1 diagnostics, and the validation of HSV-1 drug resistance mutations. Full article

Widespread endocrine disorders and infertility caused by environmental and food pollutants have drawn considerable global attention. Aflatoxins (AFTs), a prominent class of mycotoxins, are recognized as one of the key contributors to environmental and food contamination. Aflatoxin B₁ (AFB₁) is the most potent and toxic pollutant among them and is known to cause multiple toxic effects, including neuro-, nephro-, hepato-, immune-, and genotoxicity. Recently, concerns have been raised regarding AFB₁-induced infertility in both animals and humans. Exposure to AFB₁ can disrupt the structure and functionality of reproductive organs, leading to gametogenesis impairment in males, subsequently reducing fertility. The potential molecular mechanisms have been demonstrated to involve oxidative stress, cell cycle arrest, apoptosis, inflammatory responses, and autophagy. Furthermore, several signaling pathways, including nuclear factor erythroid 2-related factor 2; NOD-, LRR-, and pyrin domain-containing protein 3; nuclear factor kappa-B; p53; p21; phosphoinositide 3-kinase/protein kinase B; the mammalian target of rapamycin; adenosine 5′-monophosphate-activated protein kinase; and mitochondrial apoptotic pathways, are implicated in these processes. Various interventions, including the use of small molecules, Chinese herbal extracts, probiotic supplementation, and camel milk, have shown efficacy in ameliorating AFB₁-induced male reproductive toxicity, by targeting these signaling pathways. This review provides a comprehensive summary of the harmful impacts of AFB₁ exposure on male reproductive organs in mammals, highlighting the potential molecular mechanisms and protective agents. Full article

Introduction. Atopic dermatitis (AD) is the most prevalent inflammatory dermatological disorder, affecting a significant percentage of the global population. This chronic disease has a multifactorial and intricate pathogenesis, influenced by genetic predisposition, skin barrier dysfunction, immune dysregulation, neuroimmune mechanisms, and alterations in the skin microbiome, among other factors. Methods. The treatment of AD has faced significant clinical challenges due to the ineffectiveness of conventional therapies. However, recent advances in understanding its pathophysiology have led to the introduction of new therapeutic options. Recently, the OX40 receptor has been identified as a key factor in the development of AD. Recent studies have demonstrated that blocking the OX40 ligand with monoclonal antibodies significantly and sustainably improves the signs and symptoms of moderate to severe AD. Results. A comprehensive review of the available literature on anti-OX40 treatments in atopic dermatitis that evaluates their mechanism of action, their clinical efficacy, and the prospects of this promising therapeutic option for improving AD management is provided. Conclusions. Anti-OX40 and anti-OX40L blockers are a promising therapeutic alternative for the management of moderate–severe atopic dermatitis. Prospective analytical studies are needed to determine whether this new therapeutic target represents a qualitative advance in modifying the progression of the disease. Full article

Zirconia implants are recognized for their excellent biocompatibility, aesthetics, and favorable mechanical properties. However, the effects of zirconia surfaces on osteogenesis, particularly in the presence of macrophages, are still not well understood. This study compares two types of zirconia surfaces—ceria-stabilized zirconia/alumina nanocomposite (NANO-Zr) and 3 mol% yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP)—with titanium (Ti) substrates. Both zirconia surfaces promoted macrophage adhesion and proliferation, facilitated a shift from M1 to M2 polarization, and created an immune microenvironment conducive to osteogenesis by downregulating IL-6 and TNF-α and upregulating IL-10 and TGF-β gene expression. In macrophage co-cultures, both zirconia surfaces also supported osteoblast adhesion and proliferation, with NANO-Zr notably enhancing osteogenic differentiation and mineralization. These results highlight NANO-Zr as a promising candidate for future dental and orthopedic implant applications. Full article