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Veterinary Microbiology Jun 2024Streptococcus suis (S. suis) type 2 (SS2) is an important zoonotic pathogen causing severe neural infections in pigs and causes serious threat to public health....
Streptococcus suis (S. suis) type 2 (SS2) is an important zoonotic pathogen causing severe neural infections in pigs and causes serious threat to public health. Inflammasome activation plays an important role in the host against microbial infection but the role of inflammasome activation in the blood-brain barrier (BBB) integrity during S. suis infection is rarely studied. This study investigated the mechanism by which S. suis-induced NLRP3 inflammasome activation led to BBB disruption. Our results showed that S. suis infection activated NLRP3 inflammasome in brain microvascular endothelial cells (BMECs) leading to the secretion of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokines (CCL-2 and CXCL-2) as well as the cleavage of Gasdermin D (GSDMD) which were significantly attenuated by inflammasome inhibitor MCC950. Furthermore, S. suis infection significantly downregulated expression of tight junctions (TJs) proteins and trans-endothelial electrical resistance (TEER) while NLRP3 inhibition rescued S. suis-induced degradation of TJs proteins and significantly reduced the number of S. suis crossing BBB in transwell infection model. Moreover, recombinant IL-1β exacerbated the reduction of TJs proteins in BMECs. In murine S. suis-infection model, MCC950 reduced the bacterial load and the excessive inflammatory response in mice brain. In addition, the integrity of the BBB was protected with increased TJ proteins expression and decreased pathological injury after the inhibition of NLRP3 inflammasome, indicating NLRP3 inflammasome plays a destructive role in meningitis induced by S. suis. Our study expands the understanding on the role of NLRP3 inflammasome in bacterial meningitis, which provide the valuable information for the development of anti-infective agents targeting NLRP3 to treat bacterial meningitis.
PubMed: 38945021
DOI: 10.1016/j.vetmic.2024.110161 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024Pathogenic or likely pathogenic germline variants (PGVs) in cancer predisposition genes may play a role in lung cancer (LC) susceptibility. However, determining an...
INTRODUCTION
Pathogenic or likely pathogenic germline variants (PGVs) in cancer predisposition genes may play a role in lung cancer (LC) susceptibility. However, determining an eligible population for genetic testing remains uncertain. This study aimed to assess the prevalence of PGVs in a selected cohort of individuals with lung adenocarcinoma.
METHODS
A cross-sectional cohort study was conducted to assess the PGVs rate in lung adenocarcinoma patients with a family history of LC, young-onset presentation, history of never/light smoking, or actionable genomic alterations (AGAs). Sequencing was performed using Sophia Hereditary Cancer Solution panel F, including 144 cancer predisposition genes. Variants classified as pathogenic or likely pathogenic were included for further analysis.
RESULTS
Of 201 patients, 43 (21.4 %) exhibited PGVs, among which 64.5 % were DNA damage repair genes, and 86.1 % were clinically actionable. The main PGVs were in ATM (9.3 %), TP53 (6.9 %), BRCA2 (6.9 %), and CHEK2 (6.9 %) genes. PGVs were associated with male sex (adjusted odds ratio [aOR] 2.46, 95 % CI 1.15-5.32, p = 0.021), along with a trend toward association with AGAs (aOR 6.04, 95 % CI 0.77-49.74, p = 0.094).
CONCLUSIONS
In this study, a high PGVs prevalence was identified based on our selection criteria, which represents an effective strategy to identify candidates for germline genomic testing, potential screening strategies in close relatives, and personalized therapeutic modalities. Our results warrant further exploration in other populations to confirm them.
PubMed: 38945003
DOI: 10.1016/j.lungcan.2024.107864 -
Schizophrenia Research Jun 2024It is known that the immune system is dysregulated in schizophrenia, having a state similar to chronic neuroinflammation. The origin of this process is unknown, but it...
BACKGROUND
It is known that the immune system is dysregulated in schizophrenia, having a state similar to chronic neuroinflammation. The origin of this process is unknown, but it is known that T and B lymphocytes, which are components of the adaptive immune system, play an important role in the pathogenic mechanisms of schizophrenia.
METHODS
We analysed the membrane of PBMCs from patients diagnosed with schizophrenia through proteomic analysis (n = 5 schizophrenia and n = 5 control). We found the presence of the Kv1.3 voltage-gated potassium channel and its auxiliary subunit β1 (KCNAB1) and β2 (KCNAB2). From a sample of 90 participants, we carried out a study on lymphocytes with whole-cell patch-clamp experiments (n = 7 schizophrenia and n = 5 control), western blot (n = 40 schizophrenia and n = 40 control) and confocal microscopy to evaluate the presence and function of different channels. Kv in both cells.
RESULTS
We demonstrated the overexpression of Kv1.1, Kv1.2, Kv1.3, Kv1.6, Kv4.2, Kv4.3 and Kv7.2 channels in PBMCs from patients with schizophrenia. This study represents a groundbreaking exploration, as it involves an electrophysiological analysis performed on T and B lymphocytes from patients diagnosed of schizophrenia compared to healthy participants. We observed that B lymphocytes exhibited an increase in output current along with greater peak current amplitude and voltage conductance curves among patients with schizophrenia compared with healthy controls.
CONCLUSIONS
This study showed the importance of the B lymphocyte in schizophrenia. We know that the immune system is altered in schizophrenia, but the physiological mechanisms of this system are not very well known. We suggest that the B lymphocyte may be relevant in the pathophysiology of schizophrenia and that it should be investigated in more depth, opening a new field of knowledge and possibilities for new treatments combining antipsychotics and immunomodulators. The limitation is that all participants received antipsychotic medication, which may have influenced the differences observed between patients and controls. This implies that more studies need to be done where the groups can be separated according to the antipsychotic drug.
PubMed: 38944972
DOI: 10.1016/j.schres.2024.06.034 -
International Immunopharmacology Jun 2024Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several...
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.
PubMed: 38944950
DOI: 10.1016/j.intimp.2024.112549 -
Mutation Research Jun 2024Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion... (Review)
Review
Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.
PubMed: 38944932
DOI: 10.1016/j.mrfmmm.2024.111870 -
Veterinary Parasitology Jun 2024Gastrointestinal helminth infection, particularly by Haemonchus contortus, poses significant challenges to sheep farming worldwide. While anthelmintic drugs have been...
Gastrointestinal helminth infection, particularly by Haemonchus contortus, poses significant challenges to sheep farming worldwide. While anthelmintic drugs have been traditional control measures, the emergence of resistance calls for alternative strategies. Understanding the interaction between parasites, host, and their microbiome is crucial for management of helminth infection. This study intricately explores the interactions between microbial communities in Kashmir Merino sheep infected with H. contortus, to understand the complex interplay between host, parasite, and their microbiome. Sheep abomasal contents and H. contortus were collected from infected and control groups, processed for DNA extraction, and subjected to metagenomic sequencing of the 16 S rRNA gene. Downstream analysis unveils distinct microbial patterns, where Proteobacteria were dominant in H. contortus, while Bacteroidota and Firmicutes prevailed in the sheep abomasum. The revelation of unique genera and shifts in diversity indices underscored helminth-induced disruptions in the host. Beta diversity analysis further showed significant variations in bacterial profiles, providing insights into the intricate host, parasite, and microbiome dynamics. Additionally, this study elucidated the presence of pathogenic bacteria within H. contortus, accentuating their potential role in exacerbating sheep health issues. This finding underscores the complexity of the host-parasite-microbiome interaction showing helminth-induced microbiome alterations of the host.
PubMed: 38944892
DOI: 10.1016/j.vetpar.2024.110243 -
Gut Microbes 2024Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay...
Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundworm , and altered the host tissue transcriptome at the site of infection with the large intestinal whipworm , with a notable enhancement of type-1 inflammatory and interferon-driven gene pathways. In the absence of infection, PAC intake promoted the expansion of within the gut microbiota, increased fecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-γ-valerolactones in the cecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected with , suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the cecum dwelling ), and infection may abrogate the beneficial effects of health-promoting phytochemicals.
Topics: Animals; Gastrointestinal Microbiome; Mice; Polyphenols; Trichuris; Trichuriasis; Nematospiroides dubius; Proanthocyanidins; Mice, Inbred C57BL; Strongylida Infections; Female; Bacteria; Feces
PubMed: 38944838
DOI: 10.1080/19490976.2024.2370917 -
International Journal of Environmental... Jun 2024Antibiotic resistance, a significant public health hazard, is predicted to cause 10 million deaths worldwide by 2050. The study aimed to identify culturable bioaerosols...
Antibiotic resistance, a significant public health hazard, is predicted to cause 10 million deaths worldwide by 2050. The study aimed to identify culturable bioaerosols in the indoor air of dental units in Lahore and assess their antibiotic resistance. Air samples were collected from 10 dental unit locations at different distances, with average concentrations of fungi and bacteria falling within intermediate ranges, per the Global Index of Microbial Contamination (GIMC/m3) index. The study found higher antibiotic-resistant strains in hospital dental units, particularly during winter. The most vigorous strain, -NAJIH18, exhibited 70% resistance to ceftazidime. The research highlights the importance of quantifying microbial pollutants for evaluating their source and complexity. It suggests proactive mitigation techniques, such as focused cleaning and air filtration, to improve indoor air quality can mitigate the spread of antibiotic-resistant strains. These insights offer hope in combating the growing public health threat of antibiotic resistance.
PubMed: 38944751
DOI: 10.1080/09603123.2024.2373173 -
Genetics in Medicine : Official Journal... Jun 2024Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian...
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
PubMed: 38944749
DOI: 10.1016/j.gim.2024.101199 -
Mymensingh Medical Journal : MMJ Jul 2024Antibiotics' usefulness is threatened by multi-drugs resistance in harmful microorganisms because of abuse and regulatory problems. Emerging microbes, resistance...
Antibiotics' usefulness is threatened by multi-drugs resistance in harmful microorganisms because of abuse and regulatory problems. Emerging microbes, resistance mechanisms and antimicrobial drugs all require extensive investigation. Evaluation of the in vitro antibacterial activity of Methanolic extracts isolated from Black pepper seeds (Piper nigrum L.) against two infection causing pathogens, Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. From July 2022 and June 2023, this experimental study was conducted at the Mymensingh Medical College's Department of Pharmacology and Therapeutics in conjunction with the Department of Microbiology. The solvents Methanol and 10.0% Di-Methyl Sulfoxide (DMSO) were used to make the extract. Using the disc diffusion and broth dilution methods, the antibacterial activity of methanolic extract of black pepper seeds (MBPE) was evaluated at various doses. Using the broth dilution procedure, the conventional antibiotic Ciprofloxacin was utilized, and the outcome was contrasted with that of Methanol extracts. Methanolic extract of black pepper seeds (MBPE) at seven distinct concentrations (100, 80, 60, 40, 20, 10 and 5mg/ml) were utilized, then later in chosen concentrations as needed to confirm the extracts' more precise margin of antimicrobial sensitivity. At 80mg/ml and above doses of the MBPE, it had an inhibitory impact against the aforementioned microorganisms. For Staphylococcus aureus and Pseudomonas aeruginosa the MIC were 60 and 70mg/ml in MBPE respectively. As of the MIC of Ciprofloxacin was 1μg/ml against Staphylococcus aureus and 1.5μg/ml for Pseudomonas aeruginosa. In comparison to MICs of MBPE for the test organisms, the MIC of Ciprofloxacin was the lowest. This study clearly shows that Staphylococcus aureus and Pseudomonas aeruginosa are sensitive to the methanolic extract of black pepper seeds' antibacterial properties.
Topics: Piper nigrum; Pseudomonas aeruginosa; Plant Extracts; Staphylococcus aureus; Seeds; Anti-Bacterial Agents; Microbial Sensitivity Tests; Methanol
PubMed: 38944702
DOI: No ID Found