Immune Disruption Research Articles

Cell-free supernatants from plant growth-promoting rhizobacteria Bacillus albus strains control Aspergillus flavus disease in peanut and maize seedlings

BackgroundAspergillus flavus, a seed-borne fungal pathogen, colonizes host plants and exploits nutrients, hindering the growth of seedlings such as peanut and maize. This study investigates the effectiveness of cell-free supernatants (CFSs) from the plant growth-promoting rhizobacteria (PGPR) Bacillus albus strains NNK24 and NDP61, which belong to the Bacillus cereus group, in suppressing A. flavus AF1.ResultsThe antifungal activity of these CFSs was attributed to their surfactant properties and chemical composition. These were characterized using rapid chemical assays and ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight/mass spectrometry (UHPLC-ESI-QTOF/MS), combined with bioinformatic tools such as Global Natural Product Social Molecular Networking (GNPS) and Natural Products Atlas (NPAtlas). Identified putative antifungal compounds included two diketopiperazines (cyclo(Pro-Leu) and cyclo(2-hydroxy-Pro-Leu)), four macrolactins (7-O-succinyl macrolactin A, 7-O-methyl-5′-hydroxy-3′-heptenoate-macrolactin, macrolactin B, and macrolactin C), two siderophores (petrobactin and bacillibactin), and three cyclic lipopeptides (kurstakin 1, 2 or 3, and 4). These compounds are hypothesized to act synergistically via multiple mechanisms, including disruption of fungal membranes, iron capture, direct antibiosis, and triggering plant immunity. Both CFSs strongly suppressed the harmful effects of A. flavus AF1 and seed-borne A. flavus on peanut and maize seedlings, reducing disease incidence (DI) and disease severity index (DSI) compared to controls. The disease control efficacy (DCE) of the CFSs was comparable to that of the commercial fungicide. Additionally, the CFSs enhanced seed germination, vigor, seedling length, and weight in both peanut and maize. Vigor index (VI) values increased by 222.4–286.0% in peanuts and 181.7–216.4% in maize at 7 days after treatment (DAT).ConclusionCFSs of B. albus NNK24 and NDP61 show significant potential as bioprotective agents for sustainable agriculture. Importantly, their use eliminates the need for live bacterial cells from the B. cereus group, addressing biosafety concerns.Graphical abstract

Parasite infections: how inflammation alters brain function.

Parasitic infections can profoundly impact brain function through inflammation within the central nervous system (CNS). Once viewed as an immune-privileged site, the CNS is now recognized as vulnerable to immune disruptions from both local and systemic infections. Recent studies reveal that certain parasites, such as Toxoplasma gondii and Plasmodium falciparum, can invade the CNS or influence it indirectly by triggering neuroinflammation. These processes may disrupt brain homeostasis, influence neurotransmission, and lead to significant behavioral or cognitive changes. This review discusses the pathways by which parasites disrupt CNS function and highlights systemic inflammation as a critical link between peripheral infections and neuroinflammatory conditions, advancing understanding of parasite-associated neurological complications.

Integrating single-cell RNA-Seq and machine learning to dissect tryptophan metabolism in ulcerative colitis

BackgroundUlcerative colitis (UC) is a persistent inflammatory bowels disease (IBD) characterized by immune response dysregulation and metabolic disruptions. Tryptophan metabolism has been believed as a significant factor in UC pathogenesis, with specific metabolites influencing immune modulation and gut microbiota interactions. However, the precise regulatory mechanisms and key genes involved remain unclear.MethodsAUCell, Ucell, and other functional enrichment algorithms were utilized to determine the activation patterns of tryptophan metabolism at the UC cell level. Differential analysis identified key genes associated with tryptophan metabolism. Five machine learning algorithms, including Random Forest, Boruta algorithm, LASSO, SVM-RFE, and GBM were integrated to identify and categorize disease-specific characteristic genes.ResultsWe observed significant heterogeneity in tryptophan metabolism activity across cell types in UC, with the highest activity levels in macrophages and fibroblasts. Among the key tryptophan metabolism-related genes, CTSS, S100A11, and TUBB were predominantly expressed in macrophages and significantly upregulated in UC, highlighting their involvement in immune dysregulation and inflammation. Cross-analysis with bulk RNA data confirmed the consistent upregulation of these genes in UC samples, highly indicating their relevance in UC pathology and potential as targets for therapeutic intervention.ConclusionsThis study is the first to reveal the heterogeneity of tryptophan metabolism at the single-cell level in UC, with macrophages emerging as key contributors to inflammatory processes. The identification of CTSS, S100A11, and TUBB as key regulators of tryptophan metabolism in UC underscores their potential as biomarkers and therapeutic targets.

Shaping the Future of Myeloproliferative Neoplasm Therapy: Immune-Based Strategies and Targeted Innovations.

Numerous cutting-edge immunotherapy approaches have been developed for hematological malignancies, such as immune-checkpoint inhibitors for lymphomas, chimeric antigen receptor (CAR)-T-cell treatments for B-cell cancers, and monoclonal antibody therapies for acute myeloid leukemia (AML). However, achieving similar breakthroughs in MPNs has proven challenging. The key obstacles include the absence of universally expressed and MPN-specific surface markers, significant cellular and molecular variability among both individual patients and across different MPN subtypes, and the failure of treatments to stimulate an anti-tumor immune response due to the immune system disruptions caused by the myeloid neoplasm. Currently, there are several innovative therapies in clinical trials for MPNs. These include new JAK inhibitors with greater specificity for JAK2, as well as "add-on" medications designed to enhance the effectiveness of ruxolitinib, in both patients who are new to the drug and in those who have shown suboptimal responses. Additionally, there is ongoing exploration of novel therapeutic targets. In this review, we will explore the immunotherapy approaches that are currently used in clinical practice for MPNs, as well as emerging strategies that are likely to change the treatment of these diseases in the coming years.

Taprenepag restores maternal–fetal interface homeostasis for the treatment of neurodevelopmental disorders

Background and purposeNeurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development.Experimental ApproachThe maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons.Key resultsIn VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations.ConclusionTaprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development.

Distinct immune responses to HIV and CMV in Hofbauer cells across gestation highlight evolving placental immune dynamics.

Placental immune responses to Human Immunodeficiency Virus (HIV) and Human Cytomegalovirus (CMV) vary across gestational stages and may influence postnatal outcomes. This study investigates the innate immunity of Hofbauer cells from placentae obtained at early/mid-gestation (18-21.6 weeks) and term (>37 weeks). RNA sequencing and cytokine profiling reveal that early/mid-gestation HCs exhibit heightened differential gene expression responses compared to term HCs, indicating a distinct transcriptional activity in early pregnancy. Significant overlap in gene expression profiles of early/mid-gestation cells in response to CMV and HIV suggest similar innate immune responses, while term cells exhibit distinct patterns, reflecting the temporal evolution of placental immunity. Integration with Human Protein Atlas database reveals more placental-specific differentially expressed genes in early/mid-gestation HCs exposed to HIV and CMV compared to term cells. Functional analysis reveals downregulation of pathways related to oxygen stress, estrogen response, and KRAS signaling pathway in early/mid-gestation HCs, with HIV uniquely upregulating reactive oxygen species and CMV uniquely disrupting WNT β-Catenin signaling. In term HCs, CMV exposure upregulates antiviral interferon (IFN) signaling and inflammatory pathways. Co-expression analysis highlights distinct molecular pathway enrichments across gestation, particularly with upregulation of IFN signaling and disruption of lipid metabolism in term CMV-exposed HCs. Cytokine profiling shows enhanced expression of GM-CSF, IFN-γ, and Th2-associated cytokines in early/mid-gestation HCs, indicating heightened immune responsiveness. These findings reveal the dynamic nature of placental immunity and underscore the need for targeted interventions to address unique immune and metabolic disruptions caused by viral infections at distinct stages of pregnancy to improve fetal and infant health outcomes.

Female zebrafish are more affected than males under polystyrene microplastics exposure

Microplastics are ubiquitous in freshwater and can be absorbed into fish skin and gills, accumulate in the gut, and be transported to other tissues, thus posing a risk to fish health. Further studies are needed, however, to investigate effects such as endocrine disruption and multi-tissue toxicity. In this study, zebrafish were exposed to polystyrene (PS) microplastics and health-related indicators were measured, including skin mucus, gut damage, oxidative stress, stable isotope composition and reproduction as well as an assessment of changes to metabolites using a metabolomics approach. Results showed that concentrations of PS microplastics were higher in gills than those in the gut. Minimal impact to immunoglobulin M level and lysozyme activity in mucus indicated, however, that microplastic toxicity primarily stemmed from ingestion rather than disruption of skin mucus immunity. Female zebrafish were more affected by PS microplastics. Gut microbiota dysbiosis was induced, especially in females. Significant alterations in pathways associated with lipid and energy metabolism were observed in the liver of female fish. PS microplastics also induced sex steroid hormone disorder and reduced female egg production, possibly linked to the alteration of gut microbiota and hepatic metabolism. Combined, these results highlight the gender-specific toxicity of PS microplastics to zebrafish health, potentially harming their population.

Liquid metasurface for size-independent detection of microplastics

Microplastics (MPs) are widely distributed in water, soil, and air, drawing a global concern as a cause of chronic diseases and immune system disruption. Though as one of the most promising techniques in MP detection, the surface-enhanced Raman scattering (SERS) is heavily dependent on the distribution of the “hot spots” and the size of MPs, known as “coffee ring effect” and “size effect” respectively, imposing major challenges in the quantitative detection of various sized MPs on conventional SERS substrates. Here we present a self-healing metasurface based on plasmonic nanoparticle (NP) array at the liquid-liquid interface (LLI) and air-liquid interface (ALI). The fluidic nature of the metasurface and the repulsive forces between NPs offer atomic-level flatness and uniform distribution for “hot spots”. Additionally, MPs are dissolved in the oil phase, uniformly enriched in the form of polymer molecular chains on the liquid metasurface, irrespective of the size of the MPs. This molecular dispersity of the dissolved MPs enhances the overlap between the “hot spots” and scattering volume of MPs, significantly improving the intensity and reproducibility of SERS. The sensing platform is successfully applied in trace detections of various MPs (PS, PET, PMMA, and PC), and validated in real samples.

SURG-31. HYBRID THERAPY FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: STAGED PROCEDURE INTEGRATING OPEN SURGICAL RESECTION WITH LASER INTERSTITIAL THERMAL THERAPY

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults with a median overall survival (OS) of 15.6 months. Despite advancements, 5-year survival rates have not significantly improved. Laser interstitial thermal therapy (LITT) has been employed to treat both newly diagnosed (nGBM) and recurrent GBM (rGBM) with demonstrable safety and efficacy. Traditionally, LITT has been limited to smaller lesions given physical and thermal constraints. OBJECTIVE We present two case examples of a novel, hybrid treatment approach to GBM, utilizing both surgery and laser ablation as part of a single-staged procedure. METHODS Two geriatric (>65 years) patients with nGBM or rGBM were treated with surgical resection followed by LITT the subsequent day. Both patients underwent preoperative magnetic resonance imaging (MRI) showing multifocal disease with a dominant component, causing mass effect in the second case, and an unresectable component. RESULTS The first case underwent surgical resection of a large, multicentric rGBM in the parieto-occipital region, followed by LITT of an unresectable lesion in the inferior temporal gyrus. The second patient underwent surgical resection of the dominant temporal lobe component, and LITT of the insular component. Neither patient had intraoperative or ablation complications. Both patients had stable postoperative neurological exams and were discharged on the day after ablation, with no new deficits at follow-up. CONCLUSION The prognosis for GBM remains dismal despite significant research and attempts at advancements in patient management. Surgical resection is a critical component of the GBM treatment paradigm. However, surgery alone is not sufficient in many patients. LITT has shown promise for improving GBM outcomes, mainly due to its minimal invasiveness, enhanced immune responses, BBB disruption, and cytoreductive potential. We demonstrate a novel, hybrid approach to GBM using hybrid surgical resection and LITT in a single-staged procedure to overcome traditional constraints of LITT.

A Rare Case of Warm Autoimmune Hemolytic Anemia and Massive Splenomegaly in Uncontrolled Grave's Disease

Background: Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces autoantibodies that attack their red blood cells, leading to their destruction. Warm AIHA, the most common form of AIHA, is caused by antibodies such as IgG that are active at body temperature. Warm AIHA can be primary or associated with underlying conditions like autoimmune disorders, lymphoproliferative disorders, immunodeficiencies, and infections, due to some form of immune system disruption. Clinical signs include anemia, jaundice, and mild to moderate splenomegaly. Case Presentation: A 36-year-old man with a history of Graves' disease (GD) (on methimazole) presented with jaundice. Despite being on methimazole, his thyroid levels were uncontrolled due to medication non-adherence, so his outpatient methimazole dose had been increased to 40 mg. Initial labs were notable for the following: a white blood cell count of 1.5 k/mm3, hemoglobin (Hgb) of 5.0 g/dL, platelet count of 78 k/mm3, total bilirubin of 13.1 mg/dL, reticulocyte percentage of 13.1%, lactate dehydrogenase (LDH) of 304 U/L, undetectable haptoglobin, absolute neutrophil count (ANC) of 0.95 k/mm3, thyroid stimulating hormone <0.01 mIU/L and a free T4 of 3.77 ng/dL. CT scan of the abdomen pelvis with contrast showed splenomegaly measuring 24.4 cm. Some reticulocytes were noted on the peripheral smear. The patient was diagnosed with AIHA, with warm antibodies noted on the Coombs test. In terms of workup for the etiology of his AIHA, the following infectious workup was negative: blood parasite smear, HIV, and Lyme enzyme immunoassay. Bone marrow (BM) biopsy flow cytometry showed no immunophenotypic evidence of acute leukemia, non-Hodgkin lymphoma, or high-grade myelodysplasia. He was aggressively transfused with 5 units of PRBCs and started on 1 mg/kg of prednisone daily. He was started on filgrastim 300 mcg 2 times a week for his leukopenia. Post these treatments his hemolysis labs improved to Hgb of 10.4 g/dL, reticulocyte percentage of 4.02%, total bilirubin of 3.1mg/dL, LDH of 141 U/L and haptoglobin of 78 mg/dL. His methimazole was held inpatient due to low ANC count. A trial of lithium was started for GD which led to limited improvement. The patient was discharged on daily prednisone and planned weekly rituximab infusions for AIHA. The patient was discharged without an anti-thyroid agent, with plans for close follow-up outpatient for thyroidectomy vs radioiodine ablation. Conclusion: The patient's severe Warm AIHA appeared acute, however the massive splenomegaly indicated a chronic low-level hemolytic process. Because the patient did not have any diagnostic findings consistent with hematologic malignancy or infection, and given the context of his recent history, it is reasonable to suspect that this presentation can be attributed to uncontrolled GD. Although the exact pathophysiology of the association is still unclear, the autoimmune nature of GD and hyperthyroidism are thought to contribute to the hemolysis. Warm AIHA is the rarest hematologic manifestation of GD, and literature on the topic has been limited to single case reports. Our case is also unique in that the Warm AIHA was seen in a patient with established GD, and not as an initial presentation of the disorder. To our knowledge, this is also the first case of Warm AIHA with this severe degree of splenomegaly, which can only be explained by the chronic nature of the patient's GD. The response to treatment for AIHA suggests an autoimmune nature of the condition, but the underlying GD did not respond to medical therapy. Overall, this case adds to the literature, as a unique hematologic presentation of an uncontrolled autoimmune disorder.

Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project

Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.

Immunological tolerance in breast cancer: some reasons for development

Immunological tolerance is one of the reasons for the development and progression of malignant tumors. The tumor immune cycle regulates the normal antitumor immune response, and it’s disruption is responsible for the development of immunological tolerance. This article provides a review of russian and foreign literature published in databases such as PubMed, Medline, and Cochrane, eLibrary in the last 5 years, focusing on the emergence of immunological tolerance in breast cancer from the perspective of disrupted regulation of tumor immune cycle phases: expression of antigens on the surface of tumor cells, cancer antigen presentation, priming and activation T cells, immune infiltration of the tumor site, recognition, and elimination of tumor cells. Understanding the mechanisms underlying tumor immune cycle disruption is important for identifying new immunopathogenetic links in the development of breast cancer, as well as identifying targets to improve the effectiveness of therapy for advanced breast cancer.

Successful Treatment of Seborrheic Dermatitis with Topical Roflumilast: A Case Series

Background: Seborrheic dermatitis (SD) is a common skin disease that presents with pink scaly patches in areas with higher sebaceous gland density, such as the scalp, glabella, retroauricular folds, nasolabial folds, chest, and groin. Case Reports: This is a case series of two patients with longstanding SD that did not respond adequately to topical corticosteroids or azoles, and were successfully treated monotherapy with roflumilast cream 0.3%. Both patients responded within two months and continue to respond to treatment with topical roflumilast monotherapy. Discussion: SD is commonly considered to be caused by Malassezia yeast proliferation and activity, however recent research has revealed that the inflammatory skin disease results from immune dysregulation and skin barrier disruption with Malassezia contributing as an exacerbating factor secondary to the primary pathogenesis. Thus treatment with topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, has been studied and demonstrated to be effective in treating the signs and symptoms of SD. Topical roflumilast 0.3% is formulated as a cream and a foam, with the foam approved for the treatment of SD. These cases demonstrate a successful treatment of patients with longstanding SD with roflumilast cream 0.3%. Conclusion: These cases demonstrate that SD, treated with either roflumilast cream 0.3% or roflumilast foam 0.3% may provide improvement in signs and symptoms of SD.

INFLUENCE OF VITAMIN E ON PANCREATIC ACINAR CELL MORPHOLOGY AND SERUM AMYLASE CONCENTRATIONS IN ALCOHOL-INDUCED PANCREATIC TOXICITY.

Misusing alcohol can cause damage to different tissues in the body, resulting in conditions like alcoholic liver disease, pancreatitis, cardiomyopathy, neurotoxicity, muscle wasting, weakened immune system, hormonal disruptions, birth defects, and bone loss. The objective of this research was to evaluate how alcohol affects the exocrine pancreas histology and the levels of amylase in the blood serum. Additionally, it aimed to explore whether vitamin E provides a safeguard against alcohol-induced harm to the pancreas in rabbits. A laboratory-based experimental investigation was carried out at Peshawar Medical College involving eighteen healthy adult male domestic rabbits weighing between one to one and a half kilograms each. The rabbits were divided into three groups. Group A, serving as the control, received normal saline as a placebo. Group B was administered a daily dose of 30 percent ethanol solution (30 ml/kg/day) in normal saline. Group C received a daily oral dose of 30% ethanol solution (30 ml/kg/day) in normal saline along with vitamin E (50 mg/kg/day). Blood samples were collected for serum amylase analysis, while morphological assessment of acinar cells involved evaluating cell count, acinar size, acinar cell size, and acinar nucleus size. Serum amylase levels did not exhibit a statistically significant variance between the control and experimental groups as p-value was >0.05. Furthermore, no notable distinctions were noted in the size and number of pancreas acini, cells of pancreatic acini, and pancreatic acinar cells nuclei between the control and experimental groups in both category E4 and Category E8, as p >0.05. There were no significant variations noted in the size and number of acini in pancreas, cells in pancreatic acini, and nuclei of cells in pancreatic acini. Consequently, the protective role of vitamin E against alcohol-induced pancreatic damage was not conclusively identified.

Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Mixture toxic mechanism of phoxim and prochloraz in the hook snout carp Opsariichthysbidens

Pesticides are usually found as mixtures in surface water bodies, even though their regulation in aquatic ecosystems is usually approached individually. In this context, this work aimed to investigate the enzymatic- and transcriptional-level responses after the mixture exposure of phoxim (PHX) and prochloraz (PRC) in the livers of hook snout carp Opsariichthys bidens. These data exhibited that co-exposure to PHX and PRC induced an acute synergistic impact on O. bidens. The activities of catalase (CAT), superoxide dismutase (SOD), carboxylesterase (CarE), and caspase3 varied significantly in most of the individual and combined challenges relative to basal values, indicating the activation of oxidative stress, detoxification dysfunction, as well as cell apoptosis. Besides, the transcriptional levels of five genes (gst, erα, mn-sod, cxcl-c1c, and il-8) exhibited more pronounced changes when subjected to combined pesticide exposure in contrast to the corresponding individual compounds. The findings revealed the manifestation of endocrine dysfunction and immune disruption. These results underscored the potential biochemical and molecular toxicity posed by the combination of PHX and PRC to O. bidens, thereby contributing to a deeper comprehension of the ecological toxicity of pesticide mixtures on aquatic organisms. Importantly, the concurrent presence of PHX and PRC might exacerbate hepatocellular damage in hook snout carps, potentially attributable to their synergistic toxic interactions. This study underscored the toxicological potency inherent in the co-occurrence of PHX and PRC in influencing fish development, thereby offering valuable insights for the risk assessment of pesticide mixtures and the safeguarding of aquatic organisms.

Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity.

The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro's featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 infection.

Extended analysis on peripheral blood cytokines correlated with hepatitis B virus viral load in chronically infected patients - a systematic review and meta-analysis.

Hepatitis B Virus (HBV) can affect life quality. Monitoring and understanding the fluctuations of the HBV level of viremia related to the intricate immune activity of the host helps in the development of new treatment strategies and evaluation patterns. This meta-analysis presents the correlations between cytokines and the level of viremia in chronic HBV patients for a better comprehension of the immune mechanisms behind this infection. We used PRISMA guidelines for this meta-analysis. The databases assessed were PUBMED, WEB OF SCIENCE, SCOPUS, and Cochrane Library. ZOTERO and PlotDigitizer helped the systematic research process. We extracted information related to the correlations between cytokines and the HBV-DNA level. Effect measures included comparisons between standardized mean differences and correlation coefficients. We evaluated retrieved articles with the Newcastle-Ottawa Quality Assessment Scale (NOS). The R 4.2.2 software displayed the statistical calculation and graphical representations. From 58,169 records, we extracted 16 articles with 32 different cytokine determinations. The main interleukins included in detection panels were IL-10 and IL-21. The meta-correlation analysis comprised 1,199 chronic HBV patients. The standardized mean difference between cytokine levels in HBV patients and healthy controls was 0.82 (95% CI = [-0.19, 1.84], p = 0.11). We observed a significant, fair, pooled correlation coefficient between IL-10, IL-9, and the viral load (r = 0.52, 95% CI = [0.19, 0.85]). This meta-analysis brings novelty because it gives a first rigorous systematic look at multiple studies with many cytokines. Our research approaches a debatable issue and gives a possible solution for settling controversies. Future studies can arise towards understanding the immune disruption in HBV and the development of new, improved assays for prognosis.

LGG promotes activation of intestinal ILC3 through TLR2 receptor and inhibits salmonella typhimurium infection in mice

ABSTRACT Salmonella is a foodborne pathogen that causes disruption of intestinal mucosal immunity, leading to acute gastroenteritis in the host. In this study, we found that Salmonella Typhimurium (STM) infection of the intestinal tract of mice led to a significant increase in the proportion of Lacticaseibacillus, while the secretion of IL-22 from type 3 innate lymphoid cells (ILC3) increased significantly. Feeding Lacticaseibacillus rhamnosus GG (LGG) effectively alleviated the infection of STM in the mouse intestines. TLR2−/− mice experiments found that TLR2-expressing dendritic cells (DCs) are crucial for LGG‘s activation of ILC3. Subsequent in vitro experiments showed that heat-killed LGG (HK-LGG) could promote DCs to secrete IL-23, which in turn further promotes the activation of ILC3 and the secretion of IL-22. Finally, organoid experiments further verified that IL-22 secreted by ILC3 can enhance the intestinal mucosal immune barrier and inhibit STM infection. This study demonstrates that oral administration of LGG is a potential method for inhibiting STM infection.

Myeloid PTEN loss affects the therapeutic response by promoting stress granule assembly and impairing phagocytosis by macrophages in breast cancer

Breast cancer (BRCA) has become the most common type of cancer in women. Improving the therapeutic response remains a challenge. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a classic tumour suppressor with emerging new functions discovered in recent years, and myeloid PTEN loss has been reported to impair antitumour immunity. In this study, we revealed a novel mechanism by which myeloid PTEN potentially affects antitumour immunity in BRCA. We detected accelerated stress granule (SG) assembly under oxidative stress in PTEN-deficient bone marrow-derived macrophages (BMDMs) through the EGR1-promoted upregulation of TIAL1 transcription. PI3K/AKT/mTOR (PAM) pathway activation also promoted SG formation. ATP consumption during SG assembly in BMDMs impaired the phagocytic ability of 4T1 cells, potentially contributing to the disruption of antitumour immunity. In a BRCA neoadjuvant cohort, we observed a poorer response in myeloid PTENlow patients with G3BP1 aggregating as SGs in CD68+ cells, a finding that was consistent with the observation in our study that PTEN-deficient macrophages tended to more readily assemble SGs with impaired phagocytosis. Our results revealed the unconventional impact of SGs on BMDMs and might provide new perspectives on drug resistance and therapeutic strategies for the treatment of BRCA patients.