Upfront treatment for patients with advanced high-grade serous ovarian cancer (HGSOC) includes a multi-hour cytoreductive surgery. Although the procedure is necessary for maximal tumor cytoreduction, understanding of the biology of systemic and intratumoral responses induced by surgical cytoreduction is limited. Through analysis of matched tumor and normal tissues and peripheral blood collected at multiple time points during cytoreductive surgery in patients with HGSOC, we demonstrate that surgery leads to rapid induction of systemic inflammatory response and activation of inflammatory signaling in the tumor and normal tissue, with interleukin-6 emerging as a dominant inflammatory pathway. A parallel study in a syngeneic murine HGSOC model recapitulated these findings and demonstrated accelerated tumor growth in response to surgery. This study highlights the previously unappreciated impact of specimen collection timing on the tumor signaling networks and provides insights into stress pathways activated by surgery, generating rationale for perioperative therapeutic interventions to reduce protumorigenic effects.

The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.

Heat shock factor 1 (HSF1) is the master orchestrator of the heat shock response (HSR), a critical process for maintaining cellular health and protein homeostasis. These effects are achieved through rapid expression of molecular chaperones, the heat shock proteins (HSPs), which ensure correct protein folding, repair, degradation and stabilization of multiprotein complexes. In addition to its role in the HSR, HSF1 influences the cell cycle, including processes such as S phase progression and regulation of the p53 pathway, highlighting its importance in cellular protein synthesis and division. While HSF1 activity offers neuroprotective benefits in neurodegenerative diseases, its proteome-stabilizing function may also reinforce tumorigenic transformation. HSF1 overexpression in many types of cancer reportedly enhances cell growth enables survival, alters metabolism, weakens immune response and promotes angiogenesis or epithelial-mesenchymal transition (EMT) as these cells enter a form of "HSF1 addiction". Furthermore, the client proteins of HSF1-regulated chaperones, particularly Hsp90, include numerous key players in classical tumorigenic pathways. HSF1 thus presents a promising therapeutic target for cancer treatment, potentially in combination with HSP inhibitors to alleviate typical initiation of HSR upon their use.

Bacterial pathogens have evolved diverse strategies to manipulate host cells to establish infection. At a molecular level, this is often mediated by virulence factors that are secreted into host cells (herein referred to as effectors), which target host cellular pathways by initiating host-pathogen protein-protein interactions that alter cellular function in the host. By establishing this network of host-pathogen protein-protein interactions, pathogenic bacteria modulate and hijack host cell processes for the benefit of the pathogen, ultimately promoting survival, replication, and cell-to-cell spread within the host. Effector proteins also mediate diverse host-microbe interactions in nature, contributing to symbiotic relationships spanning from mutualism to commensalism to parasitism. While effector proteins play crucial roles in nature, molecular properties such as the transient nature of the underlying protein-protein interactions and their affinity for targeting host biological membranes often presents challenges to elucidating host targets and mechanism of action. Proximity-dependent biotin identification (termed BioID) has proven to be a valuable tool in the field of cell biology to identify candidate protein-protein interactions in eukaryotic cells, yet has remained relatively underexploited by bacterial pathogenesis researchers. Here, we discuss bacterial effector function at a molecular level, and challenges presented by traditional approaches to host target identification. We highlight the BioID approach and its potential strengths in the context of identifying host-pathogen protein-protein interactions, and explore BioID's implementation to study host-microbe interactions mediated by bacteria. Collectively, BioID represents a powerful tool for the study of bacterial effector proteins, providing new insight into our understanding of pathogenesis and other symbiotic relationships, and opportunities to identify new factors that contribute to host response to infection.

The relationship between fine particulate matter (PM2.5) and cognition has been extensively investigated. However, the causal impact of acute PM2.5 purification on cognition improvement and the underlying biological mechanisms remain relatively opaque. Our double-blinded randomized controlled trial assessed the impact of acute PM2.5 purification on executive function, underpinned by multi-omics approaches including alternative splicing (AS) analysis. A total of 93 participants experienced a two-hour exposure to either reduced and normal PM2.5 levels. We measured the cognition of healthy young adults, collected peripheral blood before and after intervention, and performed multi-omics analysis including transcriptomics, metabolomics, and proteomics. Results indicated that reducing PM2.5 by 1 μg/m3 was associated with a 0.10 % (95 % CI: [0.18 %, 0.01 %]; p = 0.031) improvement in executive function. Notably, we identified 96 AS events without concurrent transcriptional amount alterations. Multi-layered omics analyses revealed disrupted pathways in hypoxia, mitochondrial function and energy metabolism, and immune responses, validated by ELISA and biochemical assay. These findings demonstrated short-term improvements of cognition following PM2.5 purification and provide mechanistic understandings of PM2.5-induced cognition alterations. This study underscores the significance of incorporating AS in the molecular framework of multi-omics research by exploring variable exon splicing, which could enrich multi-omics analysis methodologies and expose to broader audience.

Accumulating evidence indicates associations between ambient air pollution and Kawasaki disease (KD), but the results remain inconsistent.

This systematic review and meta-analysis aimed to comprehensively summarize the current evidence on the effects of ambient air pollutants on KD.

The PubMed, Web of Science, Embase, and Scopus databases were searched up to January 18, 2025 for studies investigating the effects of ambient air pollution on KD. A fixed- or random-effects model was used to calculate pooled ORs with 95% CIs for an increase in ambient air pollutant concentration of 10 μg/m3. The risk of bias was assessed using the Risk of Bias In Nonrandomized Studies of Exposures tool, and the quality of evidence was assessed by the Grading of Recommendations, Assessment, Development, and Evaluations framework. The protocol was registered with PROSPERO (CRD42024545321).

Thirteen studies with 124,857 participants were included. Seven studies were at high risk of bias. The meta-analysis revealed an increased risk of KD after short-term postnatal exposure to PM2.5 (OR: 1.011; 95% CI: 1.003-1.019; I2 = 0%; high-quality evidence) and PM10 (OR: 1.004; 95% CI: 1.000-1.008; I2 = 38%; high-quality evidence), as well as long-term postnatal exposure to PM2.5 (OR: 1.415; 95% CI: 1.179-1.697; I2 = 41%; high-quality evidence). Prenatal exposure to carbon monoxide, nitric oxide, nitrogen oxides, and sulfur dioxide; short-term postnatal exposure to nitric oxide; and long-term postnatal exposure to carbon monoxide and nitrogen oxides were also associated with KD occurrence.

Both prenatal and postnatal exposure to several ambient pollutants are associated with the risk of KD.

Dendritic cells (DCs) are professional antigen presentation cells (APCs) that bridge innate and adaptive immune functions to contain pathogenic threats. Long noncoding RNAs (lncRNAs) are implicated in regulating biological processes, including inflammation and immunity. However, the knowledge of myeloid DC-expressed lncRNA repertoire and their regulatory functions is limited. Here we profiled lncRNA expression kinetics during monocyte-to-DC (moDC) differentiation and characterized their functional roles. Our RNA-seq data identified a repertoire of differentially expressed lncRNAs associated with moDC differentiation and a large subset of these lncRNAs are distinct from M1 or M2 macrophages. We selected two DC-enriched lncRNAs and observed that PARAL1 silencing, or overexpression modulates DC surface markers expression. Importantly, PARAL1 RNAi significantly reduced, while its overexpression upregulated the levels of multiple TLRs. Upon treatment with TLR agonists PARAL1 knockdown cells exhibit reduced NF-κB, IRF3 and IRF7 phosphorylation substantiating its role in potentiating TLR signaling. Mechanistically, PARAL1 silencing showed significant downregulation of multiple NF-κB-induced genes and time-dependent inhibition of proinflammatory cytokine secretion upon challenge with TLR agonists. Finally, PARAL1 RNAi in DCs significantly impaired antigen processing and presentation to T cells. Overall, this study characterized novel functions of PARAL1 in regulating DC differentiation, TLR-dependent innate immunity and activation of adaptive immune response.

Phenotypic plasticity is a vital biological process facilitating the persistence of organisms amid rapid environmental changes. Investigating the genetic basis of plastic traits necessitates transplantation experiments, but much of the existing research has focused on laboratory model systems. Transplant experiments in the wild may provide better understanding of how plasticity operates in the context of real-world challenges. However, performing transplantation experiments in non-model systems, such as birds, could be challenging. In this study, we aim to develop Perdix hodgsoniae (Tibetan Partridge) inhabiting the highlands of the Tibetan Plateau as a suitable system to study genetic basis underlying short-term plastic response to rapid changes in elevation. We did a first attempt of field-based transplantation experiment by exposing P. hodgsoniae individuals to extreme change in elevation from their native elevation (3,623 m) to a low elevation outside their natural distribution range (500 m). We compared changes in gene expression in these birds at different time points, pre-transplant (day 0), and post-transplant (days 3 and 22). The birds successfully survived transplantation and exhibited well-being after 22 days. We identified a total of 715 differentially expressed genes (DEGs) across these time points. Our analysis revealed a genome-wide decrease in expression following the transplantation, indicating that the birds possibly exhibited stress-induced transcriptional attenuation (SITA) because of the extreme change in elevation, suggesting a broader response at the transcriptional level, possibly as a mechanism to cope with extreme changes in the environment. Our analysis further suggested that heat stress posed an immediate challenge for the birds following the transplant, as we identified changes in expression in many genes associated with heat stress response. Our findings affirm the viability of conducting transplant experiments in the P. hodgsoniae and provides initial insights into gene expression changes associated with the plastic response to rapid changes in elevation in these birds.

Radiation, a universal component of Earth's environment, is categorized into non-ionizing and ionizing forms. While non-ionizing radiation is relatively harmless, ionizing radiation possesses sufficient energy to ionize atoms and disrupt DNA, leading to cell damage, mutation, cancer, and cell death. The extensive use of radionuclides and ionizing radiation in nuclear technology and medical applications has sparked global concern for their capacity to cause acute and chronic illnesses. Ionizing radiation induces DNA damage either directly through strand breaks and base change or indirectly by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radiolysis of water. This damage triggers a complex cellular response involving recognition of DNA damage, cell cycle arrest, DNA repair mechanisms, release of pro-inflammatory cytokines, and cell death. This review focuses on the mechanisms of radiation-induced cellular damage, recognition of DNA damage and subsequent activation of repair processes, and the critical role of the innate immune response in resolution of the injury. Emphasis is placed on pattern recognition receptors (PRRs) and related receptors that detect damage-associated molecular patterns (DAMPs) and initiate downstream signaling pathways. Radiation-induced cell death pathways are discussed in detail. Understanding these processes is crucial for developing strategies to mitigate the harmful effects of radiation and improve therapeutic outcomes.

The mosquito midgut functions as a key interface between pathogen and vector. However, studies of midgut physiology and virus infection dynamics are scarce, and in Culex tarsalis - an extremely efficient vector of West Nile virus (WNV) - nonexistent. We performed single-cell RNA sequencing on Cx. tarsalis midguts, defined multiple cell types, and determined whether specific cell types are more permissive to WNV infection. We identified 20 cell states comprising 8 distinct cell types, consistent with existing descriptions of Drosophila and Aedes aegypti midgut physiology. Most midgut cell populations were permissive to WNV infection. However, there were higher levels of WNV RNA (vRNA) in enteroendocrine cells, suggesting enhanced replication in this population. In contrast, proliferating intestinal stem cells (ISC) had the lowest levels of vRNA, a finding consistent with studies suggesting ISC proliferation in the midgut is involved in infection control. ISCs were also found to have a strong transcriptional response to WNV infection; genes involved in ribosome structure and biogenesis, and translation were significantly downregulated in WNV-infected ISC populations. Notably, we did not detect significant WNV-infection induced upregulation of canonical mosquito antiviral immune genes (e.g., AGO2, R2D2, etc.) at the whole-midgut level. Rather, we observed a significant positive correlation between immune gene expression levels and vRNA load in individual cells, suggesting that within midgut cells, high levels of vRNA may trigger antiviral responses. Our findings establish a Cx. tarsalis midgut cell atlas, and provide insight into midgut infection dynamics of WNV by characterizing cell-type specific enhancement/restriction of, and immune response to, infection at the single-cell level.

The current level of knowledge on transcriptome responses triggered by Caesalpinia sappan (CS) extract in porcine peripheral blood mononuclear cells (PBMCs) after porcine reproductive and respiratory syndrome virus (PRRSV) infection is limited. Therefore, in the present study, we aimed to detect significant genes and pathways involved in CS extract supplementation responsiveness of PBMCs after PRRSV infection. RNA sequencing was conducted on PBMCs, which were isolated from six weaned piglets. The resultant transcriptional responses were examined by mRNA sequencing. Differential expression analysis identified 263 and 274 differentially expressed genes (DEGs) between the PRRSV and CTRL groups, and the PRRSV+CS and CTRL groups, respectively. Among these, ZNF646 and KAT5 emerged as the most promising candidate genes, potentially influencing the interaction between PRRSV-infected PBMCs and CS extract supplementation through the regulation of gene networks and cellular homeostasis during stress. Two pathways were detected to be associated with CS extract supplementation responsiveness: the cellular response to stress pathway and the NF-kB signaling pathway. Consequently, our study reveals a novel mechanism underlying cellular stress response and the NF-κB signaling pathway in PRRSV-infected PBMCs, and identifies a potential application of CS extract for activating the NF-κB signaling pathway. In conclusion, by supplementing CS extract in PBMC cells infected with PRRSV, we found that CS extract modulates PRRSV infection by inducing cellular stress, which is regulated by the NF-κB signaling pathway. This induced stress creates an adverse environment for PRRSV survival. This study contributes to a deeper understanding of the therapeutic targets and pathogenesis of PRRSV infection. Importantly, our results demonstrate that CS extract has the potential to be a candidate for modulating PRRSV infection.

Intracellular protozoan parasites are the etiologic agents of important human diseases, like malaria, Chagas disease, toxoplasmosis, and leishmaniasis. Inside host cells, these parasites manipulate the host metabolism and intracellular trafficking for their own benefits and, inevitably, induce several stress response mechanisms. In this review, we discuss autophagy as a stress response mechanism that can be both (i) explored by these intracellular parasites to acquire nutrients and (ii) to restrict parasite proliferation and survival within host cells. We also discuss the immunomodulatory role of autophagy as a strategy to reduce inflammatory-mediated damage, an essential player in the pathophysiology of these parasitic diseases. At last, we propose and discuss several known autophagy modulators as possible pharmaceuticals for adjunctive therapies.

Coccidiosis is one of the most common infectious diseases in goat farming. The disease causes major economic loss in the world. In this study, we aimed to investigate the activity of heat shock protein 70 in intestine cells of goats with coccidiosis. We used total of twenty-seven goats for this purpose. Gross findings were diarrhoea, cachexia, and dehydration. In the microscopical examination, we observed proliferative enteritis with Eimeria. parasites. Immunohistochemical examinations revealed moderate to severe Hsp70 immunoreactivity in intestines. Considering Hsp70 is a stress protein with anti-apoptotic and immune regulatory features, Hsp70 immunoreactivity attributed to the stress caused by infection and anti-apoptotic activity of the protein along with immune regulatory effects of Hsp70.

The pathogenesis of alcohol-associated liver disease (ALD) is complex and multifactorial. Several intracellular, intrahepatic, and extrahepatic factors influence development of early fatty liver injury leading to inflammation and fibrosis. Alcohol metabolism, cellular stress, and gut-derived factors contribute to hepatocyte and immune cell injury leading to cytokine and chemokine production. The pathogenesis of alcohol-associated hepatitis (AH), an advanced form of acute-on-chronic liver failure due to excessive chronic intake in patients with underlying liver disease, is not well understood. While pathogenic mechanisms in early ALD are studied, the pathogenesis of AH requires further investigation to help design effective drugs for patients.

In Hepatitis B patients, the virus targets liver cells, leading to inflammation and liver damage, which can result in severe complications such as liver failure, cirrhosis, and liver cancer. Therapeutic options for liver disease are currently limited. Curcumin, a polyphenol with potential protective effects against chronic diseases like cancer, suffers from poor water solubility, restricting its pharmacological applications. This study explores the encapsulation of curcumin in glucan nanoparticles (NPs) and its impact on oxidative stress in liver cancer cells. Two sizes of curcumin-loaded glucan NPs, GC111 (111 nm) and GC398 (398 nm), were produced with nearly 100 % encapsulation efficiency. Cytotoxicity studies revealed that particle size influences the extent of observed effects, with GC111 NPs causing a greater reduction in cell viability. Additionally, the smaller GC111 NPs demonstrated a higher capacity to induce oxidative stress in cancer cells by stimulating the production of ROS, NO, and the chemokine RANTES in a concentration-dependent manner. These findings suggest that the smaller GC111 NPs are promising candidates for future studies aimed at evaluating oxidative stress-induced tumor cell death mechanisms.

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease-related deaths worldwide. It uses ESX-1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS-STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas-sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non-human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS-STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS-STING1 pathway can help develop new ways to fight tuberculosis.

The aquaculture industry is hindered by various factors. One of the most noticeable factors is infection by parasites and pathogens. Argulus stands out as a prominent and economically significant ectoparasite in freshwater aquaculture. Argulus infestation causes severe immunomodulatory effects on its hosts by promoting argulosis, causing inflammation, extensive tissue damage, and death. Indian aquaculture sector faced a loss of 62.5 million USD due to Argulus infection. However, current control methods, such as pesticides, cause serious environmental damage. Herbal treatment methods are ineffective and have limitations. Hence, a more efficient and cost-effective control method is needed. In recent years, vaccine development has emerged as a promising avenue of research. Understanding the effect of the host-parasite relationship in the host immune system is essential to develop strategies for prevention, control, and management of argulosis. These interactions provide insights into the co-evolutionary dynamics between hosts and parasites. This review provides an overview of the current knowledge on the host-searching behaviour of Argulus, host-parasite interaction and control strategies. This review also highlights the need for further research and the development of sustainable control measures for Argulus infection.

Background: Busulfan is an FDA-approved alkylating drug used in the chemotherapy of advanced acute myeloid leukemia. The precise mechanisms by which Busulfan kills spermatogonia stem cells (SSCs) are not yet completely understood. Methods: Using a murine model, we evaluated Busulfan-induced apoptosis and DNA damage signaling between testis and ovary tissues. We executed RT-qPCR, analyzed single-nuclei RNA sequencing data and performed in situ hybridization for the localization of the gene expression in the tissues. Results: The results indicate that, in contrast to female germ cells, haploid male germ cells undergo significant apoptosis following Busulfan chemotherapy. Moreover, a gene enrichment analysis revealed that reactive oxygen species may activate the inflammatory response in part through the TNF-α/NF-κB signaling pathway. Interestingly, in the testis, the mRNA levels of TNF-α and TAF7 (TATA box-binding protein-associated factor 7) are downregulated, and testosterone levels suppressed. Mechanistically, the promoter of TNF-α has a conserved motif for binding TAF7, which is necessary for its transcriptional activation and may require further in-depth study. We next analyzed the tumorigenic function of TAF7 and revealed that it is highly overexpressed in several types of human cancers, particularly testicular germ cell tumors, and associated with poor patient survival. Therefore, we executed in situ hybridization and single-nuclei RNA sequencing, finding that less TAF7 mRNA is present in SSCs after chemotherapy. Conclusions: Thus, our data indicate a possible function of TAF7 in the regulation of SSCs and spermatogenesis following downregulation by Busulfan. These findings may account for the therapeutic effects of Busulfan and underlie its potential impact on cancer chemotherapy prognosis.

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian-Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24-72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta.

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.

Insects protect themselves through their immune systems. Entomopathogenic nematodes and their bacterial symbionts are widely used for the biocontrol of economically important pests. Ascarosides are pheromones that regulate nematode behaviors, such as aggregation, avoidance, mating, dispersal, and dauer recovery and formation. However, whether ascarosides influence the immune response of insects remains unexplored. In this study, we co-injected ascarosides and symbiotic Photorhabdus luminescens subsp. kayaii H06 bacteria derived from Heterorhabditis bacteriophora H06 into the last instar larvae of Galleria mellonella. We recorded larval mortality and analyzed the expressions of AMPs, ROS/RNS, and LPSs. Our results revealed a process in which ascarosides, acting as enhancers of the symbiotic bacteria, co-induced G. mellonella immunity by significantly increasing oxidative stress responses and secreting AMPs (gallerimycin, gloverin, and cecropin). This led to a reduction in color intensity and the symbiotic bacteria load, ultimately resulting in delayed host mortality compared to either ascarosides or symbiotic bacteria. These findings demonstrate the cross-kingdom regulation of insects and symbiotic bacteria by nematode pheromones. Furthermore, our results suggest that G. mellonella larvae may employ nematode pheromones secreted by IJs to modulate insect immunity during early infection, particularly in the presence of symbiotic bacteria, for enhancing resistance to invasive bacteria in the hemolymph.

The genus Brassica is an important source of food in the Mediterranean diet with documented nutritional and medicinal properties. However, few studies have investigated the phytochemical composition and the biological activity of wild Sicilian taxa. Thus, we aimed to study the chemical profile and the antioxidant potential, in vitro and in LPS-stimulated RAW 264.7 cells, of a methanolic extract of leaves of wild Brassica macrocarpa Guss (B. macrocarpa) (Egadi Islands; Sicily-Italy). B. macrocarpa methanolic extract showed a large amount of glucosinolates and different phenolic compounds. It exhibited antioxidant activity in the DPPH assay and in LPS-stimulated RAW 264.7 cells, being able to reduce NO and ROS levels and NOS2 mRNA expression. Our study demonstrated that Sicilian B. macrocarpa methanolic extract, in LPS-stimulated macrophages, efficiently counteracts oxidative stress and displays radical scavenging activity. Future studies are required to identify the contribution of the single phytocomponents, to characterize the action mechanism, and to reveal possible applications in human health.

A bioactive Pleurotus eryngii aqueous extract powder (SPAE) was obtained by spray drying and its performance in terms of physicochemical properties, in vitro digestion, inflammatory factors, and modulation of the intestinal microbiota was explored. The results indicated that the SPAE exhibited a more uniform particle size distribution than P. eryngii polysaccharide (PEP). Meanwhile, a typical absorption peak observed at 843 cm-1 in the SPAE FTIR spectra indicated the existence of α-glycosidic bonds. SPAE exhibited higher antioxidant abilities and superior resistance to digestion in vitro. In addition, SPAE supplementation to mice significantly reduced the release of factors that promote inflammation, enhanced the secretion of anti-inflammatory factors, and sustained maximum production of short-chain fatty acids (SCFAs). Additionally, it significantly enhanced the relative abundance of SCFAs-producing Akkermansia and reduced the abundance of Ruminococcus and Clostridiides in intestines of mice. These results show the potential of SPAE as a novel material with prebiotic effects for the food and pharmaceutical industries.

While the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen, Candida albicans, activates macrophage IRE1α through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response to C. albicans infection. Moreover, lipopolysaccharide treatment was also able to activate IRE1α prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1α occurs through non-canonical mechanisms. During C. albicans infection, we observed that IRE1α activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1α activity displayed inefficient phagosome maturation, enabling C. albicans to lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1α activity supports phagosomal calcium flux after phagocytosis of C. albicans, which is crucial for phagosome maturation. Importantly, deletion of IRE1α activity decreased the fungicidal activity of phagocytes in vivo during systemic C. albicans infection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.

To investigate the potential protective effect of prior cold stimulation on broiler intestine induced by acute cold stress (ACS). A total of 384 one-day-old broilers were divided into control (CON), ACS, cold stimulation Ⅰ (CS3+ACS), and cold stimulation Ⅱ (CS9+ACS) groups. Broilers in CON and ACS groups were reared normally, and birds in CS3+ACS and CS9+ACS groups were reared at 3℃ and 9℃ below CON group for 5 h, respectively, on alternate days from d 15 to 35. Broilers in ACS, CS3+ACS, and CS9+ACS groups were subjected to 10℃ for 24 h on d 43. Eventually, small intestine tissues were collected for histopathological observation and indexes detection. The results showed that intestinal tissues in all ACS-broilers exhibited inflammatory cell infiltrates, microvilli disruption, reduced villus length in jejunum and increased crypt depth in jejunum and ileum. Whereas these phenomena were relatively light in CS3+ACS group. Compared to CON group, mRNA expression of the TLR4/MyD88/NF-κB pathway-related genes (TLR4, MyD88, NF-κBp65, COX-2, iNOS, PTGEs, TNF-α), Th1/Th17-derived cytokines (IL-1β, IL-2, IL-8, IL-12, IFN-γ, IL-17), and HSPs (HSP40, HSP60, HSP70, HSP90) was upregulated (P < 0.05), and that of Th2-deviated cytokines (IL-4, IL-6, IL-10, IL-13) and IκBα was downregulated (P < 0.05) in small intestine in almost all ACS-broilers. Compared to ACS group, mRNA expression of most of the TLR4/MyD88/NF-κB pathway-related genes, Th1/Th17-derived cytokines, and HSPs was downregulated and that of Th2-derived cytokines was upregulated in CS3+ACS group (P < 0.05). Protein expression levels of TLR4, MyD88, p-p65/p65, p-IκBα/IκBα, IKK, TNF-α, IL-1β, IL-10, and HSPs were similar to their mRNA expression. The concentration of sIgA and activities of CAT, SOD, and GSH-px were decreased and MDA and H2O2 were increased in ACS and CS9+ACS groups compared to CON group (P < 0.05). Therefore, cold stress caused oxidative stress and inflammation, leading to gut immune dysfunction; while mild cold stimulation at 3℃ below normal rearing temperature alleviated cold stress-induced intestinal injure and dysfunction by modulating the TLR4/MyD88/NF-κB pathway in broilers.

Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) are epidemiologically correlated disorders with a worldwide growing prevalence. While the mechanisms leading to the onset and development of these conditions are not fully understood, predictive tissue representations for studying the coordinated interactions between central organs that regulate energy metabolism, particularly the liver and pancreatic islets, are needed. Here, a dual pump-less recirculating organ-on-chip platform that combines human pluripotent stem cell (sc)-derived sc-liver and sc-islet organoids is presented. The platform reproduces key aspects of the metabolic cross-talk between both organs, including glucose levels and selected hormones, and supports the viability and functionality of both sc-islet and sc-liver organoids while preserving a reduced release of pro-inflammatory cytokines. In a model of metabolic disruption in response to treatment with high lipids and fructose, sc-liver organoids exhibit hallmarks of steatosis and insulin resistance, while sc-islets produce pro-inflammatory cytokines on-chip. Finally, the platform reproduces known effects of anti-diabetic drugs on-chip. Taken together, the platform provides a basis for functional studies of obesity, T2DM, and MASLD on-chip, as well as for testing potential therapeutic interventions.

Air pollution, a serious risk factor for human health, can lead to immune damage and various diseases. Long-term exposure to air pollutants can trigger oxidative stress and inflammatory responses (the main sources of immune impairment) in the body. Exercise has been shown to modulate anti-inflammatory and antioxidant statuses, enhance immune cell activity, as well as protect against immune damage caused by air pollution. However, the underlying mechanisms involved in the protective effects of exercise on pollutant-induced damage and the safe threshold for exercise in polluted environments remain elusive. In contrast to the extensive research on the pathogenesis of air pollution and the preventive role of exercise in enhancing fitness, investigations into exercise resistance to injury caused by air pollution are still in their infancy. In this review, we analyze evidence from humans, animals, and cell experiments on the combined effects of exercise and air pollution on immune health outcomes, with an emphasis on oxidative stress, inflammatory responses, and immune cells. We also propose possible mechanisms and directions for future research on exercise resistance to pollutant-induced damage in the body. Furthermore, we suggest strengthening epidemiological studies at different population levels and investigations on immune cells to guide how to determine the safety thresholds for exercise in polluted environments.

Cardiovascular disease is the leading cause of death. In addition to the well-known risk factors associated with cardiovascular disease, such as age, diabetes mellitus, smoking, hypertension, and obesity, there has been a growing concern regarding cardiac complications stemming from the Gram-negative bacteria Helicobacter pylori. While H. pylori is most commonly associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma, it has also been implicated in extra gastric manifestations, encompassing cardiac, neurologic, ocular, and dermatologic issues. Key virulent factors for coronary artery disease include the vacuolating cytotoxin gene A and the cytotoxin-associated gene A. The most likely pathogenic mechanism of the relationship between H. pylori and coronary artery disease is initiating a chronic inflammatory process associated with infection and the modifications of classic risk factors. These alterations lead to the creation of prothrombotic and procoagulant environments. Here, we review the cardiac manifestations of H. pylori and the underlying pathophysiological mechanisms.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

This study explored the protective capacity of the essential oil (EO) of Cymbopogon citratus against oxidative stress induced by hydrogen peroxide (H2O2) and the inflammatory potential in zebrafish. Using five concentrations of EO (0.39, 0.78, 1.56, 3.12, and 6.25 μg/mL) in the presence of 7.5 mM H2O2, we analyzed the effects on neutrophil migration, caudal fin regeneration, cellular apoptosis, production of reactive oxygen species (ROS), and activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) after 96 h of exposure. A significant decrease in neutrophil migration was observed in all EO treatments compared to the control. Higher concentrations of EO (3.12 and 6.25 μg/mL) resulted in a significant decrease in caudal fin regeneration compared to the control. SOD activity was reduced at all EO concentrations, CAT activity significantly decreased at 3.12 μg/mL, and GST activity increased at 0.78 μg/mL and 1.56 μg/mL, compared to the control group. No significant changes in ROS production were detected. A reduction in cellular apoptosis was evident at all EO concentrations, suggesting that C. citratus EO exhibits anti-inflammatory properties, influences regenerative processes, and protects against oxidative stress and apoptosis.

The Asian corn borer, Ostrinia furnacalis (Guenée) (Lepidoptera: Crambidae), is one of the most harmful pests of maize in Asia. It poses a significant threat to maize production, causing economic losses due to its strong ecological adaptation. In this study, we compared and analyzed the hemolymph proteome between freezing and resistance-freezing O. furnacalis strains using two-dimensional gel electrophoresis to gain insights into the mechanisms of cold resistance. The results revealed that 300-400 hemolymph protein spots were common, with 24 spots showing differences between the two strains. Spectrometry analysis revealed 21 protein spots, including 17 upregulated spots and 4 downregulated ones. The expression of upregulation/downregulation proteins plays a crucial role in the metabolism, energy supply, and defense reaction of insects. Proteomics research not only provides a method for investigating protein expression patterns but also identifies numerous attractive candidates for further exploration.

Cellular stress responses are crucial for maintaining cellular homeostasis. Stress granules (SGs), activated by eIF2α kinases in response to various stimuli, play a pivotal role in dealing with diverse stress conditions. Viral infection, as one kind of cellular stress, triggers specific cellular programs aimed at overcoming virus-induced stresses. Recent studies have revealed that virus-derived stress responses are tightly linked to the host's antiviral innate immunity. Virus infection-induced SGs act as platforms for antiviral sensors, facilitating the initiation of protective antiviral responses called "antiviral stress granules" (avSGs). However, many viruses, including coronaviruses, have evolved strategies to suppress avSG formation, thereby counteracting the host's immune responses. This review discusses the intricate relationship between cellular stress responses and antiviral innate immunity, with a specific focus on coronaviruses. Furthermore, the diverse mechanisms employed by viruses to counteract avSGs are described.

Background: Pro-inflammatory cytokines are implicated in depression caused by both environmental- and alcohol-induced stress. The purpose of the study was to investigate the cytokine levels in serum and hippocampus following induction of depression-like behaviors (DLB) by either forced swimming test (FST) or ethanol-induced DLB (EID). We also investigated the effect of prior administration of antidepressant drug fluoxetine on cytokines in animals exposed to both models of DLB. Methods: Animals were pretreated with fluoxetine before inducing DLB, while DLB was induced in some animals using FST and ethanol in different groups of rats without fluoxetine pretreatment. The ELISA was used to detect changes in cytokine (IL-1β, IL-6, and TNF-α) levels in serum and hippocampus. Results: The mean levels of IL-1β and IL-6 measured in serum and hippocampus were significantly higher in FST and EID models when compared to the control group. The serum concentrations of IL-1β and IL-6 were significantly reduced in animals pre-treated with 5 mg/kg and 10 mg/kg of fluoxetine in both FST and EID models when compared to the untreated FST and EID groups respectively. Conclusions: In conclusion, both environment and alcohol can induce stress and DLB in rats with similar intensity, and their mechanisms of DLB induction involve activation of pro-inflammatory cytokines. Moreover, fluoxetine can prevent stress-induced inflammation in models of DLB.

The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.

This is the first genome-wide transcriptional profiling study using RNA-sequencing to investigate osteoblast responses to different titanium surface topographies, specifically between machined, smooth and acid-etched, microrough surfaces. Rat femoral osteoblasts were cultured on machine-smooth and acid-etched microrough titanium disks. The culture system was validated through a series of assays confirming reduced osteoblast attachment, slower proliferation, and faster differentiation on microrough surfaces. RNA-sequencing analysis of osteoblasts at an early stage of culture revealed that gene expression was highly correlated (r = 0.975) between the two topographies, but 1.38 % genes were upregulated and 0.37 % were downregulated on microrough surfaces. Upregulated transcripts were enriched for immune system, plasma membrane, response to external stimulus, and positive regulation to stimulus processes. Structural mapping confirmed microrough surface-promoted gene sharing and networking in signaling pathways and immune system/responses. Target-specific pathway analysis revealed that Rho family G-protein signaling pathways and actin genes, responsible for the formation of stress fibers, cytoplasmic projections, and focal adhesion, were upregulated on microrough surfaces without upregulation of core genes triggered by cell-to-cell interactions. Furthermore, disulfide-linked or -targeted extracellular matrix (ECM) or membranous glycoproteins such as laminin, fibronectin, CD36, and thrombospondin were highly expressed on microrough surfaces. Finally, proliferating cell nuclear antigen (PCNA) and cyclin D1, whose co-expression reduces cell proliferation, were upregulated on microrough surfaces. Thus, osteoblasts on microrough surfaces were characterized by upregulation of genes related to a wide range of functions associated with the immune system, stress/stimulus responses, proliferation control, skeletal and cytoplasmic signaling, ECM-integrin receptor interactions, and ECM-membranous glycoprotein interactions, furthering our knowledge of the surface-dependent expression of osteoblastic biomarkers on titanium.

Insulin-positive (+) cells (IPCs), detected in multiple organs, are of great interest as a probable alternative to ameliorate pancreatic beta-cells dysfunction and insulin deficiency in diabetes. Liver is a potential source of IPCs due to it common embryological origin with pancreas. We previously demonstrated the presence of IPCs in the liver of healthy and diabetic rats, but detailed description and analysis of the factors, which potentially can induced ectopic hepatic expression of insulin in type 1 (T1D) and type 2 diabetes (T2D), were not performed. In present study we evaluate mass of hepatic IPCs in the rat models of T1D and T2D and discuss factors, which may stimulate it generation: glycaemia, organ injury, involving of hepatic stem/progenitor cell compartment, expression of transcription factors and inflammation. Quantity of IPCs in the liver was up by 1.7-fold in rats with T1D and 10-fold in T2D compared to non-diabetic (ND) rats. We concluded that ectopic hepatic expression of insulin gene is activated by combined action of a number of factors, with inflammation playing a decision role.

Coronavirus disease-19 (COVID-19) can induce severe inflammation of the lungs and respiratory system. Severe COVID-19 is frequently associated with hyper inflammation and hyper-ferritinemia. High iron levels are known to trigger pro-inflammatory effects. Cumulative iron loading negatively impacts on a patients innate immune effector functions and increases the risk for infection related complications. Prognosis of severe acute respiratory SARS-CoV-2 patients may be impacted by iron excess. Iron is an essential co-factor for numerous essential cellular enzymes and vital cellular operations. Viruses hijack cells in order to replicate, and efficient replication requires an iron-replete host. Utilizing iron loaded cells in culture we evaluated their susceptibility to infection by pseudovirus expressing the SARS-CoV-2 spike protein and resultant cellular inflammatory response. We observed that, high levels of iron enhanced host cell ACE2 receptor expression contributing to higher infectivity of pseudovirus. In vitro Cellular iron overload also synergistically enhanced the levels of; reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines (IL-1β, IL-6, IL-8 & TNF-α) and chemokine (CXCL-1&CCL-4) production in response to inflammatory stimulation of cells with spike protein. These results were confirmed using an in vivo mouse model. In future, limiting iron levels may be a promising adjuvant strategy in treating viral infection.

Fucoidans are sulfated polysaccharides detected mainly in the cell walls of brown seaweeds. Here, we examined the effects of single doses of fucoidan derived from Ericaria crinita (formerly Cystoseira crinita) on carrageenan-induced paw inflammation in rats. The serum levels of TNF-α, IL-1β, IL-6, and IL-10 of rats with LPS-induced systemic inflammation after 14 days of treatment were also evaluated. Subchronic treatment with fucoidan from E. crinita attenuated the inflammation during the late phase of the degraded carrageenan-induced paw edema (3rd to 5th hour after carrageenan injection) with peak activity at the 3rd hour after the application. Both doses of fucoidan from E. crinita (25 and 50 mg/kg bw) significantly decreased the levels of all tested pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the serum of rats with a model of system inflammation but had no effect on the anti-inflammatory cytokine IL-10. The results showed that the repeated application of fucoidan has a more prominent effect on the levels of some pro-inflammatory cytokines in serum in comparison to a single dose of the sulfated polysaccharide. This reveals the potential of E. crinita fucoidan as an anti-inflammatory agent. Furthermore, E. crinita fucoidan exhibited in vitro antioxidant capacity, determined by 2,2-diphenyl-1-picryl-hydrazyl radical scavenging and ferric reducing antioxidant power assays as follows: IC50 = 412 µg/mL and 118.72 μM Trolox equivalent/g, respectively.