DrugVirus.info 2.0: an integrative data portal for broad-spectrum antivirals (BSA) and BSA-containing drug combinations (BCCs).

Viruses can cross species barriers and cause unpredictable outbreaks in man with substantial economic and public health burdens. Broad-spectrum antivirals, (BSAs, compounds inhibiting several human viruses), and BSA-containing drug combinations (BCCs) are deemed as immediate therapeutic options that fill the void between virus identification and vaccine development. Here, we present DrugVirus.info 2.0 (https://drugvirus.info), an integrative interactive portal for exploration and analysis of BSAs and BCCs, that greatly expands the database and functionality of DrugVirus.info 1.0 webserver. Through the data portal that now expands the spectrum of BSAs and provides information on BCCs, we developed two modules for (i) interactive analysis of users' own antiviral drug and combination screening data and their comparison with published datasets, and (ii) exploration of the structure-activity relationship between various BSAs. The updated portal provides an essential toolbox for antiviral drug development and repurposing applications aiming to identify existing and novel treatments of emerging and re-emerging viral threats.

Altered Blood Molecular Markers of Cardiovascular Function in Rats after Intrauterine Hypoxia and Drug Therapy.

Many children and adults who have suffered prenatal hypoxia at an early age develop many serious diseases. This disease is an actual problem of pediatric cardiology and little studied. The aim was to analyze the cardioprotective effect of L-arginine, Thiotriazoline, Angioline, and Mildronate on the cardiovascular system of rats after prenatal hypoxia. Methods: The experiments were carried out on 50 female white rats; intraperitoneal sodium nitrite solution was administered daily to pregnant female rats after 16 days at a dose of 50 mg/kg. Control pregnant rats received saline. The offspring were divided into groups: 1-intact; 2-the control group of rat pups after PH, treated daily with physiological saline; 3-six groups of rat pups after PH, treated daily from the 1st to the 30th day after birth. Heat shock protein HSP70 was determined by enzyme immunoassay, ST2 Nitrotyrosine, and eNOS was observed by ELISA. Results: Angiolin showed a high cardioprotective effect even a month after discontinuation of the drug, and after introduction, the highest decrease in ST2 nitrotyrosine was revealed. Thiotriazoline and L-arginine have an antioxidant effect and a positive effect on eNOS expression, increasing the concentration of HSP70. Mildronate increased the expression of eNOS and the concentration of HSP70 in the blood of experimental rats after a course of administration, but did not show an antioxidant effect and did not reduce the concentration of nitrotyrosine. The results obtained indicate the cardioprotective effect of modulators of the NO system with different mechanisms of action of drugs after prenatal hypoxia.

Seven classes of antiviral agents.

The viral epidemics and pandemics have stimulated the development of known and the discovery of novel antiviral agents. About a hundred mono- and combination antiviral drugs have been already approved, whereas thousands are in development. Here, we briefly reviewed 7 classes of antiviral agents: neutralizing antibodies, neutralizing recombinant soluble human receptors, antiviral CRISPR/Cas systems, interferons, antiviral peptides, antiviral nucleic acid polymers, and antiviral small molecules. Interferons and some small molecules alone or in combinations possess broad-spectrum antiviral activity, which could be beneficial for treatment of emerging and re-emerging viral infections.

Therapeutic Effectiveness of Interferon-α2b against COVID-19 with Community-Acquired Pneumonia: The Ukrainian Experience.

Despite several targeted antiviral drugs against SARS-CoV-2 currently being available, the application of type I interferons (IFNs) still deserves attention as an alternative antiviral strategy. This study aimed to assess the therapeutic effectiveness of IFN-α in hospitalized patients with COVID-19-associated pneumonia. The prospective cohort study included 130 adult patients with coronavirus disease (COVID-19). A dose of 80,000 IU of IFN-α2b was administered daily intranasally for 10 days. Adding IFN-α2b to standard therapy reduces the length of the hospital stay by 3 days (p < 0.001). The level of CT-diagnosed lung injuries was reduced from 35% to 15% (p = 0.011) and CT injuries decreased from 50% to 15% (p = 0.017) by discharge. In the group of patients receiving IFN-α2b, the SpO2 index before and after treatment increased from 94 (92-96, Q1-Q3) to 96 (96-98, Q1-Q3) (p < 0.001), while the percentage of patients with normal saturation increased (from 33.9% to 74.6%, p < 0.05), but the level of SpO2 decreased in the low (from 52.5% to 16.9%) and very low (from 13.6% to 8.5%) categories. The addition of IFN-α2b to standard therapy has a positive effect on the course of severe COVID-19.

Oral Administration of Myelin Oligodendrocyte Glycoprotein Attenuates Experimental Autoimmune Encephalomyelitis through Induction of Th2/Treg Cells and Suppression of Th1/Th17 Immune Responses.

Multiple Sclerosis (MS) is a demyelinating autoimmune disorder of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) has been widely used to determine the pathogenesis of the disease and evaluate new treatment strategies for MS. Therefore, we investigated the efficacy of oral administration of a Myelin Oligodendrocyte Glycoprotein (MOG) in the treatment of EAE. Female C57BL/6 mice were utilized in three groups (Control group, received PBS orally; prevention group, oral administration of MOG35-55 two weeks before EAE induction; treatment group, oral administration of MOG35-55 after EAE induction). MOG administration, both as prevention and treatment, significantly controlled clinical score, weight loss, CNS inflammation, and demyelination, mainly through the modulation of T cell proliferation, and reduction in pro-inflammatory cytokines and transcription factors, including TNF-α, IFN-γ, IL-17, T-bet, and ROR-γt. MOG administration, both as prevention and treatment, also induced anti-inflammatory cytokines and transcription factors, including IL-4, TGF-ß, GATA-3, and Foxp3. The results showed that oral administration of MOG, both as prevention and treatment, could efficiently control EAE development. Immunomodulatory mechanisms include the induction of Th2 and Treg cells and the suppression of pro-inflammatory Th1 and Th17 cells.

Genetic interaction between the non-homologous end-joining factors during B and T lymphocyte development: In vivo mouse models.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double-strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, MRI) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation.

Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.

ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks.

Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.

Nucleotide excision repair driven by the dissociation of CAK from TFIIH.

The transcription/DNA repair factor TFIIH is organized into a core that associates with the CDK-activating kinase (CAK) complex. Using chromatin immunoprecipitation, we have followed the composition of TFIIH over time after UV irradiation of repair-proficient or -deficient human cells. We show that TFIIH changes subunit composition in response to DNA damage. The CAK is released from the core during nucleotide excision repair (NER). Using reconstituted in vitro NER assay, we show that XPA catalyzes the detachment of the CAK from the core, together with the arrival of the other NER-specific factors. The release of the CAK from the core TFIIH promotes the incision/excision of the damaged oligonucleotide and thereby the repair of the DNA. Following repair, the CAK reappears with the core TFIIH on the chromatin, together with the resumption of transcription. Our findings demonstrate that the composition of TFIIH is dynamic to adapt its engagement in distinct cellular processes.

Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining.

Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway that is required for assembly of antigen receptor variable region gene segments by V(D)J recombination. Recombination activating gene endonuclease initiates V(D)J recombination by generating DSBs between two V(D)J coding gene segments and flanking recombination signal sequences (RS), with the two coding ends and two RS ends joined by C-NHEJ to form coding joins and signal joins, respectively. During C-NHEJ, recombination activating gene factor generates two coding ends as covalently sealed hairpins and RS ends as blunt 5'-phosphorylated DSBs. Opening and processing of coding end hairpins before joining by C-NHEJ requires the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). However, C-NHEJ of RS ends, which do not require processing, occurs relatively normally in the absence of DNA-PKcs. The XRCC4-like factor (XLF) is a C-NHEJ component that is not required for C-NHEJ of chromosomal signal joins or coding joins because of functional redundancy with ataxia telangiectasia mutated kinase, a protein that also has some functional overlap with DNA-PKcs in this process. Here, we show that XLF has dramatic functional redundancy with DNA-PKcs in the V(D)J SJ joining process, which is nearly abrogated in their combined absence. Moreover, we show that XLF functionally overlaps with DNA-PKcs in normal mouse development, promotion of genomic stability in mouse fibroblasts, and in IgH class switch recombination in mature B cells. Our findings suggest that DNA-PKcs has fundamental roles in C-NHEJ processes beyond end processing that have been masked by functional overlaps with XLF.

Histone methyltransferase DOT1L drives recovery of gene expression after a genotoxic attack.

UV-induced DNA damage causes repression of RNA synthesis. Following the removal of DNA lesions, transcription recovery operates through a process that is not understood yet. Here we show that knocking-out of the histone methyltransferase DOT1L in mouse embryonic fibroblasts (MEF(DOT1L)) leads to a UV hypersensitivity coupled to a deficient recovery of transcription initiation after UV irradiation. However, DOT1L is not implicated in the removal of the UV-induced DNA damage by the nucleotide excision repair pathway. Using FRAP and ChIP experiments we established that DOT1L promotes the formation of the pre-initiation complex on the promoters of UV-repressed genes and the appearance of transcriptionally active chromatin marks. Treatment with Trichostatin A, relaxing chromatin, recovers both transcription initiation and UV-survival. Our data suggest that DOT1L secures an open chromatin structure in order to reactivate RNA Pol II transcription initiation after a genotoxic attack.

Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair.

The classical nonhomologous DNA end-joining (C-NHEJ) double-strand break (DSB) repair pathway in mammalian cells maintains genome stability and is required for V(D)J recombination and lymphocyte development. Mutations in the XLF C-NHEJ factor or ataxia telangiectasia-mutated (ATM) DSB response protein cause radiosensitivity and immunodeficiency in humans. Although potential roles for XLF in C-NHEJ are unknown, ATM activates a general DSB response by phosphorylating substrates, including histone H2AX and 53BP1, which are assembled into chromatin complexes around DSBs. In mice, C-NHEJ, V(D)J recombination, and lymphocyte development are, at most, modestly impaired in the absence of XLF or ATM, but are severely impaired in the absence of both. Redundant functions of XLF and ATM depend on ATM kinase activity; correspondingly, combined XLF and H2AX deficiency severely impairs V(D)J recombination, even though H2AX deficiency alone has little impact on this process. These and other findings suggest that XLF may provide functions that overlap more broadly with assembled DSB response factors on chromatin. As one test of this notion, we generated mice and cells with a combined deficiency for XLF and 53BP1. In this context, 53BP1 deficiency, although leading to genome instability, has only modest effects on V(D)J recombination or lymphocyte development. Strikingly, we find that combined XLF/53BP1 deficiency in mice severely impairs C-NHEJ, V(D)J recombination, and lymphocyte development while also leading to general genomic instability and growth defects. We conclude that XLF is functionally redundant with multiple members of the ATM-dependent DNA damage response in facilitating C-NHEJ and discuss implications of our findings for potential functions of these factors.

Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1).

Classical nonhomologous DNA end-joining (C-NHEJ), which is a major DNA double-strand break (DSB) repair pathway in mammalian cells, plays a dominant role in joining DSBs during Ig heavy chain (IgH) class switch recombination (CSR) in activated B lymphocytes. However, in B cells deficient for one or more requisite C-NHEJ factors, such as DNA ligase 4 (Lig4) or XRCC4, end-joining during CSR occurs by a distinct alternative end-joining (A-EJ) pathway. A-EJ also has been implicated in joining DSBs found in oncogenic chromosomal translocations. DNA ligase 3 (Lig3) and its cofactor XRCC1 are widely considered to be requisite A-EJ factors, based on biochemical studies or extrachromosomal substrate end-joining studies. However, potential roles for these factors in A-EJ of endogenous chromosomal DSBs have not been tested. Here, we report that Xrcc1 inactivation via conditional gene-targeted deletion in WT or XRCC4-deficient primary B cells does not have an impact on either CSR or IgH/c-myc translocations in activated B lymphocytes. Indeed, homozygous deletion of Xrcc1 does not impair A-EJ of I-SceI-induced DSBs in XRCC4-deficient pro-B-cell lines. Correspondingly, substantial depletion of Lig3 in Lig4-deficient primary B cells or B-cell lines does not impair A-EJ of CSR-mediated DSBs or formation of IgH/c-myc translocations. Our findings firmly demonstrate that XRCC1 is not a requisite factor for A-EJ of chromosomal DSBs and raise the possibility that DNA ligase 1 (Lig1) may contribute more to A-EJ than previously considered.

Exploring Leptospira interrogans FDAARGOS_203: Insights into AMR and Anti-Phage Defense.

Leptospira, which are known to be important disease-causing agents transmitted between animals and humans, result in significant illness and, in some cases, significant death in human populations. This purpose of this study was to examine the genomic structure of Leptospira interrogans serovar Copenhageni strain FDAARGOS_203 to identify the specific genetic factors that contribute to antimicrobial resistance (AMR) and defense against phages. The genome, consisting of two contigs totaling 4,630,574 base pairs, underwent thorough examination for protein-coding sequences, transfer RNA genes, and ribosomal RNA genes. A total of twenty-two antibiotic resistance genes that specifically target essential cellular processes such as cell wall synthesis, DNA replication, and protein synthesis have been identified. Significant among these were gidB, gdpD, and ggsA, each involved in separate aspects of antibiotic resistance. In addition, the investigation explored the defense mechanisms of bacteriophages, revealing the presence of defense islands that contain a range of anti-phage systems, including RM_Type_IV, PrrC, Borvo, CAS_Class1-Subtype-IC, and CAS_Class1-Subtype-IB. This comprehensive genomic analysis enhances our understanding of the molecular mechanisms that determine Leptospira's ability to adapt to various environments. The identified genetic factors linked to AMR and defense against phages not only enhance our scientific comprehension, but also provide a basis for focused interventions to reduce the impact of leptospirosis.

Current treatment options for leptospirosis: a mini-review.

Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually. This mini-review explores effective treatment strategies for leptospirosis, considering its epidemiology, clinical manifestations, and current therapeutic approaches. Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. Furthermore, novel treatment options, such as bacteriophages and newly synthesized/natural compounds, are discussed, and the findings are expected to provide insights into promising approaches for combating leptospirosis.

Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.

Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

Exploring Paxlovid Efficacy in COVID-19 Patients with MAFLD: Insights from a Single-Center Prospective Cohort Study.

This study investigates the intricate interplay between Metabolic-associated Fatty Liver Disease (MAFLD) and COVID-19, exploring the impact of MAFLD on disease severity, outcomes, and the efficacy of the antiviral agent Paxlovid (nirmatrelvir/ritonavir). MAFLD, affecting a quarter of the global population, emerges as a potential risk factor for severe COVID-19, yet the underlying pathophysiological mechanisms remain elusive. This study focuses on the clinical significance of Paxlovid, the first orally bioavailable antiviral agent granted Emergency Use Authorization in the United States. Notably, outcomes from phase II/III trials exhibit an 88% relative risk reduction in COVID-19-associated hospitalization or mortality among high-risk patients. Despite conflicting data on the association between MAFLD and COVID-19 severity, this research strives to bridge the gap by evaluating the effectiveness of Paxlovid in MAFLD patients with COVID-19, addressing the scarcity of relevant studies.

Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes.

COVID-19 remains a significant global concern, particularly for individuals with type 2 diabetes who face an elevated risk of hospitalization and mortality. Metformin, a primary treatment for type 2 diabetes, demonstrates promising pleiotropic properties that may substantially mitigate disease severity and expedite recovery. Our study of the gut microbiota and the mRNA expression of pro-inflammatory and anti-inflammatory T-lymphocyte subpopulations showed that metformin increases bacterial diversity while modulating gene expression related to T-lymphocytes. This study found that people who did not take metformin had a downregulated expression of FOXP3 by 6.62-fold, upregulated expression of RORC by 29.0-fold, and upregulated TBX21 by 1.78-fold, compared to the control group. On the other hand, metformin patients showed a 1.96-fold upregulation in FOXP3 expression compared to the control group, along with a 1.84-fold downregulation in RORC expression and an 11.4-fold downregulation in TBX21 expression. Additionally, we found a correlation with gut microbiota (F/B ratio and alpha-diversity index) and pro-inflammatory biomarkers. This novel observation of metformin's impact on T-cells and gut microbiota opens new horizons for further exploration through clinical trials to validate and confirm our data. The potential of metformin to modulate immune responses and enhance gut microbiota diversity suggests a promising avenue for therapeutic interventions in individuals with type 2 diabetes facing an increased risk of severe outcomes from COVID-19.

Comprehensive Analysis of Antiphage Defense Mechanisms: Serovar-Specific Patterns.

Leptospirosis is a major zoonotic disease caused by pathogenic spirochetes in the genus Leptospira, affecting over a million people annually and causing approximately 60,000 deaths. Leptospira interrogans, a key causative agent, likely possesses defense systems against bacteriophages (leptophages), yet these systems are not well understood. We analyzed 402 genomes of L. interrogans using the DefenseFinder tool to identify and characterize the antiphage defense systems. We detected 24 unique systems, with CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated proteins), PrrC, Borvo, and Restriction-Modification (R-M) being the most prevalent. Notably, Cas were identified in all strains, indicating their central role in phage defense. Furthermore, there were variations in the antiphage system distribution across different serovars, suggesting unique evolutionary adaptations. For instance, Retron was found exclusively in the Canicola serovar, while prokaryotic Argonaute proteins (pAgo) were only detected in the Grippotyphosa serovar. These findings significantly enhance our understanding of Leptospira's antiphage defense mechanisms. They reveal the potential for the development of serovar-specific phage-based therapies and underscore the importance of further exploring these defense systems.

Exploring the interplay between posttraumatic stress disorder, gut microbiota, and inflammatory biomarkers: a comprehensive meta-analysis.

Introduction: Posttraumatic stress disorder (PTSD) is the most common mental health disorder to develop following exposure to trauma. Studies have reported conflicting results regarding changes in immune biomarkers and alterations in the abundance of bacterial taxa and microbial diversity in patients with PTSD. Aim: The purpose of this meta-analysis is to summarize existing studies examining gut microbiota characteristics and changes in immune biomarkers in patients with PTSD. Methods: Relevant studies were systematically searched in PubMed, Scopus, and Embase, published in English between January 1, 1960, and December 1, 2023. The outcomes included changes in abundance and diversity in gut microbiota (gut microbiota part) and changes in immune biomarkers (immune part). Results: The meta-analysis included a total of 15 studies, with 9 focusing on changes in inflammatory biomarkers and 6 focusing on changes in gut microbiota composition in patients with PTSD. No differences were observed between groups for all inflammatory biomarkers (P≥0.05). Two of the six studies found that people with PTSD had less alpha diversity. However, the overall Standardized Mean Difference (SMD) for the Shannon Diversity Index was not significant (SMD 0.27, 95% CI -0.62-0.609, p = 0.110). Regarding changes in abundance, in two of the studies, a significant decrease in Lachnospiraceae bacteria was observed. Conclusion: This meta-analysis provides a comprehensive overview of gut microbiota characteristics in PTSD, suggesting potential associations with immune dysregulation. Future research should address study limitations, explore causal relationships, and consider additional factors influencing immune function in individuals with PTSD. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023476590.