Search

Inflammation and synapse loss have been associated with deficits in social behavior and are involved in pathophysiology of many neuropsychiatric disorders. Synapse loss, characterized by reduction in dendritic spines can significantly disrupt synaptic connectivity and neural circuitry underlying social behavior. Chronic stress is known to induce loss of spines and dendrites in the prefrontal cortex (PFC), a brain region implicated in social behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of type I Interferon (IFN-I) signaling in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found increased expression of type I IFN receptor (IFNAR) in microglia following CUS. Conditional knockout of microglial IFNAR in adult mice rescued CUS-induced social behavior deficits and synapse loss. Bulk RNA sequencing data show that microglial IFNAR deletion attenuated CUS-mediated changes in the expression of genes such as Keratin 20 (Krt20), Claudin-5 (Cldn5) and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. Cldn5 and Nr4a1 are known for their roles in synaptic plasticity. Krt20 is an intermediate filament protein responsible for the structural integrity of epithelial cells. The reduction in Krt20 following CUS presents a novel insight into the potential contribution of cytokeratin in stress-induced alterations in neuroplasticity. Overall, these results suggest that microglial IFNAR plays a critical role in regulating synaptic plasticity and social behavior deficits associated with chronic stress conditions., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The animal studies were approved (#AWC-20-0148) by the Animal Welfare Committee (AWC) of the University of Texas Health Science Center at Houston (UTHealth Houston)., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Chronic stress, a risk factor for many neuropsychiatric conditions, causes dysregulation in the immune system in both humans and animal models. Additionally, inflammation and synapse loss have been associated with deficits in social behavior. The complement system, a key player of innate immunity, has been linked to social behavior impairments caused by chronic stress. However, it is not known whether complement inhibition can help prevent neuroinflammation and behavioral deficits caused by chronic stress. In this study, we investigated the potential of a site-targeted complement inhibitor to ameliorate chronic stress-induced changes in social behavior and inflammatory markers in the prefrontal cortex (PFC) and hippocampus. Specifically, we investigated the use of C2-Crry, which comprises a natural antibody-derived single-chain antibody (ScFv) targeting domain-designated C2, linked to Crry, a C3 activation inhibitor. The C2 targeting domain recognizes danger-associated molecular patterns consisting of a subset of phospholipids that become exposed following cell stress or injury. We found that systemic administration of C2-Crry attenuated chronic stress-induced social behavioral impairments in mice. Furthermore, C2-Crry administration significantly decreased microglia/macrophage and astrocyte activation markers in the PFC and hippocampus. These findings suggest that site-targeted complement inhibition could offer a promising, safe, and effective strategy for treating chronic stress induced behavioral and immune function disorders.

Organophosphates (OPs) are found in hundreds of important products used worldwide; however, they have been associated with adverse long-term health consequences ranging from neurodevelopmental deficits to age-related neurological diseases. OP exposure has also been implicated in Gulf War Illness; a cluster of medically unexplained chronic symptoms estimated to affect 25-32% of veterans of the Persian Gulf war in 1991. The development of multiple types of chronic illnesses in these veterans at an early age compared to the general population has led to the suggestion that they are experiencing signs of premature or accelerated aging. The process of cellular senescence and the development of the senescence-associated secretory phenotype (SASP) is believed to lead to chronic inflammation, chronic illnesses, as well as accelerated biological aging, and a role of environmental exposures in these processes has been suggested, but not extensively studied to date. In the studies described here, we evaluated the persistent effects of a single (acute) exposure of a representative nerve agent OP, diisopropylfluorophosphate (DFP) 4.0 mg/kg on cognitive function, noncognitive behaviors, cellular senescence markers and proinflammatory cytokines in the mouse brain. The results indicated modest, but persistent DFP-related impairments in spatial learning and working memory, but not contextual or cued fear conditioning. DFP exposure was also not associated with negative effects on weight or impairments of the various noncognitive (e.g., motor function or exploratory activity) behavioral assessments. Both histology and quantitative PCR experiments indicated that DFP was associated with persistent alterations in several senescence markers and proinflammatory cytokines in brain regions that are relevant to the performance of the memory-related tasks (e.g., hippocampus, prefrontal cortex). The results thus suggest that single acute exposures to OPs like DFP can lead to persistent impairments in specific domains of cognition that may be related to alterations in cellular senescence and inflammaging in the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Terry, Beck, Zona, Itokazu, Tripathi, Madeshiya and Pillai.)

Introduction: The prostatic disorder is associated with benign prostatic hyperplasia (BPH) and prostate cancer (CaP). Evidently, prevalent transcription factors and signaling pathways define their relationship. The etiology of the prostatic disorder is multifactorial including heavy metal toxicity like lead (Pb), Cadmium (Cd), and genetic factors. This study elucidates the association between heavy metal toxicity Pb, Cd, and CYP1A1 gene polymorphism with BPH and CaP., Methods: a case-control study with (BPH, n = 104), (CaP, n = 58) and (controls, n =107) patients. Heavy metal Pb and Cd estimation by atomic absorption spectrophotometer. The polymorphism of the CYP1A1 T>C (rs4646903) gene was analyzed byPCR-RFLP., Result: Higher levels of Pb and Cd were found in BPH and CaP followed by the control group (P-value: < 0.05). Pb and Cd show a significant correlation among prostate volume in CaP. Additionally, PSA, IPSS score, and pre void volume were positively co-related with Pb in BPH patients. The posthoc test defines the level of Pb and Cd as significantly elevated in the mutant genotype, highest among homozygous mutant genotype of CYP1A1gene among BPH. In CaP, Pb is significantly higher among the homozygous mutant type of CYP1A1 gene. The risk is also influenced by smoking, tobacco, and alcohol., Conclusion: The heavy metal toxicity Pb and Cd were reported to raise the risk of BPH and CaP. However, a person with heavy metal toxicity especially in BPH has a high-risk genetic susceptibility to the CYP1A1 gene in the north Indian population., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The recent discovery of innate lymphoid cells (ILCs) has provided new insights into our understanding of the pathogenesis of many disease conditions with immune dysregulation. Type 1 innate lymphoid cells (ILC1s) induce type I immunity and are characterized by the expression of signature cytokine IFN-γ and the master transcription factor T-bet; ILC2s stimulate type II immune responses and are defined by the expression of signature cytokines IL-5 and IL-13, and transcription factors ROR-α and GATA3; ILC3s requires the transcription factor RORγt and produce IL-22 and IL-17. ILCs are largely tissue-resident and are enriched at barrier surfaces of the mammalian body. Increasing evidence shows that inflammation is involved in the pathogenesis of depression. Although few studies have directly investigated the role of ILCs in depression, several studies have examined the levels of cytokines produced by ILCs in depressed subjects. This review summarizes the potential roles of ILCs in depression. A better understanding of the biology of ILCs may lead to the development of new therapeutic strategies for the management of depression.

Scope: Reactive oxygen species production by innate immune cells plays a central role in host defense against invading pathogens at wound-site. A weakened host-defense results in persistent infection leading to wound chronicity. Fermented Papaya Preparation (FPP), a complex sugar matrix, bolsters respiratory burst activity and improves wound healing outcomes in chronic wound patients. The objective of the current study was to identify underlying molecular factor/s responsible for augmenting macrophage host defense mechanisms following FPP supplementation., Methods and Results: In depth LC-MS/MS analysis of cells supplemented with FPP led to identification of myo-inositol as a key determinant of FPP activity towards improving macrophage function. Myo-inositol, in quantities that is present in FPP, significantly improved macrophage respiratory burst and phagocytosis via de novo synthesis pathway of ISYNA1. In addition, myo-inositol transporters, HMIT and SMIT1, played a significant role in such activity. Blocking these pathways using siRNA attenuated FPP-induced improved macrophage host defense activities. FPP supplementation emerged as a novel approach to increase intracellular myo-inositol levels. Such supplementation also modified wound microenvironment in chronic wound patients to augment myo-inositol levels in wound fluid., Conclusion: These observations indicate that myo-inositol in FPP influences multiple aspects of macrophage function critical for host defense against invading pathogens., (© 2022 Wiley-VCH GmbH.)

Impaired re-epithelialization characterized by hyperkeratotic nonmigratory wound epithelium is a hallmark of nonhealing diabetic wounds. In chronic wounds, the copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte (KC) activator. This work sought to understand the signal transduction pathway responsible for wound re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57BL/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering KC proliferation and migration. OSM activated the Jak-signal transducer and activator of transcription pathway as manifested by signal transducer and activator of transcription 3 phosphorylation. Such signal transduction in the human KC induced TP63, the master regulator of KC function. Elevated TP63 induced ITGB1, a known effector of KC migration. In diabetic wounds, OSM was more abundant than the level in nondiabetic wounds. However, in diabetic wounds, OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued the compromised KC migration caused by glycated OSM. Finally, topical application of recombinant OSM improved KC migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound site, OSM is inactivated by glycation, and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Increased levels of pro-inflammatory cytokines have been reported in postmortem brain samples and in the blood of depressed subjects. However, the inflammatory pathways that lead to depressive-like symptoms are not well understood. Using the learned helplessness (LH) model of depression, we examined the role of C1q, the initiator of classical complement pathway in mediating stress-induced depressive-like behavior in mice. We observed no significant changes in social behavior, despair behavior, spatial memory, and aggressive behavior between the wild type (WT) and C1q knockout (KO) mice. However, C1q deletion exacerbated the inescapable electric foot shock-induced learned helplessness behavior in mice. We found significant reductions in C1q mRNA levels in the prefrontal cortex (PFC) of WT helpless mice as compared to the naïve mice. Increased levels of pro-inflammatory cytokines were found in the PFC of C1q KO mice. These findings suggest that classical complement pathway-mediated learned helplessness behavior is accompanied by neuroinflammatory changes under stressful conditions., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Metabolic syndrome (MetS) is an inflammatory disorder, in which various cytokines play important role in tilting balance towards disease state. Interleukin-10 (IL-10) is an important antiinflammatory cytokine, but its genetic polymorphisms and serum levels in Indian MetS subjects are unknown. Three IL-10 gene polymorphisms (-1082A>G (rs1800896), -819C>T (rs1800872) and -592C>A (rs1800871)) were genotyped with PCR-RFLP in MetS subjects (n = 384) and age/sex matched control subjects (n = 386). Serum IL-10 was measured using enzyme-linked immunosorbent assay. Serum IL-10 level was significantly low in MetS subject and significantly correlated with clinicobiochemical parameters of MetS. Of three investigated promoter polymorphisms, IL-10 -819C> T and -592C>A were significantly associated with risk of MetS. The mutant alleles -819T and -592A of IL-10 gene polymorphism were significantly higher in MetS subjects compared to controls. Of the four different haplotypes obtained, common ACC haplotype and rare GTA haplotype of IL-10 polymorphisms were associated with MetS. The mean of fasting insulin and HOMA-IR were significantly different between the genotypes of both -819 C>T and -592C>A polymorphisms of IL-10 in MetS subjects. These results suggested that polymorphisms in IL-10 gene (-819C>T and -592C>A), haplotypes (ACC and GTA) and serum level are significantly associated with risk of MetS. IL- 10 -819C>T and -592C>A polymorphic variants are also significantly associated with insulin level and homeostasis model assessment-insulin resistance in north Indian MetS subjects.

Monocyte chemoattractant protein-1 (MCP-1), encoded by gene CCL-2 (Chemokine C-C motif 2), is the ligand of chemokine receptor CCR-2. Concurrent clinical alteration in several metabolic aspects, including central obesity, dysglycemia, dyslipidemia and hypertension, is clinically characterized as metabolic syndrome (MetS). Role of MCP-1 in each of these aspects has been established in vitro and in animal studies as well. We here report genetic association of -2518 A>G MCP-1 (rs 1024611) gene polymorphism and level of MCP-1 with MetS in North Indian subjects. We analysed (n=386, controls and n=384, MetS subjects) for MCP-1 gene polymorphism using PCR-RFLP, its serum level using ELISA, anthropometric (body mass index, waist and hip circumferences, waist-hip ratio and blood pressure) and biochemical (serum lipids, plasma glucose and insulin levels) variables in a genetic association study. The body mass index, waist circumference, hip circumference, waist-hip ratio, blood pressure, serum lipids, insulin and fasting plasma glucose level were significantly high in MetS subjects. Regression analysis showed significant correlation of body mass index, waist and hip circumference, systolic/diastolic blood pressure, fasting glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein fasting insulin and HOMA-IR with MetS. MCP-1 allele and genotype were significantly associated with MetS. Serum MCP-1 level was high in overall cases. In conclusions, the MCP-1 2518A>G (rs 1024611) polymorphism has significant impact on risk of MetS, and MCP-1 level correlates with anthropometric and biochemical risk factors of MetS., (© 2015 John Wiley & Sons Ltd.)

Background: Cholelithiasis is associated in 54%-98% of patients with carcinoma of the gallbladder, and a high incidence among females suggests a role of female hormones in the etiology of the disease. Cytochrome P450C17α (CYP-17) is a key enzyme involved in estrogen metabolism and polymorphisms in CYP-17 are associated with altered serum levels of estrogens. Thus, we investigated whether the CYP-17 MspA1 gene polymorphism might impact on risk of gall bladder cancers or gallstones, as well as to determine if this gene polymorphism might be linked with estrogen serum levels and lipid profile among the North Indian gall bladder cancer or gallstone patients., Materials and Methods: CYP-17 gene polymorphisms (MspA1) were genotyped with PCR-RFLP in cancer patients (n=96), stone patients (n=102), cancer+stone patients (n=52) and age/sex matched control subjects (n=256). Lipid profile was estimated using a commercial kit and serum estrogen was measured using ELISA., Results: The majority of the patients in all groups were females. The lipid profile and estrogen level were significantly higher among the study as compared to control groups. The frequency of mutant allele A2 of CYP17 MspA1 gene polymorphism was higher among cancer (OR=5.13, 95% CI+3.10-8.51, p=0.0001), stone (OR=5.69, 95%CI=3.46-9.37, p=0.0001) and cancer+stone (OR=3.54, 95%CI=1.90-6.60, p=0.0001) when compared with the control group. However there was no significant association between genotypes of CYP17 MspA1 gene polymorphism and circulating serum level of estrogen and lipid profile., Conclusions: A higher frequency of mutant genotype A1A2 as well as mutant allele A2 of CYP-17 gene polymorphism is significantly associated with risk of gallbladder cancer and stones. Elevated levels of estrogen and an altered lipid profile can be used as predictors ofgall bladder stones and cancer in post menopausal females in India.