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Cureus May 2024Background There is little evidence that pesticide exposure is the primary cause of acquired aplastic anemia (AAA), even though the prevalence of aplastic anemia (AA) is...
Background There is little evidence that pesticide exposure is the primary cause of acquired aplastic anemia (AAA), even though the prevalence of aplastic anemia (AA) is substantially higher in underdeveloped countries than in affluent countries. AA caused by pesticides has not yet been fully understood. This study aimed to examine the potential link between plasma levels of malondialdehyde (MDA) and organochlorine pesticides (OCPs) as risk factors for developing AAA in the North Indian population. Methods This case-control study was conducted at a tertiary care hospital in North India. A total of 99 participants were chosen for the study, of whom 45 were cases of AA. These cases attended the Clinical Hematology department over a period of 1.5 years (May 2018 to November 2019). Forty-five controls were age and sex-matched, apparently healthy subjects. Written informed consent was obtained from each subject before performing the study. Exclusion criteria included patients unwilling to give consent, those using medication to treat AA, those genetically predisposed to AA, those with characteristics including granuloma and dysplasia of bone marrow, any other systemic illness, and subjects with a history of smoking, drinking, or using tobacco in any form. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to evaluate the plasma levels of organochlorines. The estimation of plasma MDA, i.e., the lipid peroxide content, was measured. Results The severity of AA is significantly associated with plasma levels of α-Hexachlorocyclohexane (p = 0.040), Heptachlor (p = 0.006), Aldrin (p < 0.001), p,p'-Dichlorodiphenyldichloroethane (p = 0.004), Endosulfan sulfate (p = 0.010), and Methoxychlor (p = 0.001). There was a statistically non-significant difference in MDA levels between cases and controls (p = 0.145); however, a statistically significant linear increase in MDA levels (p < 0.001) was observed according to the severity of AA. Conclusion Our study suggests that oxidative stress may be linked to the severity of AA. Pesticide exposure (plasma organochlorine levels) could act as a stressor, potentially initiating an alarmin response of oxidative stress in the form of lipid peroxidation (MDA) from damaged tissue, which could then lead to suppression of hematopoiesis and be a possible factor in the development of AA.
PubMed: 38841016
DOI: 10.7759/cureus.59698 -
Parasite Immunology Jun 2024Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the... (Review)
Review
Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the roles of the receptor for advanced glycation end products (RAGE) during repeated infestations by the tick Haemaphysalis longicornis using RAGE mice. In primary infestation, a large blood pool developed, which was flooded with numerous RBCs, especially during the rapid feeding phase of the tick both in wild-type (wt) and RAGE mice. Very few inflammatory cells were detected around the zones of haemorrhage in the primary infestations. However, the number of inflammatory cells gradually increased in the subsequent tick infestations, and during the third infestations, the number of inflammatory cells reached to the highest level (350.3 ± 16.8 cells/focus). The site of attachment was totally occupied by the inflammatory cells in wt mice, whereas very few cells were detected at the ticks' biting sites in RAGE mice. RAGE was highly expressed during the third infestation in wt mice. In the third infestation, infiltration of CD44 lymphocytes, eosinophils and expression of S100A8 and S100B significantly increased at the biting sites of ticks in wt, but not in RAGE mice. In addition, peripheral eosinophil counts significantly increased in wt but not in RAGE mice. Taken together, our study revealed that RAGE-mediated inflammation and eosinophils played crucial roles in the tick-induced inflammatory reactions.
Topics: Animals; Ixodidae; Receptor for Advanced Glycation End Products; Mice; Inflammation; Mice, Knockout; Tick Infestations; Mice, Inbred C57BL; Female; Feeding Behavior; Haemaphysalis longicornis
PubMed: 38838041
DOI: 10.1111/pim.13039 -
Frontiers in Immunology 2024Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus...
Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus infection (RSV). The current understanding of ILC2 activation during RSV infection, is that ILC2s are activated by alarmins, including IL-33, released from airway epithelial cells in response to viral-mediated damage. Thus, high levels of RSV neutralizing maternal antibody generated from maternal immunization would be expected to reduce IL-33 production and mitigate ILC2 activation. Here we report that lung ILC2s from mice born to RSV-immunized dams become activated despite undetectable RSV replication. We also report, for the first time, expression of activating and inhibitory Fcgamma receptors on ILC2s that are differentially expressed in offspring born to immunized versus unimmunized dams. Alternatively, ex vivo IL-33-mediated activation of ILC2s was mitigated following the addition of antibody: antigen immune complexes. Further studies are needed to confirm the role of Fcgamma receptor ligation by immune complexes as an alternative mechanism of ILC2 regulation in RSV-associated eosinophilic lung inflammation.
Topics: Animals; Respiratory Syncytial Virus Infections; Mice; Female; Mice, Inbred BALB C; Lung; Interleukin-33; Respiratory Syncytial Viruses; Lymphocytes; Immunization; Receptors, IgG; Antibodies, Viral; Pregnancy; Respiratory Syncytial Virus Vaccines
PubMed: 38827738
DOI: 10.3389/fimmu.2024.1374818 -
Experimental & Molecular Medicine Jun 2024Interleukin-33 (IL-33), a member of the IL-1 family, is a cytokine released in response to tissue damage and is recognized as an alarmin. The multifaceted roles of IL-33... (Review)
Review
Interleukin-33 (IL-33), a member of the IL-1 family, is a cytokine released in response to tissue damage and is recognized as an alarmin. The multifaceted roles of IL-33 in tumor progression have sparked controversy within the scientific community. However, most findings generally indicate that endogenous IL-33 has a protumor effect, while exogenous IL-33 often has an antitumor effect in most cases. This review covers the general characteristics of IL-33 and its effects on tumor growth, with detailed information on the immunological mechanisms associated with dendritic cells (DCs). Notably, DCs possess the capability to uptake, process, and present antigens to CD8 T cells, positioning them as professional antigen-presenting cells. Recent findings from our research highlight the direct association between the tumor-suppressive effects of exogenous IL-33 and a novel subset of highly immunogenic cDC1s. Exogenous IL-33 induces the development of these highly immunogenic cDC1s through the activation of other ST2 immune cells both in vivo and in vitro. Recognizing the pivotal role of the immunogenicity of DC vaccines in DC-based tumor immunotherapy, we propose compelling methods to enhance this immunogenicity through the addition of IL-33 and the promotion of highly immunogenic DC generation.
PubMed: 38825642
DOI: 10.1038/s12276-024-01249-4 -
Frontiers in Immunology 2024During inflammation and tissue regeneration, the alarmin High Mobility Group Box 1 (HMGB1), in its reduced isoform, enhances the activity of the chemokine CXCL12,...
During inflammation and tissue regeneration, the alarmin High Mobility Group Box 1 (HMGB1), in its reduced isoform, enhances the activity of the chemokine CXCL12, forming a heterocomplex that acts via the chemokine receptor CXCR4. Despite the established roles of both HMGB1 and CXCL12 in tumor progression and metastatic spread to distal sites, the role of the CXCL12/HMGB1 heterocomplex in cancer has never been investigated. By employing a newly established mass spectrometry protocol that allows an unambiguous distinction between reduced (red-HMGB1) and oxidized (ox-HMGB1) HMGB1 isoforms in cell lysates, we demonstrate that human epithelial cells derived from breast (MCF-7 and MDA-MB-231) and prostate (PC-3) cancer predominantly express red-HMGB1, while primary CD3 T lymphocytes from peripheral blood express both HMGB1 isoforms. All these cancer cells release HMGB1 in the extracellular microenvironment together with varying concentrations of thioredoxin and thioredoxin reductase. The CXCL12/HMGB1 heterocomplex enhances, via CXCR4, the directional migration and invasiveness of cancer cells characterized by high metastatic potential that possess a fully active thioredoxin system, contributing to maintain red-HMGB1. On the contrary, cancer cells with low metastatic potential, lack thioredoxin reductase, promptly uptake CXCL12 and fail to respond to the heterocomplex. Our study demonstrates that the responsiveness of cancer cells to the CXCL12/HMGB1 heterocomplex, resulting in enhanced cell migration and invasiveness, depends on the maintenance of HMGB1 in its reduced isoform, and suggests disruption of the heterocomplex as a potential therapeutic target to inhibit invasion and metastatic spread in cancer therapies.
Topics: Humans; HMGB1 Protein; Receptors, CXCR4; Cell Movement; Chemokine CXCL12; Protein Isoforms; Cell Line, Tumor; Female; Tumor Microenvironment; Male; Neoplasms
PubMed: 38803493
DOI: 10.3389/fimmu.2024.1358800 -
Molecular Cancer Therapeutics May 2024AB598 is a CD39 inhibitory antibody being pursued for the treatment of solid tumors in combination with chemotherapy and immunotherapy. CD39 metabolizes extracellular...
AB598 is a CD39 inhibitory antibody being pursued for the treatment of solid tumors in combination with chemotherapy and immunotherapy. CD39 metabolizes extracellular ATP (eATP), an alarmin capable of promoting anti-tumor immune responses, into adenosine, an immuno-inhibitory metabolite. By inhibiting CD39, the consumption of eATP is reduced, resulting in a pro-inflammatory milieu in which eATP can activate myeloid cells to promote anti-tumor immunity. The preclinical characterization of AB598 provides a mechanistic rationale for combining AB598 with chemotherapy in the clinic. Chemotherapy can induce ATP release from tumor cells and, when preserved by AB598, both chemotherapy-induced eATP and exogenously added ATP promote the function of monocyte-derived dendritic cells via P2Y11 signaling. Inhibition of CD39 in the presence of ATP can promote inflammasome activation in in vitro-derived macrophages, an effect mediated by P2X7. In a MOLP8 murine xenograft model, AB598 results in full inhibition of intratumoral enzymatic activity, an increase in intratumoral ATP, a decrease of extracellular CD39 on tumor cells, and ultimately, control of tumor growth. In cynomolgus monkeys, systemically dosed AB598 results in effective enzymatic inhibition in tissues, full peripheral and tissue target engagement, and a reduction in cell surface CD39 both in tissues and in the periphery. Taken together, these data support a promising therapeutic strategy of harnessing the eATP generated by standard-of-care chemotherapies to prime the tumor microenvironment for a productive anti-tumor immune response.
PubMed: 38797955
DOI: 10.1158/1535-7163.MCT-23-0865 -
Pharmaceuticals (Basel, Switzerland) May 2024The Pulsatilla decoction is a well-known herbal remedy used in clinical settings for treating vulvovaginal candidiasis (VVC). However, the specific mechanism that makes...
Transcriptomics Reveals Effect of Decoction Butanol Extract in Alleviating Vulvovaginal Candidiasis by Inhibiting Neutrophil Chemotaxis and Activation via TLR4 Signaling.
The Pulsatilla decoction is a well-known herbal remedy used in clinical settings for treating vulvovaginal candidiasis (VVC). However, the specific mechanism that makes it effective is still unclear. Recent studies have shown that in cases of VVC, neutrophils recruited to the vagina, influenced by heparan sulfate (HS), do not successfully engulf (). Instead, they release many inflammatory factors that cause damage to the vaginal mucosa. This study aims to understand the molecular mechanism by which the n-butanol extract of Pulsatilla decoction (BEPD) treats VVC through transcriptomics. High-performance liquid chromatography was used to identify the primary active components of BEPD. A VVC mouse model was induced using an estrogen-dependent method and the mice were treated daily with BEPD (20 mg/kg, 40 mg/kg, and 80 mg/kg) for seven days. The vaginal lavage fluid of the mice was analyzed for various experimental indices, including fungal morphology, fungal burden, degree of neutrophil infiltration, and cytokines. Various assessments were then performed on mouse vaginal tissues, including pathological assessment, immunohistochemistry, immunofluorescence, Western blot (WB), quantitative real-time PCR, and transcriptome assays. Our results showed that BEPD reduced vaginal redness and swelling, decreased white discharge, inhibited hyphae formation, reduced neutrophil infiltration and fungal burden, and attenuated vaginal tissue damage compared with the VVC model group. The high-dose BEPD group even restored the damaged vaginal tissue to normal levels. The medium- and high-dose groups of BEPD also significantly reduced the levels of IL-1β, IL-6, TNF-α, and LDH. Additionally, transcriptomic results showed that BEPD regulated several chemokine (CXCL1, CXCL3, and CXCL5) and S100 alarmin (S100A8 and S100A9) genes, suggesting that BEPD may treat VVC by affecting chemokine- and alarmin-mediated neutrophil chemotaxis. Finally, we verified that BEPD protects the vaginal mucosa of VVC mice by inhibiting neutrophil recruitment and chemotaxis in an animal model of VVC via the TLR4/MyD88/NF-κB pathway. This study provides further evidence to elucidate the mechanism of BEPD treatment of VVC.
PubMed: 38794163
DOI: 10.3390/ph17050594 -
International Journal of Molecular... May 2024Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and...
Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and labor. Although the specific triggers for their release in utero remain unclear, it is thought that they may contribute to the initiation of parturition by influencing cellular stress mechanisms that make the fetal membranes (FMs) more susceptible to rupture. DAMPs induce inflammation in many different tissue types. Indeed, they precipitate the subsequent release of several proinflammatory cytokines that are known to be key for the weakening of FMs. Previously, we have shown that in vitro stretch of human amnion epithelial cells (hAECs) induces a cellular stress response that increases high-mobility group box-1 (HMGB1) secretion. We have also shown that cell-free fetal DNA (cffDNA) induces a cytokine response in FM explants that is fetal sex-specific. Therefore, the aim of this work was to further investigate the link between stretch and the DAMPs HMGB1 and cffDNA in the FM. These data show that stretch increases the level of cffDNA released from hAECs. It also confirms the importance of the sex of the fetus by demonstrating that female cffDNA induced more cellular stress than male fetuses. Our data treating hAECs and human amnion mesenchymal cells with HMGB1 show that it has a differential effect on the ability of the cells of the amnion to upregulate the proinflammatory cytokines and propagate a proinflammatory signal through the FM that may weaken it. Finally, our data show that sulforaphane (SFN), a potent activator of Nrf2, is able to mitigate the proinflammatory effects of stretch by decreasing the levels of HMGB1 release and ROS generation after stretch and modulating the increase of key cytokines after cell stress. HMGB1 and cffDNA are two of the few DAMPs that are known to induce cytokine release and matrix metalloproteinase (MMP) activation in the FMs; thus, these data support the general thesis that they can function as potential central players in the normal mechanisms of FM weakening during the normal distension of this tissue at the end of a normal pregnancy.
Topics: Humans; HMGB1 Protein; Female; Pregnancy; Inflammation; Extraembryonic Membranes; Cell-Free Nucleic Acids; Male; Amnion; Cytokines; Epithelial Cells; Cells, Cultured; Alarmins
PubMed: 38791199
DOI: 10.3390/ijms25105161 -
Cell Reports. Medicine Jun 2024Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the...
Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.
Topics: Cancer-Associated Fibroblasts; Humans; Esophageal Neoplasms; Drug Resistance, Neoplasm; Calgranulin A; Animals; Mice; Tumor Microenvironment; Cell Line, Tumor; Cellular Reprogramming; Signal Transduction; Basigin; rhoA GTP-Binding Protein; Esophageal Squamous Cell Carcinoma; Xenograft Model Antitumor Assays; Female
PubMed: 38776909
DOI: 10.1016/j.xcrm.2024.101576 -
The Journal of Dermatology May 2024Malignant cutaneous melanoma is the leading cause of death for skin cancer to date, with globally increasing incidence rates. In this epidemiological scenario,... (Review)
Review
Malignant cutaneous melanoma is the leading cause of death for skin cancer to date, with globally increasing incidence rates. In this epidemiological scenario, international scientific research is exerting efforts to identify new clinical strategies aimed at the prognostic amelioration of the disease. Very promising and groundbreaking in this context is the scientific interest related to alarmins and their pioneering utility in the setting of the pathogenetic understanding, diagnosis, prognosis, and therapy for malignant cutaneous melanoma. However, the scientific investigations on this matter should not overlook their still well-presented dual and contradictory role. The aim of our critical analysis is to provide an up-to-date overview of the emerging evidence concerning the dichotomous role of alarmins in the aforementioned clinical settings. Our literature revision was based on the extensive body of both preclinical and clinical findings published on the PubMed database over the past 5 years. In addition to this, we offer a special focus on potentially revolutionary new therapeutic frontiers, which, on the strength of their earliest successes in other clinical areas, could inaugurate a new era of personalized and precision medicine in the field of dermato-oncology.
PubMed: 38775220
DOI: 10.1111/1346-8138.17278