Search Results (75)

Neuropathic pain, a chronic condition arising from injury or dysfunction of the somatosensory nervous system, is characterized by persistent hypersensitivity and spontaneous pain. The chemokine receptor CCR5 (C-C motif chemokine receptor 5) has recently been identified as a critical mediator in neuroinflammation and neuropathic pain signaling pathways. Expressed on immune cells and neurons, CCR5 regulates immune cell recruitment and activation, thereby contributing to neuronal sensitization and maintenance of pain states. This review examines the currently characterized molecular mechanisms through which CCR5 modulates neuropathic pain pathophysiology and assesses the potential of CCR5 antagonists as novel therapeutic agents for the management of chronic neuropathic pain. Understanding the involvement of CCR5 in pain modulation may facilitate the development of targeted treatments with improved efficacy and safety profiles. Full article

Misregulation of C-C chemokine receptor 7 (CCR7) has been linked to multiple autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, and ankylosing spondylitis. As a G-protein-coupled receptor, located on the cell membrane, CCR7 can be targeted by inhibiting one of its two ligands, C-C chemokine ligand 19 (CCL19), to regulate its function. In this study, we examined signaling events downstream of CCL19 binding that provide a mechanism for regulation of the immune response. We used a CCR7 antagonist, CCL19_8-83, in immune studies in vivo, as a platform for a pharmaceutical to define the molecular events that are involved in regulating the humoral adaptive immune response. We found that in the presence of a T-cell-dependent antigen, C57BL/6 mice treated during antigen exposure with CCL19_8-83 generated significantly higher levels of IgG1, the dominant isotype in extracellular bacterial infections that can activate complement, and IgG2c, the dominant isotype during viral and intracellular bacterial infections. Inhibiting ERK5 signaling downstream of CCR7 activation by CCL19, or disruption of CCL19 expression in CCL19^−/− mice, also resulted in higher levels of IgG1 when compared to control mice. Differences in levels of IL-4 or other cytokines or lymphocyte types between wild-type and ERK5-deficient T cells did not account for antibody levels. Since pertussis-toxin-induced inhibition of lymphocyte chemotaxis is linked to elevated levels of IgG, we examined the effect of ERK5 on chemotaxis to CCR7 ligand CCL19. We found that disruption of ERK5 in T cells, or global disruption of CCL19 or CCR7, inhibited chemotaxis of T cells to CCL19, a mechanism that enhances sensitization during the exposure to an immunogen. Since CCR7 and its ligands have been linked to autoimmunity, these studies may provide insight into mechanisms that can be targeted to control autoimmune responses. Full article

Ferritic/martensitic (F/M) steel is a candidate material for key structures in fourth-generation nuclear energy systems (such as fusion reactors and fast reactors). Irradiation hardening behavior is a core index to evaluate the material’s stable performance in a high-neutron-irradiation environment. In this study, based on 2048 composition and property data, a correlation model between key elements and their interactions and irradiation hardening in F/M steel was constructed using a Bayesian optimization neural network, which realized quantitative prediction of the effect of composition on hardening behavior. Studies have shown that the addition of about 9.0% Cr, about 0.8% Si, Mo content higher than about 0.25%, and the addition of Ti, Mn can effectively suppress the irradiation hardening of F/M steel, while the addition of N, Ta, and C will aggravate its irradiation hardening, and the addition of W and V has little effect on the irradiation hardening of F/M steel. There is an interaction between the two elements. C-Cr has a strong synergistic mechanism, which will cause serious hardening when the content is higher than 0.05% and the Cr content is higher than 10%. Cr-Si has a strong antagonistic mechanism, which can achieve the comprehensive irradiation hardening effect in the 9Cr-0.8Si combination. N-Mn needs N controlled lower than 0.01%. Mo-W needs to control Mo content higher than 0.5% to alleviate irradiation hardening. There is a weak synergistic effect in Si-V; when the content is between 0.3% and 0.8% and the V content is between 0.2% and 0.3%, it can assist in optimizing the composition of F/M steel. Through the optimization of multi-element combination, the composition of F/M steel with lower irradiation hardening can be designed. Full article

Background/Objectives: IBDs are chronic relapsing inflammatory intestinal disorders whose precise etiology is still only poorly defined: critical for their pathogenesis is the CCL20/CCR6 axis, whose modulation by small molecules may represent an innovative therapeutic approach. The aim of the present work is to test the potential efficacy of two molecules, MR120, a small selective CCR6 antagonist, active in TNBS- and chronic DSS-induced murine models of intestinal inflammation, and its derivative MR452, a well-tolerated agent endowed with improved anti-chemotactic in vitro properties, in the adoptive transfer colitis model. To the best of our knowledge, this is the first attempt to use adoptive transfer colitis to test modulators of the CCL20/CCR6 axis. Methods and Results: The induction of colitis in immunocompromised mice receiving CD4⁺CD25⁻ T cells i.p. resulted in a moderate inflammation and was met with limited protective responses following daily subcutaneous administration of MR120 or MR452 for 8 weeks. Both compounds significantly reduced colonic myeloperoxidase activity, and MR452 also lowered CCL20 levels in the gut, but they failed to prevent the increase in the Disease Activity Index, colon wall thickening, and macroscopic inflammation score. Conclusions: Our findings suggest that, despite the beneficial effects played by MR120 against subacute TNBS- and chronic DSS-induced colitis, the pharmacological targeting of the CCL20/CCR6 axis in the adoptive transfer model has a negligible effect in ameliorating the IBD-like phenotype driven by the altered intestinal immune homeostasis and by the disrupted function of immune-suppressive Treg cells. Full article

CNOT2, a central component of the CCR4-NOT transcription complex subunit 2, plays a pivotal role in the regulation of gene expression and metabolism. CNOT2 is involved in various cellular processes, including transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability. CNOT2 specifically contributes to the structural integrity and enzymatic activity of the CCR4-NOT complex with transcription factors and RNA-binding proteins. Recent studies have elucidated its involvement in cellular differentiation, immune response modulation, and the maintenance of genomic stability. Abnormal regulation of CNOT2 has been implicated in a spectrum of pathological conditions, including oncogenesis, neurodegenerative disorders, and metabolic dysfunctions. This review comprehensively examines the interplay between CNOT2 and p53, elucidating their collaborative and antagonistic interactions in various cellular contexts. CNOT2 is primarily involved in transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability, thereby influencing diverse biological processes such as cell proliferation, apoptosis, and differentiation. Conversely, p53 is renowned for its role in maintaining genomic integrity, inducing cell cycle arrest, apoptosis, and senescence in response to cellular stress and DNA damage. Emerging evidence suggests that CNOT2 can modulate p53 activity through multiple mechanisms, including the regulation of p53 mRNA stability and the modulation of p53 target gene expression. The dysregulation of CNOT2 and p53 interactions has been implicated in the pathogenesis and progression of various cancers, highlighting their potential as therapeutic targets. Additionally, CNOT2 regulates c-Myc, a well-known oncogene, in cancer cells. This review shows the essential roles of CNOT2 in maintaining cancer cellular homeostasis and explores its interactions within the CCR4-NOT complex that influence transcriptional and post-transcriptional regulation. Furthermore, we investigate the potential of CNOT2 as a biomarker and therapeutic target across various disease states, highlighting its significance in disease progression and treatment responsiveness. Full article

Background/Objectives: We reported previously that antagonists at chemokine receptors CCR2 and CCR3 have fluid-sparing effects during resuscitation from hemorrhagic shock. Because CCR1 shares several chemokine ligands with CCR2/3, we tested whether the CCR1 antagonist BX471 also reduces fluid requirements to maintain hemodynamics. Methods: Sprague Dawley rats were hemorrhaged for 30 min, followed by fluid resuscitation to maintain blood pressure for 60 min (series 1) and 180 min (series 2). Series 1: Animals received vehicle (n = 5), 0.05 μmol/kg (n = 5), or 0.5 μmol/kg (n = 4) BX471 at t = 30 min. Series 2: Animals received vehicle (n = 8) or 0.5 μmol/kg (n = 7) BX471 at t = 30 min. Hemodynamics, fluid requirements, blood gases, and lactate were monitored. Serum concentrations of CCR1 ligands (CCL3/4/5/7) were determined at baseline and at the conclusion of the experiments. Tissue (small/large intestine, lung) wet/dry (W/D) weight ratios, lung myeloperoxidase activity, and a panel of inflammation markers in tissue extracts were measured. Results: All animals could be resuscitated to target blood pressures. Series 1: A total of 0.5 μmol/kg BX471 reduced fluid requirements by more than 60% (p < 0.05 vs. vehicle and 0.05 μmol/kg BX471). Series 2: Systemic CCL3/5/7 levels increased during the experiment (p < 0.05). BX471-treatment reduced fluid requirements by more than 60% (p < 0.05) and prevented increases in CCL3/7. W/D ratios of large intestine and of the sum of all tissues were lower with BX471 treatment (p < 0.05). BX471-treatment reduced TNFα and IL6 concentrations in large intestine extracts (p < 0.05). Conclusions: Our findings suggest CCR1 as a new therapeutic target to reduce fluid requirements during resuscitation from hemorrhagic shock. Full article

Background: Referred pain frequently co-exists with visceral pain. However, the exact mechanism governing referred somatic hyperalgesia remains elusive. Methods: By injecting 20% acetic acid into the stomach, we established a mouse model of gastric ulcer (GU). Hematoxylin and eosin (H&E) staining was used as the evaluation criterion for the gastric ulcer model. Evan’s blue (EB) and von Frey tests detected the somatic sensitized area. The DRG neurons distributed among the spinal segments of the sensitized area were prepared for biochemical and electrophysiological experiments. The CCR2 antagonist was intraperitoneally (i.p.) injected into GU mice to test the effect of blocking CCR2 on somatic neurogenic inflammation. Results: GU not only instigated neurogenic plasma extravasation and referred somatic allodynia in the upper back regions spanning the T9 to T11 segments but also augmented the co-expression of T-type Ca²⁺ channels and CCR2 and led to the gating properties of T-type Ca²⁺ channel alteration in T9–T11 small-diameter DRG neurons. Moreover, the administration of the CCR2 antagonist inhibited the T-type Ca²⁺ channel activation, consequently mitigating neurogenic inflammation and referred somatic hyperalgesia. The application of the CCR2 agonist to normal T9–T11 small-diameter DRG neurons simulates the changes in the gating properties of T-type Ca²⁺ channel that occur in the GU group. Conclusions: Therefore, these findings indicate that CCR2 may function as a critical regulator in the generation of neurogenic inflammation and mechanical allodynia by modulating the gating properties of the T-type Ca²⁺ channels. Full article

The development of chirality descriptors for quantitative chirality structure–activity relationship (QCSAR) modeling has always attracted attention, owing to the importance of chiral molecules in pharmaceutical, agriculture, food, and fragrance industries, and environmental toxicology. The utility of a multidimensional space of novel relative chirality indices (RCIs) in the QCSAR modeling of twenty CCR2 antagonists is reported upon in this paper. The numerical characterization of chirality by the RCI approach gives a large pool of chirality descriptors with different degrees of mutual correlation (the correlation coefficient among the computed descriptors varied from 0.02 to 0.99). In the present study, the final data set contains 198 chirality descriptors for each of the twenty CCR2 antagonist molecules, providing a multidimensional space for modeling. The data reduction using principal component analysis resulted in the extraction of eight principal components (PCs). The linear regression using the principal component scores (PCSs) resulted in a three-predictor prediction model with good statistics: R² = 0.823; Adj R² = 0.790. The regression models were rebuilt using the chirality descriptors (RCIs) that are most correlated with each of the scores (PCSs) of the three principal components. The R² value for the regression models with three RCIs as the predictors is 0.742 and the five-fold cross validation, R_cv², is 0.839. The new chirality descriptors, namely, the RCIs calculated using a different weighting scheme, provide a multidimensional space of chirality descriptors for a set of chiral molecules, and such a multidimensional chirality space is a powerful tool to build quantitative chiral structure–activity relationship (QCSAR) models. Full article

Sarcopenia corresponds to a decrease in muscle mass and strength. CCL5 is a new myokine whose expression, along with the CCR5 receptor, is increased in sarcopenic muscle. Therefore, we evaluated whether CCL5 and CCR5 induce a sarcopenic-like effect on skeletal muscle tissue and cultured muscle cells. Electroporation in the tibialis anterior (TA) muscle of mice was used to overexpress CCL5. The TA muscles were analyzed by measuring the fiber diameter, the content of sarcomeric proteins, and the gene expression of E3-ligases. C₂C₁₂ myotubes and single-isolated flexor digitorum brevis (FDB) fibers were also treated with recombinant CCL5 (rCCL5). The participation of CCR5 was evaluated using the antagonist maraviroc (MVC). Protein and structural analyses were performed. The results showed that TA overexpression of CCL5 led to sarcopenia by reducing muscle strength and mass, muscle-fiber diameter, and sarcomeric protein content, and by upregulating E3-ligases. The same sarcopenic phenotype was observed in myotubes and FDB fibers. We showed increased reactive oxygen species (ROS) production and carbonylated proteins, denoting oxidative stress induced by CCL5. When the CCR5 was antagonized, the effects produced by rCCL5 were prevented. In conclusion, we report for the first time that CCL5 is a novel myokine that exerts a sarcopenic-like effect through the CCR5 receptor. Full article

Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which promote hypersensitivity and inflammation. Accumulating evidence suggests that CCR2, CCR5, and their ligands (CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11 CCL12, and/or CCL13) play a role in rodent models of pain and obesity, as well as in patients with diabetes and obesity. It was proven that the blockade of CCR2 and CCR5, including the simultaneous blockade of both receptors by dual antagonists, effectively reduces hypersensitivity to thermal and mechanical stimuli in chronic pain states, including diabetic neuropathy. The present review discusses these chemokine receptors and the role of their ligands in diabetes and obesity, as well as their involvement in diabetic neuropathy and obesity-induced hypersensitivity. Full article

Aeromonas salmonicida is a major pathogenic bacterium that poses a significant threat to salmonid fish. Yadong County, located in the Xizang Autonomous Region, is renowned for its characteristic industry of Salmo trutta aquaculture. In recent years, the outbreak of Bacterial Gill Disease (BGD) has led to substantial economic losses for S. trutta farmers. Our prior research identified A. salmonicida as one of the primary culprits behind BGD. To mitigate the impact of A. salmonicida on S. trutta, we conducted a comprehensive study aimed at identifying genes associated with resistance to A. salmonicida. This involved transcriptome sequencing and 16S rRNA sequencing of intestinal flora, providing valuable insights for the study of disease resistance in S. trutta. In this study, we identified 324 genera with 5171 ASVs in the susceptible group and 293 genera with 5669 ASVs in the resistant group. Notably, Methylobacterium and Sphingomonas were common bacteria present in the salmon’s gut, and their proportions remained relatively stable before and after infection. Shewanella, with its antagonistic relationship with Aeromonas, may play a crucial role in the salmon’s defense against A. salmonicida. Several related genes were identified, including angptl4, cipcb, grasp, ccr9a, sulf1, mtmr11, B3GNT3, mt2, PLXDC1, and ank1b. Full article

C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL19_8-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca²⁺ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ β2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL19_8-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent β2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS. Full article

The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies. Full article

CC chemokine receptor 2 (CCR2) has been linked to many inflammatory and immune diseases, making it a relevant drug target. Yet, all CCR2 antagonists developed so far have failed in clinical trials; thus, novel strategies are needed to target this receptor. Targeted protein degradation represents a novel approach to inhibit protein function by hijacking the cellular degradation machinery, such as the proteasome, to degrade the protein of interest. Here, we aimed to determine the amenability of CCR2 to chemically induced degradation by using a CCR2 fusion protein containing a HaloTag7 and HiBiT tag (CCR2-HaloTag-HiBiT). After characterization of the CCR2 construct, we used luminescence-based assays and immunofluorescence to quantify CCR2 levels, as well as a label-free, phenotypic assay to investigate the functional effect of CCR2 degradation. Treatment with HaloPROTAC3, which selectively degrades HaloTag fusion proteins, led to concentration- and time-dependent degradation of CCR2-HaloTag-HiBiT. HaloPROTAC3 induced degradation via the proteasome, as degradation was fully blocked with proteasomal inhibitors. Finally, functional assays showed that degradation of CCR2-HaloTag-HiBiT leads to a reduced functional response after agonist stimulation. Overall, our results indicate that CCR2 is amenable to targeted degradation, paving the way for the future development of CCR2 chemical degraders. Full article

Treatment with CCR-4 antagonists has been shown to be protective against the development of invasive pulmonary aspergillosis in animal models. Herein, we present a case of fatal invasive pulmonary aspergillosis in a patient receiving Mogamulizumab. A 64-year-old man with refractory mycosis fungoides was found to have diffuse bilateral pulmonary nodules during a chest CT in June 2022. Bronchoalveolar lavage (BAL) fungal and bacterial cultures and galactomannan were negative, as well as serum beta-glucan and galactomannan. Histology showed a lymphoid infiltrate with a negative fungal stain, so a presumptive diagnosis of lymphoma infiltration was made, and the patient started the CCR-4 antagonist Mogamulizumab treatment in August 2022. He had no symptoms until November when he presented to the hematology clinic reporting dyspnea. He had neutrophilic leukocytosis (18.610 cells/µL), his c-reactive protein was 27 mg/dL, and his skin lesions from mycosis fungoides were just starting to improve. A CT scan showed large diffuse bilateral severely necrotic cavitated lesions with thick walls and apparently synchronous evolution. Beta-glucan was 31 pg/mL (wako method), while serum galactomannan 3.6. BAL was positive for Aspergillus fumigatus culture and galactomannan. Patient started voriconazole but, despite being in a stable condition, he suddenly died after two days. Discussion: Paradoxically, worsening of the chronic pulmonary aspergillosis has been reported after nivolumab treatment, and immune reconstitution syndromes are usually seen during neutrophil recovery after intensive chemotherapy. Our patient already presented indolent lung lesions from 5 months before and he remained completely asymptomatic until the aspergillosis diagnosis when he quickly passed away. Even if a progression of the lesions was expected in 5 months, this case had an atypical presentation. During the 5-month period, he had no pulmonary symptoms, and his c-reactive protein was negative. Furthermore, in the setting of the natural progression of subacute/chronic aspergillosis, a different radiological picture was expected with a less severe and probably asynchronous evolution. We think that the immune restoration associated with Mogamulizumab (also supported by the concurrent clinical response of the skin lesions) could have been detrimental in this case, exacerbating a catastrophic immune response or alternatively masquerading the clinical progression of aspergillosis. Clinicians should be aware of immune reconstitution syndromes possibly leading to fatal outcomes in immunocompromised patients starting CCR-4 antagonists. Full article