Thalamic Nucleus Reuniens Glutamatergic Neurons Mediate Colorectal Visceral Pain in Mice via 5-HT2B Receptors.

Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by abdominal pain and visceral hypersensitivity. Reducing visceral hypersensitivity is the key to effectively relieving abdominal pain in IBS. Increasing evidence has confirmed that the thalamic nucleus reuniens (Re) and 5-hydroxytryptamine (5-HT) neurotransmitter system play an important role in the development of colorectal visceral pain, whereas the exact mechanisms remain largely unclear. In this study, we found that high expression of the 5-HT2B receptors in the Re glutamatergic neurons promoted colorectal visceral pain. Specifically, we found that neonatal maternal deprivation (NMD) mice exhibited visceral hyperalgesia and enhanced spontaneous synaptic transmission in the Re brain region. Colorectal distension (CRD) stimulation induced a large amount of c-Fos expression in the Re brain region of NMD mice, predominantly in glutamatergic neurons. Furthermore, optogenetic manipulation of glutamatergic neuronal activity in the Re altered colorectal visceral pain responses in CON and NMD mice. In addition, we demonstrated that 5-HT2B receptor expression on the Re glutamatergic neurons was upregulated and ultimately promoted colorectal visceral pain in NMD mice. These findings suggest a critical role of the 5HT2B receptors on the Re glutamatergic neurons in the regulation of colorectal visceral pain.

First molecular survey of tick-borne protozoan and bacterial pathogens in the questing tick population in Bangladesh.

Questing ticks carry various tick-borne pathogens (TBPs) that are responsible for causing tick-borne diseases (TBDs) in humans and animals around the globe, especially in the tropics and sub-tropics. Information on the distribution of ticks and TBPs in a specific geography is crucial for the formulation of mitigation measures against TBDs. Therefore, this study aimed to survey the TBPs in the questing tick population in Bangladesh. A total of 2748 questing hard ticks were collected from the pastures in Sylhet, Bandarban, Sirajganj, Dhaka, and Mymensingh districts through the flagging method. After morphological identification, the ticks were grouped into 142 pools based on their species, sexes, life stages, and collection sites. The genomic DNA extracted from tick specimens was screened for 14 pathogens, namely Babesia bigemina (AMA-1), Babesia bovis (RAP-1), Babesia naoakii (AMA-1), Babesia ovis (18S rRNA), Theileria luwenshuni (18S rRNA), Theileria annulata (Tams-1), Theileria orientalis (MPSP), Anaplasma marginale (groEL), Anaplasma phagocytophilum (16S rRNA), Anaplasma bovis (16S rRNA), Anaplasma platys (16S rRNA), Ehrlichia spp. (16S rRNA), Rickettsia spp. (gltA), and Borrelia (Bo.) spp. (flagellin B) using genus and species-specific polymerase chain reaction (PCR) assays. The prevalence of the detected pathogens was calculated using the maximum likelihood method (MLE) with 95 % confidence interval (CI). Among 2748 ixodid ticks, 2332 (84.86 %) and 416 (15.14 %) were identified as Haemaphysalis bispinosa and Rhipicephalus microplus, respectively. Haemaphysalis bispinosa was found to carry all the seven detected pathogens, while larvae of R. microplus were found to carry only Bo. theileri. Among the TBPs, the highest detection rate was observed in A. bovis (20/142 pools, 0.81 %, CI: 0.51-1.20), followed by T. orientalis (19/142 pools, 0.72 %, CI: 0.44-1.09), T. luwenshuni (9/142 pools, 0.34 %, CI: 0.16-0.62), B. ovis (4/142 pools, 0.15 %, CI: 0.05 - 0.34) and Bo. theileri (4/142 pools, 0.15 %, CI: 0.05-0.34), Ehrlichia ewingii (3/142 pools, 0.11 %, CI: 0.03-0.29), and Babesia bigemina (1/142, 0.04 %, CI: 0.00 - 0.16). This study reports the existence of T. luwenshuni, E. ewingii, and Bo. theileri in Bangladesh for the first time. The novel findings of this study are the foremost documentation of transovarian transmission of B. bigemina and E. ewingii in H. bispinosa and also provide primary molecular evidence on the presence of E. ewingii and Bo. theileri in H. bispinosa. Therefore, this study may shed light on the circulating TBPs in ticks in the natural environment and thereby advocate awareness among physicians and veterinarians to control and prevent TBDs in Bangladesh.

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING.

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

Hidden Valley Polarization, Piezoelectricity, and Dzyaloshinskii-Moriya Interactions of Janus Vanadium Dichalcogenides.

Due to the lack of inversion symmetry and the discovery of room-temperature ferromagnetism, two-dimensional semiconducting vanadium-based van der Waals transition-metal dichalcogenides (V-TMDs) are drawing attention for their possible application in spintronics and valleytronics. Here, we show the functional properties enriched by the broken inversion, out-of-plane mirror, and time-reversal symmetries of Janus H-VXY TMDs (X, Y = S, Se, Te). By first-principles calculations, we reveal the intrinsic xy easy-plane magnetism of the Janus vanadium-based TMD monolayers and systematically study their hidden valley polarization and giant magneto band structure. Their strong nearest-neighbor exchange strengths lead to near-room-temperature magnetic phase transitions. The Janus H-VXY system also exhibits piezoelectricity with nonzero e31 and e21. Interestingly, it is found that the right-handed Dzyaloshinskii-Moriya interaction has nonzero in-plane components in our Janus system, with fluctuating magnitudes determined by competence between relaxed bond-angle and atomic index of ligands.

Multipiezo Effect in Altermagnetic V2SeTeO Monolayer.

Strain engineering has been used as an efficient method to modulate various properties of quantum materials and electronic devices. One may establish piezo effects based on a disciplined response to the strain in multifunctional nanosystems. Inspired by a recent theoretical proposal on the interesting piezomagnetism and C-paired valley polarization in the V2Se2O monolayer, we predict a stable altermagnetic Janus monolayer V2SeTeO using density functional theory calculations. It exhibits a novel "multipiezo" effect combining piezoelectricity, piezovalley, and piezomagnetism. Most interestingly, the valley polarization and the net magnetization under strain in V2SeTeO exceed these in V2Se2O, along with the additional large piezoelectric coefficient. The "multipiezo" effect makes Janus monolayer V2SeTeO as a tantalizing material for potential applications in nanoelectronics, optoelectronics, spintronics, and valleytronics.

Phase patterning of metallic glasses through superfast quenching of ion irradiation-induced thermal spikes.

Amorphous metallic glasses (MGs) convert to crystalline solids upon annealing at a high temperature. Such a phase change, however, does not occur with the local melting caused by damage cascades introduced by ion irradiation, although the resulting thermal spikes can reach temperatures > 1000 K. This is because the quenching rate of the local melting zone is several orders of magnitude higher than the critical cooling rate for MG formation. Thus the amorphous structure is sustained. This mechanism increases the highest temperature at which irradiated MG sustains amorphous phase. More interestingly, if an irradiated MG is pre-annealed to form a polycrystalline structure, ion irradiation can locally convert this crystalline phase to an amorphous phase if the grains are nanometers in size and comparable to the damage cascade volume size. Combining pre-annealing and site selective ion irradiation, patterned crystalline-amorphous heterogeneous structures have been fabricated. This finding opens new doors for various applications.

Rab27a-mediated exosome secretion in anterior cingulate cortex contributes to colorectal visceral pain in adult mice with neonatal maternal deprivation.

Chronic visceral pain is a common symptom of irritable bowel syndrome (IBS). Exosomes are involved in the development of pain. Rab27a can mediate the release of exosomes. The purpose of this study is to investigate how Rab27a-mediated exosome secretion in the anterior cingulate cortex (ACC) regulates visceral hyperalgesia induced with neonatal maternal deprivation (NMD) in adult mice. The colorectal distension method was adopted to measure visceral pain. The BCA protein assay kit was applied to detect the exosome protein concentration. Western blotting, quantitative PCR, and immunofluorescence technique were adopted to detect the expression of Rab27a and the markers of exosomes. Exosomes extracted from ACC were more in NMD mice than in control (CON) mice. Injection of the exosome-specific inhibitor GW4869 in ACC attenuated colorectal visceral pain of NMD mice. Injection of NMD-derived exosomes produced colorectal visceral pain in CON mice. Rab27a was upregulated in ACC of NMD mice. Rab27a was highly expressed in ACC neurons of NMD mice, rather than astrocytes and microglia. Injection of Rab27a-siRNA reduced the release of exosomes and attenuated the colorectal visceral pain in NMD mice. This study suggested that overexpression of Rab27a increased exosome secretion in ACC neurons, thus contributing to visceral hyperalgesia in NMD mice.NEW & NOTEWORTHY This work demonstrated that the expression of Rab27a in the anterior cingulate cortex was upregulated, which mediated multivesicular bodies trafficking to the plasma membrane and led to the increased release of neuronal exosomes, thus contributing to colorectal visceral pain in neonatal maternal deprivation (NMD) mice. Blocking the release of exosomes or downregulation of Rab27a could alleviate colorectal visceral pain in NMD mice. These data may provide a promising strategy for the treatment of visceral pain in irritable bowel syndrome patients.

Ischemic preconditioning attenuates endoplasmic reticulum stress-dependent apoptosis of hepatocytes by regulating autophagy in hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI) usually occurs during subtotal hepatectomy and severely damages liver function during the perioperative period. Endoplasmic reticulum stress (ERS) dependent apoptosis has been suggested to play a crucial role in HIRI progression. The present study focused on the regulatory effect of autophagy activation induced by ischemic preconditioning (IPC) on ERS-dependent apoptosis of hepatocytes in HIRI. A HIRI mouse model and oxygen-glucose deprivation/reperfusion (OGD/R) AML-12 hepatocyte cell lines were constructed to evaluate the protective effect of IPC in vivo and in vitro. The protein levels of p-eIF2α, CHOP, and cleaved caspase-12 were used to evaluate the ERS-dependent apoptosis, whereas LC3-II and p62 were considered as the autophagy activation markers. The beneficial molecular chaperones GRP78, HSP60, and HSP70 were also tested to evaluate autophagy. HIRI significantly increased ERS-dependent apoptosis markers and the number of apoptotic cells and damaged liver function. The ERS inhibitor salubrinal significantly alleviated liver injury in HIRI and OGD/R hepatocytes. Furthermore, both remote IPC and direct IPC significantly alleviated liver injury and inflammatory cell infiltration. IPC also upregulated LC3-II, downregulated p62 expression, and increased the mRNA levels of GRP78, HSP60, and HSP70 in HIRI mice and OGD/R hepatocytes, indicating the activation of autophagy by IPC. The autophagy inhibitor 3-methyladenine significantly attenuated the protective effects of IPC on ERS-dependent apoptosis and liver function, whereas the autophagy activator rapamycin mimicked the protective effects of IPC on ERS-dependent apoptosis in vivo and in vitro, suggesting a regulatory role of autophagy in ERS-dependent apoptosis. These results demonstrated that IPC could induce moderate autophagy and upregulate a few molecular chaperones to strengthen endogenous defense mechanisms, which is beneficial for alleviating ERS-dependent apoptosis and protecting hepatocytes from HIRI.

Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

The pro-inflammatory phenotype of microglia usually induces neuroinflammatory reactions in neuropathic pain. Glycometabolism shift to glycolysis can promote the pro-inflammatory phenotype transition of microglia. The omics data analysis suggest a critical role for Lyn dysregulation in neuropathic pain. The present study aimed at exploring the mechanism of Lyn-mediated glycolysis enhancement of microglia in neuropathic pain. Neuropathic pain model was established by chronic constriction injury (CCI), then pain thresholds and Lyn expression were measured. Lyn inhibitor Bafetinib and siRNA-lyn knockdown were administrated intrathecally to evaluate the effects of Lyn on pain thresholds, glycolysis and interferon regulatory factor 5 (IRF5) nuclear translocation of microglia in vivo and in vitro. ChIP was carried out to observe the binding of transcription factors SP1, PU.1 to glycolytic gene promoters by IRF5 knockdown. Finally, the relationship between glycolysis and pro-inflammatory phenotype transition of microglia was evaluated. CCI led to the upregulation of Lyn expression and glycolysis enhancement in microglia of spinal dorsal horn. Bafetinib or siRNA-lyn knockdown intrathecally alleviated pain hyperalgesia, suppressed glycolysis enhancement and inhibited nuclear translocation of IRF5 in CCI mice. Also, IRF5 promoted the binding of transcription factors SP1, PU.1 to glycolytic gene promoters, and then the enhanced glycolysis facilitated the proliferation and pro-inflammatory phenotype transition of microglia and contributed to neuropathic pain. Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

Protective Efficiency Comparison of Direct and Remote Ischemic Preconditioning on Ischemia Reperfusion Injury of the Liver in Patients Undergoing Partial Hepatectomy.

Objective: Ischemia reperfusion injury greatly damages liver function and deteriorates the prognosis of patients undergoing partial hepatectomy. This study is to compare the protective efficiency of direct and remote ischemic preconditioning (DIPC and RIPC) on ischemia reperfusion injury of the liver in patients undergoing partial hepatectomy. Methods: 90 patients scheduled for partial hepatectomy were enrolled and randomly divided into control (n = 30), DIPC (n = 30), and RIPC (n = 30) groups. Baseline and surgery characteristics were collected, and ischemic preconditioning methods were carried out. Intraoperative hemodynamics, liver function and liver reserve capacity, oxidative stress, and inflammatory responses were measured, and the incidence of postoperative adverse reactions was calculated finally. Results: 10 patients were excluded from the study, and finally, the eligible patients in three groups were 27, 28, and 25, separately. No significant differences were observed in baseline and surgery characteristics among the three groups. SBP and DBP were significantly higher after hepatic portal vein occlusion while they were significantly lower after surgery in the DIPC and RIPC groups compared with that in the control group, SBP and DBP were of great fluctuation at different time points in the control group while they showed much more stabilization in the DIPC and RIPC groups. ALT, AST, and TBIL were significantly decreased on days 1, 3, and 5 after surgery, and ICG R15 was significantly decreased while ICG K value and EHBF were significantly increased on day 1 after surgery in the DIPC and RIPC groups compared with that in the control group. Moreover, antioxidant enzyme SOD was increased, and inflammatory factors TNF-α and IL-1ß were decreased 24 hours after surgery in the DIPC and RIPC groups compared with that in the control group. DIPC and RIPC also decreased hospital stays and the incidence of nausea, vomiting, and hypertension. Conclusion: DIPC and RIPC both alleviated ischemia reperfusion injury of the liver and reduced perioperative complications with similar protective efficiency in patients undergoing partial hepatectomy.

Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.

A paraventricular hypothalamic nucleus input to ventral of lateral septal nucleus controls chronic visceral pain.

ABSTRACT: Irritable bowel syndrome is a functional gastrointestinal disorder characterized by chronic visceral pain with complex etiology and difficult treatment. Accumulated evidence has confirmed that the sensitization of the central nervous system plays an important role in the development of visceral pain, whereas the exact mechanisms of action of the neural pathways remain largely unknown. In this study, a distinct neural circuit was identified from the paraventricular hypothalamic (PVH) to the ventral of lateral septal (LSV) region. This circuit was responsible for regulating visceral pain. In particular, the data indicated that the PVH CaMKIIα-positive neurons inputs to the LSV CaMKIIα-positive neurons were only activated by colorectal distention rather than somatic stimulations. The PVH-LSV CaMKIIα + projection pathway was further confirmed by experiments containing a viral tracer. Optogenetic inhibition of PVH CaMKIIα + inputs to LSV CaMKIIα-positive neurons suppressed visceral pain, whereas selective activation of the PVH-LSV CaMKIIα + projection evoked visceral pain. These findings suggest the critical role of the PVH-LSV CaMKIIα + circuit in regulating visceral pain.

Identification of a Glutamatergic Claustrum-Anterior Cingulate Cortex Circuit for Visceral Pain Processing.

Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of in vivo circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal activity and visceral pain behaviors. Chemogenetic activation or inhibition of ACC neural activities reversed the effects of optogenetic manipulation of CL neural activities on visceral pain responses. Importantly, molecular detection showed that NMD significantly enhances the expression of NMDA receptors and activated CaMKIIα in the ACC postsynaptic density (PSD) region. Together, our data establish a functional role for CL→ACC glutamatergic neurons in gating visceral pain, thus providing a potential treatment strategy for visceral pain.SIGNIFICANCE STATEMENT Studies have shown that sensitization of anterior cingulate cortex (ACC) plays an important role in chronic pain. However, it is as yet unknown whether there is a specific brain region and a distinct neural circuit that helps the ACC to distinguish visceral and somatic pain. The present study demonstrates that claustrum (CL) glutamatergic neurons maybe responding to colorectal distention (CRD) rather than somatic stimulation and that a CL glutamatergic projection to ACC glutamatergic neuron regulates visceral pain in mice. Furthermore, excessive NMDA receptors and overactive CaMKIIα in the ACC postsynaptic density (PSD) region were observed in mice with chronic visceral pain. Together, these findings reveal a novel neural circuity underlying the central sensitization of chronic visceral pain.

Full-Length Transcriptomic Sequencing and Temporal Transcriptome Expression Profiling Analyses Offer Insights into Terpenoid Biosynthesis in Artemisia argyi.

Artemisiae argyi Folium is a traditional herbal medicine used for moxibustion heat therapy in China. The volatile oils in A.argyi leaves are closely related to its medicinal value. Records suggest that the levels of these terpenoids components within the leaves vary as a function of harvest time, with June being the optimal time for A. argyi harvesting, owing to the high levels of active ingredients during this month. However, the molecular mechanisms governing terpenoid biosynthesis and the time-dependent changes in this activity remain unclear. In this study, GC-MS analysis revealed that volatile oil levels varied across four different harvest months (April, May, June, and July) in A. argyi leaves, and the primarily terpenoids components (including both monoterpenes and sesquiterpenes) reached peak levels in early June. Through single-molecule real-time (SMRT) sequencing, corrected by Illumina RNA-sequencing (RNA-Seq), 44 full-length transcripts potentially involved in terpenoid biosynthesis were identified in this study. Differentially expressed genes (DEGs) exhibiting time-dependent expression patterns were divided into 12 coexpression clusters. Integrated chemical and transcriptomic analyses revealed distinct time-specific transcriptomic patterns associated with terpenoid biosynthesis. Subsequent hierarchical clustering and correlation analyses ultimately identified six transcripts that were closely linked to the production of these two types of terpenoid within A. argyi leaves, revealing that the structural diversity of terpenoid is related to the generation of the diverse terpene skeletons by prenyltransferase (TPS) family of enzymes. These findings can guide further studies of the molecular mechanisms underlying the quality of A. argyi leaves, aiding in the selection of optimal timing for harvests of A. argyi.

DISTRIBUTION PREDICTION OF HYALOMMA ASIATICUM (ACARI: IXODIDAE) IN A LOCALIZED REGION IN NORTHWESTERN CHINA.

Hyalomma tick species are considered the competent vector tick species that carry and transmit Crimean-Congo hemorrhagic fever virus (CCHFV) to humans and animals. Hyalomma asiaticum is one of the major tick species widespread in the Xinjiang Uygur Autonomous Region (XUAR) of China. To determine the potential prevalence of H. asiaticum in XUAR, species distribution modeling was performed using MaxEnt algorithm assembled with bioclimatic variables and curated tick presence records. The results indicate that potential habitats of H. asiaticum mainly cover the northern and western XUAR. The suitable habitats included the west rim of the Taklimakan Desert, Turpan Basin, and Junggar Basin. The models show a mean area under the curve of 0.865 ± 0.068 for H. asiaticum based on 10-fold cross-validation. Despite limited tick presence records used in the study, this work describes the potential distribution and the association of important bioclimatic variables that are crucial for the survival of H. asiaticum in many arid areas in XUAR. The model could be helpful in tick distribution study and surveillance of CCHFV in the region.

Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis.

BACKGROUND: Chronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model. METHODS: C57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms. RESULTS: Huc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy. CONCLUSION: Huc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis.

Glycometabolism Reprogramming of Glial Cells in Central Nervous System: Novel Target for Neuropathic Pain.

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

Depression of long non-coding RNA SOX2 overlapping transcript attenuates lipopolysaccharide-induced injury in bronchial epithelial cells via miR-455-3p/phosphatase and tensin homolog axis and phosphatidylinositol 3-kinase/protein kinase B pathway.

Airway inflammation is associated with various respiratory diseases, and previous research has confirmed that long non-coding RNAs (lncRNAs) play imperative roles in inflammatory responses. However, the function of lncRNA SOX2 overlapping transcript (SOX2-OT) in airway inflammation remains enigmatic. This study aimed to investigate the effects of SOX2-OT on lipopolysaccharide (LPS)-induced cell injury in human bronchial epithelial cells, BEAS-2B, and its potential mechanisms. The results showed increased cell apoptotic ratio, production of inflammatory cytokines, higher expression of adhesion molecules and activation of NF-κB in LPS-stimulated BEAS-2B cells. In LPS-stimulated BEAS-2B cells, SOX2-OT up-regulation and miR-455-3p down-regulation emerged simultaneously. SOX2-OT knockdown or miR-455-3p over-expression restrained LPS-induced inflammation and injury. SOX2-OT sponged to miR-455-3p and functioned as a ceRNA. In addition, phosphatase and tensin homolog (PTEN) served as an endogenous target of miR-455-3p to modulate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and disturb the alleviated consequence of miR-455-3p over-expression on LPS-induced BEAS-2B cell inflammation and cell injury. Our data demonstrated that SOX2-OT plays a pivotal role in LPS-induced inflammation and injury in BEAS-2B cells and exerts its function through the miR-455-3p/PTEN axis and modulation of the PI3K/AKT pathway.