C-176 reduces inflammation-induced pain by blocking the cGAS-STING pathway in microglia.

OBJECTIVE: Inflammatory pain, is caused by lesions or diseases of the somatosensory tissue, is a prevalent chronic condition that profoundly impacts the quality of life. However, clinical treatment for this type of pain remains limited. Traditionally, the stimulation of microglia and subsequent inflammatory reactions are considered crucial elements to promote the worsening of inflammatory pain. Recent research has shown the crucial importance of the cGAS-STING pathway in promoting inflammation. It is still uncertain if the cGAS-STING pathway plays the role in the fundamental cause of inflammatory pain. We aim to explore the treatment of inflammatory pain by interfering with cGAS-STING signaling pathway. METHODS: In this study, we established an inflammatory pain model by CFA into the plantar of mice. Activation of microglia, various inflammatory factors and cGAS-STING protein in the spinal dorsal horn were evaluated. Immunofluorescence staining was used to observe the cellular localization of cGAS and STING. The cGAS-STING pathway proteins expression and mRNA expression of indicated microglial M1/M2 phenotypic markers in the BV2 microglia were detected. STING inhibitor C-176 was intrathecal injected into mice with inflammatory pain, and the pain behavior and microglia were observed. RESULTS: This research showed that injecting CFA into the left hind paw of mice caused mechanical allodynia and increased inflammation in the spine. Our research results suggested that the cGAS-STING pathway had a function in the inflammation mediated by microglia in the spinal cord dorsal horn. Blocking the cGAS-STING pathway using STING antagonists (C-176) led to reduced release of inflammatory factors and prevented M1 polarization of BV2 microglia in a laboratory setting. Additionally, intrathecal administration of C-176 reduced the allodynia in CFA treated mice. CONCLUSION: Our results suggest that inhibiting microglial polarization through the cGAS-STING pathway represents a potential novel therapeutic strategy for inflammatory pain.

The Effect of Multi-Fields Synergy from Electric/Light/Thermal/Force Technologies on Photovoltaic Performance of Ba0.06 Bi0.47 Na0.47 TiO3 Ferroelectric Ceramics via the Mg/Co Substitution at A/B Sites.

Currently, it is widely reported that the photovoltaic effect in ferroelectric materials can be promoted by the application of a piezoelectric force, an external electric field, and intense light illumination. Here, a semiconducting ferroelectric composition is introduced, (1-x) Ba0.06 Bi0.47 Na0.47 TiO3 -xMgCoO3 (abbreviated as xMgCo, where x = 0.02-0.08), synthesized through Mg/Co ions codoping. This process effectively narrows the optical bandgaps to a spectrum of 1.38-3.06 eV. Notably, the system exhibits a substantial increase in short-circuit photocurrent density (Jsc ), by the synergy of the electric, light, and thermal fields. The Jsc can still be further enhanced by the extra introduction of a force field. Additionally, the Jsc also shows an obvious increase after the high field pre-poling. The generation of a considerable number of oxygen vacancies due to the Co2+ /Co3+ mixed valence state (in a 1:3 ratio) contributes to the reduced optimal bandgap. The integration of Mg2+ ion at the A-site restrains the loss and sustains robust ferroelectricity (Pr  = 24.1 µC cm-2 ), high polarizability under an electric field, and a significant piezoelectric coefficient (d33  = 102 pC N-1 ). This study provides a novel perspective on the physical phenomena arising from the synergy of multiple fields in ferroelectric photovoltaic materials.

TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration.

AIMS: TFG-related axonal Charcot-Marie-Tooth (CMT) disease is a late-onset, autosomal dominant, hereditary motor, and sensory neuropathy characterized by slowly progressive weakness and atrophy of the distal muscles. The objective of this study was to determine the common pathogenic mechanism of TFG-related CMT type 2 (CMT2) caused by different mutations and establish a direct association between TFG haploinsufficiency and neurodegeneration. METHODS: Three individuals carrying the TFG p.G269V mutation but with varying disease durations were studied. The effect of the p.G269V mutation was confirmed by analyzing protein samples extracted from the blood of two individuals. The functional consequences of both CMT2 mutant gene products were evaluated in vitro. The effect of TFG deficiency in the nervous system was examined using zebrafish models and cultured mouse neurons. RESULTS: Overexpression of p.G269V TFG failed to enhance soluble TFG levels by generating insoluble TFG aggregates. TFG deficiency disrupted neurite outgrowth and induced neuronal apoptosis both in vivo and in vitro and further impaired locomotor capacity in zebrafish, which was consistent with the phenotype in patients. Wnt signaling was activated as a protective factor in response to TFG deficiency. CONCLUSION: CMT2-related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

Postsynaptic glutamate response downregulates within presynaptic exaggerated glutamate release by activating TRPV1 in the spinal dorsal horn.

Activating primary afferent TRPV1-positive (TRPV1+) fibers in the spinal dorsal horn triggers exaggerated glutamate release and induces acute pain. However, whether the glutamate postsynaptic responses on dorsal horn neurons are regulated by excessive glutamate is unknown, largely due to intrinsic technical difficulties. In the present study, capsaicin, a specific TRPV1 agonist, was used to activate TRPV1+ fibers in the spinal dorsal horn. Combining three-dimensional (3-D) holographic photostimulation and whole-cell recordings on acute spinal cord slices from adult rodents, we found that postsynaptic glutamate responses were attenuated when activating TRPV1+ fibers with capsaicin. Electron microscopy and Western blot studies found that postsynaptic GluA1 (a subtype of ionotropic glutamate receptors) on the postsynaptic membrane was decreased by acute capsaicin treatment. Therefore, postsynaptic glutamate receptor occupancy and/or downmodulation may underlie this postsynaptic attenuation. Our data thus clarify a scenario in which postsynaptic glutamate responses are largely downregulated upon TRPV1+ activation, and this change may contribute to homeostasis in the dorsal horn circuit when "acute pain" occurs.

Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain.

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

Clinical Features and Peripheral Blood T Lymphocyte Subsets in Hand, Foot, and Mouth Disease According to Different Pathogens.

OBJECTIVE: To investigate the changes in lymphocyte subsets that are caused by infection with different pathogens in children with hand, foot, and mouth disease. METHODS: T lymphocyte subsets were measured in the patients' peripheral blood, and serum, throat swab, and fecal samples were tested for enterovirus. RESULTS: Fecal and throat swab samples exhibited similar positive detection rates, and were significantly more likely to be positive, compared to serum samples (P < 0.01). The EV71-positive group exhibited significantly lower CD4 + TM cell counts (QR: 1.058), compared to the CD4 + TM cell counts in the CoxA16-positive group (QR: 1.391; P < 0.05). CONCLUSIONS: Throat swab and fecal samples exhibited significantly higher positive detection rates, compared to serum samples. In addition, EV71-infected children exhibited significantly lower CD4+ T-cell counts, compared to CoxA16-infected children, which suggests that EV71 infection may be associated with a poorer prognosis.

[Expression of PH20 in primary and metastatic breast cancer and its pathological significance].

OBJECTIVE: To evaluate the expression pattern of PH20 in primary and metastatic breast cancer and its relationship to tumor metastatic potential. METHODS: Anti-PH20 antibody was synthesized by injection of conjugated human PH20 peptides into rabbits. Immunohistochemical study was performed on 53 cases of human breast cancer. Western blot was used to detect PH20 expression in 5 cases of breast cancer with available fresh tissue. Two oligonucleotide probes were prepared for in-situ hybridization using breast tissue microarray. RESULTS: Normal breast tissue did not express PH20 (0/3), while 58.4% (31/53) of breast cancer cases did. The highest expression rate was found in metastatic foci in regional lymph nodes (83.3%), followed by primary breast cancer tissue in cases with lymph node secondaries (70.8%). The breast cancer cases with no any metastasis had an expression rate of 48.2%. The immunohistochemical staining results were further confirmed by Western blotting. In-situ hybridization showed PH20 RNA in 75% of the breast cancer tissue (21/28). Two of the 17 cases of normal breast tissue showed weak expression in some ductolobular units. CONCLUSIONS: The expression of PH20 has a positive correlation with metastatic potential in breast cancer. It is possible that PH20 may play an important role in the invasive growth and metastasis of breast cancer cells, via mechanisms such as digestion of surrounding stromal tissue and release of FGF-2.