Application value of MRI-guided wire localization to the non-palpable breast lesions only shown in Breast MRI.

Introduction: Magnetic resonance imaging (MRI)-guided wire localization can be applied to assist to remove suspected breast lesions accurately. This study aimed to evaluate the clinical application value of this technique in Chinese women. Methods: A total of 126 patients (131 lesions) who had underwent such technique in our hospital from April 2017 to June 2023 were enrolled. 1.5T MRI system and a wire localization device were used. Image characteristics, clinical features and postoperative pathology were collected and analyzed. Results: All of 126 patients (131 lesions) were successfully localized by MRI and excised for biopsy. There were 39 malignant lesions (29.77%) and 92 benign lesions (70.23%). There was no significant correlation between the morphology of DCE-MRI and the ratio of malignant lesions (P=0.763), while there was a statistical correlation between the BPE, TIC curve and the malignancy rate (P<0.05). All the lesions were assessed according to BI-RADS category of MRI (C4A=77, C4B=40, C4C=12, C5=2). The malignancy rates were as follows: 16.88% for 4A lesions (13/77), 37.50% for 4B lesions (15/40), 75.00% for 4C lesions (9/12) and 100% for 5 lesions (2/2). There was a significant correlation between the BI-RADS category and the incidence of benign-to-malignant lesions (P<0.001). Conclusion: MRI-guided wire localization can assist to remove suspected breast lesions early, safely and accurately. This technique makes up for the deficiency of X-ray and ultrasound, improves the accuracy of diagnosis and resection therapy in intraductal carcinoma and early invasive carcinoma, and helps to improve the the prognosis of breast cancer.

PGC-1α activation ameliorates cancer-induced bone pain via inhibiting apoptosis of GABAergic interneurons.

Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.

Efficacy of Bleomycin-Lauromacrogol Foam in Pediatric Macrocystic Lymphatic Malformations With and Without Intracapsular Hemorrhage.

BACKGROUND: Sclerotherapy is purportedly less effective in patients with hemorrhagic than with non-hemorrhagic lymphatic malformations (LMs). We aimed to compare the efficacy of bleomycin-lauromacrogol foam (BLF) sclerotherapy in the treatment of macrocystic LMs with and without intralesional hemorrhage. METHODS: Fifty-five children with macrocystic LMs admitted to the Pediatric Surgery Department were retrospectively included. The patients were allocated into a hemorrhage group (23 cases) or a non-hemorrhage group (32 cases) based on the occurrence of an intracapsular hemorrhage. The diagnosis was confirmed by physical examination, color ultrasound, magnetic resonance imaging, and puncture findings. BLF was injected into the capsule after draining the cystic fluid under color ultrasound guidance. Patients whose lesions were unchanged or showed minor change after 1 month were treated again using the same method. Changes in lesion size and the number of treatments were recorded. Effectiveness was classified as excellent (volume reduction ≥90%), good (50%≤volume reduction<90%), or poor (volume reduction <50%). RESULTS: In the hemorrhage group, 17, 6, and 0 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 100%. In the non-hemorrhage group, 23, 7, and 2 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 93.8%. There was no significant difference in efficacy rate between groups (P = 0.767). CONCLUSIONS: BLF is an effective and safe treatment for macrocystic LMs with bleeding. The results were similar in patients with and without bleeding. LEVEL OF EVIDENCE: Treatment, Level III.

Matrix metalloproteinases as attractive therapeutic targets for chronic pain: A narrative review.

Chronic pain constitutes an abnormal pain state that detrimentally affects the quality of life, daily activities, occupational performance, and stability of mood. Despite the prevalence of chronic pain, effective drugs with potent abirritation and minimal side effects remain elusive. Substantial studies have revealed aberrant activation of the matrix metalloproteinases (MMPs) in multiple chronic pain models. Additionally, emerging evidence has demonstrated that the downregulation of MMPs can alleviate chronic pain in diverse animal models, underscoring the unique and crucial role of MMPs in different stages and types of chronic pain. This review delves into the mechanistic insights and roles of MMPs in modulating chronic pain. The aberrant activation of MMPs has been linked to neuropathic pain through mechanisms involving myelin abnormalities in peripheral nerve and spinal dorsal horn (SDH), hyperexcitability of dorsal root ganglion (DRG) neurons, activation of N-methyl-d-aspartate receptors (NMDAR) and Ca2+-dependent signals, glial cell activation, and proinflammatory cytokines release. Different MMPs also contribute significantly to inflammatory pain and cancer pain. Furthermore, we summarized the substantial therapeutic potential of MMP pharmacological inhibitors across different types of chronic pain. Overall, our findings underscore the promising therapeutic prospects of MMPs targeting for managing chronic pain.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

Interleukin-17: A Putative Novel Pharmacological Target for Pathological Pain.

Pathological pain imposes a huge burden on the economy and the lives of patients. At present, drugs used for the treatment of pathological pain have only modest efficacy and are also plagued by adverse effects and risk for misuse and abuse. Therefore, understanding the mechanisms of pathological pain is essential for the development of novel analgesics. Several lines of evidence indicate that interleukin-17 (IL-17) is upregulated in rodent models of pathological pain in the periphery and central nervous system. Besides, the administration of IL-17 antibody alleviated pathological pain. Moreover, IL-17 administration led to mechanical allodynia which was alleviated by the IL-17 antibody. In this review, we summarized and discussed the therapeutic potential of targeting IL-17 for pathological pain. The upregulation of IL-17 promoted the development of pathological pain by promoting neuroinflammation, enhancing the excitability of dorsal root ganglion neurons, and promoting the communication of glial cells and neurons in the spinal cord. In general, the existing research shows that IL-17 is an attractive therapeutic target for pathologic pain, but the underlying mechanisms still need to be investigated.

Exploring the oral-gut microbiota during thyroid cancer: Factors affecting the thyroid functions and cancer development.

Thyroid cancer (TC) is categorized into papillary, follicular, medullary, and anaplastic. The TC is increasing in several countries, including China, the United States, the United Kingdom, Canada, France, Australia, Germany, Japan, Spain, and Italy. Thus, this review comprehensively covers the factors that affect thyroid gland function, TC types, risk factors, and symptoms. Lifestyle factors (such as nutrient consumption and smoking) and pollutants (such as chemicals and heavy metals) increased the thyroid-stimulating hormone (TSH) levels which are directly related to TC prevalence. The conventional and recent TC treatments are also highlighted. The role of the oral and gut microbiota as well as the application of probiotics on TC are also discussed. The variations in the composition of oral and gut microbes influence the thyroid function indirectly through alteration in metabolites (such as short-chain fatty acids) that are eminent for cellular energy metabolism. Maintenance of healthy gut and oral microbiota can help in regulating thyroid function by regulating iodine uptake. Oral or gut microbial dysbiosis can be considered as an early diagnosis factor or TC marker. High TSH during TC can increase the oral microbial diversity while disrupting the high ratio of Firmicutes and Bacteroidetes in the gut. Supplementation of probiotics as an adjuvant in TC treatment is beneficial. However, needs more extensive research to explore the direct effect of probiotics on thyroid function.

Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes.

Doxorubicin (DOX), one of the most effective and widely used anticancer drugs, has the major limitation of cancer treatment-related cardiotoxicity (CTRTOX) in the clinic. Reactive oxygen species (ROS) generation and mitochondrial dysfunction are well-known consequences of DOX-induced injury to cardiomyocytes. This study aimed to explore the mitochondrial functional consequences and associated mechanisms of pretreatment with carvedilol, a ß-blocking agent known to exert protection against DOX toxicity. When disease modeling was performed using cultured rat cardiac muscle cells (H9c2 cells) and human iPSC-derived cardiomyocytes (iPSC-CMs), we found that prophylactic carvedilol mitigated not only the DOX-induced suppression of mitochondrial function but that the mitochondrial functional readout of carvedilol-pretreated cells mimicked the readout of cells overexpressing the major regulator of mitochondrial biogenesis, PGC-1α. Carvedilol pretreatment reduces mitochondrial oxidants, decreases cell death in both H9c2 cells and human iPSC-CM and maintains the cellular 'redox poise' as determined by sustained expression of the redox sensor Keap1 and prevention of DOX-induced Nrf2 nuclear translocation. These results indicate that, in addition to the already known ROS-scavenging effects, carvedilol has a hitherto unrecognized pro-reducing property against the oxidizing conditions induced by DOX treatment, the sequalae of DOX-induced mitochondrial dysfunction and compromised cell viability. The novel findings of our preclinical studies suggest future trial design of carvedilol prophylaxis, such as prescreening for redox state, might be an alternative strategy for preventing oxidative stress writ large in lieu of the current lack of clinical evidence for ROS-scavenging agents.

Microfat exerts an anti-fibrotic effect on human hypertrophic scar via fetuin-A/ETV4 axis.

BACKGROUND: Hypertrophic scar is a fibrotic disease following wound healing and is characterized by excessive extracellular matrix deposition. Autologous microfat grafting proves an effective strategy for the treatment thereof as it could improve the texture of scars and relieve relevant symptoms. This study aims to explore the potential mechanisms underlying the anti-fibrotic effect of microfat on hypertrophic scars. METHODS: In this study, we injected microfat into transplanted hypertrophic scars in mouse models and investigated the subsequent histological changes and differential expression of mRNAs therein. As for in vitro studies, we co-cultured microfat and hypertrophic scar fibroblasts (HSFs) and analyzed molecular profile changes in HSFs co-cultured with microfat by RNA sequencing. Moreover, to identify the key transcription factors (TFs) which might be responsible for the anti-fibrotic function of microfat, we screened the differentially expressed TFs and transfected HSFs with lentivirus to overexpress or knockdown certain differentially expressed TFs. Furthermore, comparative secretome analyses were conducted to investigate the proteins secreted by co-cultured microfat; changes in gene expression of HSFs were examined after the administration of the potential anti-fibrotic protein. Finally, the relationship between the key TF in HSFs and the microfat-secreted anti-fibrotic adipokine was analyzed. RESULTS: The anti-fibrotic effect of microfat was confirmed by in vivo transplanted hypertrophic scar models, as the number of α-SMA-positive myofibroblasts was decreased and the expression of fibrosis-related genes downregulated. Co-cultured microfat suppressed the extracellular matrix production of HSFs in in vitro experiment, and the transcription factor ETV4 was primarily differentially expressed in HSFs when compared with normal skin fibroblasts. Overexpression of ETV4 significantly decreased the expression of fibrosis-related genes in HSFs at both mRNA and protein levels. Fetuin-A secreted by microfat could also downregulate the expression of fibrosis-related genes in HSFs, partially through upregulating ETV4 expression. CONCLUSIONS: Our results demonstrated that transcription factor ETV4 is essential for the anti-fibrotic effect of microfat on hypertrophic scars, and that fetuin-A secreted by microfat could suppress the fibrotic characteristic of HSFs through upregulating ETV4 expression. Microfat wields an alleviative influence over hypertrophic scars via fetuin-A/ETV4 axis.

New insight in urological cancer therapy: From epithelial-mesenchymal transition (EMT) to application of nano-biomaterials.

A high number of cancer-related deaths (up to 90) are due to metastasis and simple definition of metastasis is new colony formation of tumor cells in a secondary site. In tumor cells, epithelial-mesenchymal transition (EMT) stimulates metastasis and invasion, and it is a common characteristic of malignant tumors. Prostate cancer, bladder cancer and renal cancer are three main types of urological tumors that their malignant and aggressive behaviors are due to abnormal proliferation and metastasis. EMT has been well-documented as a mechanism for promoting invasion of tumor cells and in the current review, a special attention is directed towards understanding role of EMT in malignancy, metastasis and therapy response of urological cancers. The invasion and metastatic characteristics of urological tumors enhance due to EMT induction and this is essential for ensuring survival and ability in developing new colonies in neighboring and distant tissues and organs. When EMT induction occurs, malignant behavior of tumor cells enhances and their tend in developing therapy resistance especially chemoresistance promotes that is one of the underlying reasons for therapy failure and patient death. The lncRNAs, microRNAs, eIF5A2, Notch-4 and hypoxia are among common modulators of EMT mechanism in urological tumors. Moreover, anti-tumor compounds such as metformin can be utilized in suppressing malignancy of urological tumors. Besides, genes and epigenetic factors modulating EMT mechanism can be therapeutically targeted for interfering malignancy of urological tumors. Nanomaterials are new emerging agents in urological cancer therapy that they can improve potential of current therapeutics by their targeted delivery to tumor site. The important hallmarks of urological cancers including growth, invasion and angiogenesis can be suppressed by cargo-loaded nanomaterials. Moreover, nanomaterials can improve chemotherapy potential in urological cancer elimination and by providing phototherapy, they mediate synergistic tumor suppression. The clinical application depends on development of biocompatible nanomaterials.

Collagen-Specific HSP47+ Myofibroblasts and CD163+ Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS-CoV-2 Infections.

Background Cardiac fibrosis complicates SARS-CoV-2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress-inducible chaperone protein that regulates biosynthesis and secretion of procollagen in heart tissue, with the goal of elucidating molecular mechanisms underlying cardiac fibrosis in subjects with this viral infection. Methods and Results Using human autopsy tissue, immunofluorescence, and immunohistochemistry, we quantified Hsp47+ cells and collagen α 1(l) in hearts from people with SARS-CoV-2 infections. Because macrophages are also linked to inflammation, we measured CD163+ cells in the same tissues. We observed irregular groups of spindle-shaped HSP47+ and CD163+ cells as well as increased collagen α 1(I) deposition, each proximate to one another in "hot spots" of ≈40% of hearts after SARS-CoV-2 infection (HSP47+ P<0.05 versus nonfibrotics and P<0.001 versus controls). Because HSP47+ cells are consistent with myofibroblasts, subjects with hot spots are termed "profibrotic." The remaining 60% of subjects dying with COVID-19 without hot spots are referred to as "nonfibrotic." No control subject exhibited hot spots. Conclusions Colocalization of myofibroblasts, M2(CD163+) macrophages, and collagen α 1(l) may be the first evidence of a COVID-19-related "profibrotic phenotype" in human hearts in situ. The potential public health and diagnostic implications of these observations require follow-up to further define mechanisms of viral-mediated cardiac fibrosis.

Effect of da Vinci robot-assisted versus traditional thoracoscopic bronchial sleeve lobectomy.

OBJECTIVE: To analyze the short-term effect of Da Vinci robot-assisted thoracoscopic (RATS) bronchial sleeve lobectomy, so as to summarize its safety and effectiveness. METHODS: It was a retrospective single-center study with the inclusion of 22 cases receiving RATS lobectomy and 49 cases of traditional thoracoscopic surgery. Further comparison was performed focusing on the baseline characteristics and perioperative performance of the two groups. RESULTS: Compared with the traditional thoracoscopic surgery group, RATS group had more advantages in the number of lymph nodes dissected (P = 0.003), shorter postoperative length of stay in the hospital (P = 0.040), shorter drainage time (P = 0.022), reduced drainage volume (P = 0.001). Moreover, this study found for the first time that there was a shortening in the operation of sleeve lobectomy by using Da Vinci robot-assisted surgical system (P = 0.001). The operation cost of RATS group is more expensive (96000 ± 9100.782 vs 63000 ± 5102.563 yuan; P＜0.001). CONCLUSION: Compared with the traditional thoracoscopic bronchial sleeve lobectomy, RATS lobectomy shows advantages of higher operating sensitivity, shorter operation time, faster postoperative recovery, and more lymph nodes dissected. Collectively, RATS bronchial sleeve lobectomy is safe and effective in operation.

Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.

Nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

The Emerging Role of Quercetin in the Treatment of Chronic Pain.

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.

Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.

SIRT1: A promising therapeutic target for chronic pain.

Chronic pain remains an unresolved problem. Current treatments have limited efficacy. Thus, novel therapeutic targets are urgently required for the development of more effective analgesics. An increasing number of studies have proved that sirtuin 1 (SIRT1) agonists can relieve chronic pain. In this review, we summarize recent progress in understanding the roles and mechanisms of SIRT1 in mediating chronic pain associated with peripheral nerve injury, chemotherapy-induced peripheral neuropathy, spinal cord injury, bone cancer, and complete Freund's adjuvant injection. Emerging studies have indicated that SIRT1 activation may exert positive effects on chronic pain relief by regulating inflammation, oxidative stress, and mitochondrial dysfunction. Therefore, SIRT1 agonists may serve as potential therapeutic drugs for chronic pain.

Adipocytokines: Emerging therapeutic targets for pain management.

Although pain has lower mortality rates than cancer, diabetes and stroke, pain is a predominate source of distress and disability. However, the management of pain remains an enormous problem. Many drugs used to pain treatment have more or less side effects. Therefore, the development of novel therapeutic target is critical for the treatment of pain. Notably, studies have shown that adipocytokines have a dual role in pain. Growing shreds of evidence shows that the levels of adipocytokines are upregulated or downregulated in the development of pain. In addition, substantial evidence indicates that regulation of adipocytokines levels in models of pain attenuates or promotes pain behaviors. In this review, we summarized and discussed the effect of adipocytokines in pain. These evidence indicates that adipocytokines attenuate or promote pain behaviors through interacting with their receptors, activating serotonin pathway, interacting with µ-opioid receptor, activating microglia, infiltrating macrophage and so on. Overall, adipocytokines have some potential in treating pain, but the underlying mechanisms remain unclear and need to be further studied.

Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation.

BACKGROUND: Our previous study indicated that reactive oxygen species (ROS) are critically involved in chronic pain. Sestrin2 (Sesn2), a novel stress-inducible protein, is evidenced to reduce the generation of ROS. The study examined the role of Sesn2 in osteoarthritis (OA) pain and delineated the underlying molecular mechanisms. METHODS: In the present study, we investigated the impact of Sesn2 on mitochondrial biogenesis in a rat model of OA pain. After adeno-associated viral (AAV)-Sesn2EGFP was injected for 14 days, OA was induced by intra-articular injection of monosodium iodoacetate (MIA). We assessed pain behaviors (weight-bearing asymmetry and paw withdrawal threshold) and explored possible mechanisms in the L4-6 spinal cord. RESULTS: Our results showed that overexpression of Sesn2 in the spinal cord alleviated pain behaviors in OA rats. Moreover, overexpression of Sesn2 increased the activity of AMP-activated protein kinase (AMPK) signaling and significantly restored mitochondrial biogenesis. Besides, Sesn2 overexpression inhibited the activation of astrocytes and microglia, and decreased the production of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the spinal cord of the OA pain rats. These effects were significantly reversed by an AMPK inhibitor. CONCLUSIONS: Collectively, these results suggest that Sesn2 overexpression ameliorates mechanical allodynia and weight-bearing asymmetry in OA rats via activation of AMPK/PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Moreover, Sesn2 overexpression attenuates OA-induced neuroinflammation at least partly by activating AMPK signaling. Sesn2 may become an encouraging therapeutic strategy for OA pain relief and other disorders.

ß2-adrenoreceptor agonist ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of mitochondrial biogenesis.

Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment and so far no effective drug is available for treatment of the serious side effect. Previous studies have demonstrated ß2-adrenoreceptor (ADRB2) agonists can attenuate neuropathic pain. However, the role of ADRB2 in paclitaxel -induced neuropathic pain (PINP) remains unclear. In this study, we investigated the effect of formoterol, a long-acting ADRB2 agonist, and related mechanisms in PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to evaluate mechanical allodynia. Western blot was used to examine the expression of ADRB2, peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factors 1 (NRF1) and mitochondrial transcription factor A (TFAM) and the immunofluorescence was to detect the cellular localization of ADRB2 and PGC-1α in the spinal cord. Moreover, we measured mitochondrial DNA (mtDNA) copy number by qPCR. In our study, formoterol attenuated established PINP and delayed the onset of PINP. Formoterol restored ADRB2 expression as well as mtDNA copy number and PGC-1α, NRF1, and TFAM protein expression, which are major genes involved in mitochondrial biogenesis, in the spinal cord of PINP rats. Moreover, we found the analgesic effect of formoterol against PINP was partially abolished by PGC-1α inhibitor SR-18292. Collectively, these results demonstrated the activation of ADRB2 with formoterol ameliorates PINP at least partially through induction of mitochondrial biogenesis.