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Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin‐induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL‐18, KIM‐1, and NGAL levels, whereas ALA treatment significantly reduced KIM‐1 levels compared to the gentamicin‐only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF‐2, CAS‐3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF‐B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin‐induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections. [ABSTRACT FROM AUTHOR]

The aim of our study was to investigate the potential effects of alpha-lipoic acid (ALA) and resatorvid (RES) on gentamicin-induced hepatotoxicity. Thirty-four rats were divided into the following groups: Healthy control (n=6), Gentamicin (GNT, 80 mg/kg, n=7), GNT + Sham (10% hydroalcoholic solution, n=7), GNT + RES (5 mg/kg, n=7), and GNT + ALA (100 mg/kg, n=7). In the GNT group, a statistically significant increase in ALT levels and a significant decrease in total protein (TP) and albumin (TA) levels were observed compared to the control group. On the other hand, a significant increase in NRF-2, NF-κB, NR4A2 and CAS-3 expression was detected in the GNT group as compared to the control group. Simultaneous administration of RES or ALA with GNT led to a significant decrease in ALT levels compared to the GNT group. In addition, these treatments caused a significant increase in TP and TA levels. RES administration caused a significant decrease in gene expression compared to the GNT group. On the other hand, simultaneous ALA treatment with GNT caused a significant decrease in NRF-2, CAS-3 and NF-κB expression and partially reduced NR4A2 expression. These findings draw attention to the potential of RES or ALA to alleviate gentamicin-induced hepatotoxicity and to their increased efficacy in the treatment of infections. [ABSTRACT FROM AUTHOR]

Abstract Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin‐induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL‐18, KIM‐1, and NGAL levels, whereas ALA treatment significantly reduced KIM‐1 levels compared to the gentamicin‐only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF‐2, CAS‐3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF‐B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin‐induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections.

Abstract Background Acute lung injury (ALI) is a critical inflammatory response syndrome that rapidly develops into acute respiratory distress syndrome (ARDS). Currently, no effective therapeutic modalities are available for patients with ALI/ARDS. According to recent studies, inhibiting both the release of pro-inflammatory cytokines and the formation of reactive oxygen species (ROS) as early as possible may be a promising therapy for ALI. Results In this study, a ROS-responsive nano-delivery system based on oxidation-sensitive chitosan (Ox-CS) was fabricated for the simultaneous delivery of Ce NPs and RT. The in vitro experiments have shown that the Ox-CS/Ceria-Resatorvid nanoparticles (Ox-CS/CeRT NPs) were rapidly and efficiently internalised by inflammatory endothelial cells. Biological evaluations validated the significant attenuation of ROS-induced oxidative stress and cell apoptosis by Ox-CS/CeRT NPs, while maintaining mitochondrial function. Additionally, Ox-CS/CeRT NPs effectively inhibited the release of pro-inflammatory factors. After intraperitoneal (i.p.) administration, Ox-CS/CeRT NPs passively targeted the lungs of LPS-induced inflamed mice and released the drug activated by the high ROS levels in inflammatory tissues. Finally, Ox-CS/CeRT NPs significantly alleviated LPS-induced lung injury through inhibiting both oxidative stress and pro-inflammatory cytokine expression. Conclusions The created Ox-CS/CeRT NPs could act as a prospective nano-delivery system for a combination of anti-inflammatory and anti-oxidant therapy of ALI. Graphical Abstract

Background: Acute lung injury (ALI) is a critical inflammatory response syndrome that rapidly develops into acute respiratory distress syndrome (ARDS). Currently, no effective therapeutic modalities are available for patients with ALI/ARDS. According to recent studies, inhibiting both the release of pro-inflammatory cytokines and the formation of reactive oxygen species (ROS) as early as possible may be a promising therapy for ALI. Results: In this study, a ROS-responsive nano-delivery system based on oxidation-sensitive chitosan (Ox-CS) was fabricated for the simultaneous delivery of Ce NPs and RT. The in vitro experiments have shown that the Ox-CS/Ceria-Resatorvid nanoparticles (Ox-CS/CeRT NPs) were rapidly and efficiently internalised by inflammatory endothelial cells. Biological evaluations validated the significant attenuation of ROS-induced oxidative stress and cell apoptosis by Ox-CS/CeRT NPs, while maintaining mitochondrial function. Additionally, Ox-CS/CeRT NPs effectively inhibited the release of pro-inflammatory factors. After intraperitoneal (i.p.) administration, Ox-CS/CeRT NPs passively targeted the lungs of LPS-induced inflamed mice and released the drug activated by the high ROS levels in inflammatory tissues. Finally, Ox-CS/CeRT NPs significantly alleviated LPS-induced lung injury through inhibiting both oxidative stress and pro-inflammatory cytokine expression. Conclusions: The created Ox-CS/CeRT NPs could act as a prospective nano-delivery system for a combination of anti-inflammatory and anti-oxidant therapy of ALI. [ABSTRACT FROM AUTHOR]

Abstract Objectives Innate immunity plays a significant role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA), which is characterized by synovial inflammation and condylar cartilage degradation. We are urged to investigate the impact of Resatorvid, a preventative drug that inhibits Toll-like receptor 4 (TLR4), on experimental inflammatory TMJOA pathology. Methods An intra-articular injection of complete Freund’s adjuvant (CFA) was used to induce an experimental inflammatory mouse TMJOA model, and TLR4 expression was identified by immunofluorescent labeling. Intraperitoneal injections of Resatorvid were administered to CFA-induced TMJOA mice, and the pathology of TMJOA animals with and without Resatorvid treatment was examined by H&E, Safranin-O/Fast Green, and TRAP staining, as well as micro-CT, immunohistochemistry, and immunofluorescence. The impact of Resatorvid on chondrocyte pyroptosis and macrophage inflammation was further investigated using ATDC5 chondrocytes and RAW264.7 macrophages pretreated with relevant antagonists. Results CFA-induced TMJOA mice revealed remarkable synovial inflammation, together with a time course of cartilage degradation and bone destruction, with TLR4 elevated in the synovium and condylar cartilage. Prophylactic treatment with Resatorvid mitigated synovial inflammation, cartilage degeneration, and bone destruction in CFA-induced TMJOA mice and downregulated MyD88/NF-κB expression. Ex vivo studies demonstrated that Resatorvid treatment alleviated NOD-like receptor protein 3 (NLRP3)-mediated chondrocyte pyroptosis and degeneration and relieved macrophage inflammation by preventing reactive oxygen species (ROS) production through NLRP3 signaling. Conclusion Prophylactic treatment with Resatorvid alleviates TMJOA pathology by inhibiting chondrocyte pyroptosis and degeneration, as well as ROS-induced macrophage inflammation, through TLR4/MyD88/NF-κB/NLRP3.

BackgroundAn increase in the demand for a functional cure has accelerated research on new methods of therapy for chronic hepatitis B, which is mainly focused on restoring antiviral immunity for controlling viral infections. Previously, we had described elongation factor Tu GTP-binding domain containing 2 (EFTUD2) as an innate immune regulator and suggested that it might be an antiviral target.MethodsIn this study, we generated the Epro-LUC-HepG2 cell model for screening compounds that target EFTUD2. Plerixafor and resatorvid were screened from 261 immunity and inflammation-related compounds due to their ability to highly upregulate EFTUD2. The effects of plerixafor and resatorvid on hepatitis B virus (HBV) were examined in HepAD38 cells and HBV-infected HepG2-NTCP cells.ResultsThe dual-luciferase reporter assays showed that the EFTUD2 promoter hEFTUD2pro-0.5 kb had the strongest activity. In Epro-LUC-HepG2 cells, plerixafor and resatorvid significantly upregulated the activity of the EFTUD2 promoter and the expression of the gene and protein. In HepAD38 cells and HBV-infected HepG2-NTCP cells, treatment with plerixafor and resatorvid strongly inhibited HBsAg, HBV DNA, HBV RNAs, and cccDNA in a dose-dependent manner. Furthermore, the anti-HBV effect was enhanced when entecavir was administered along with either of the previous two compounds, and the effect could be blocked by knocking down EFTUD2.ConclusionWe established a convenient model for screening compounds that target EFTUD2 and further identified plerixafor and resatorvid as novel HBV inhibitors in vitro. Our findings provided information on the development of a new class of anti-HBV agents that act on host factors rather than viral enzymes.

Weixu Luo,1,* Yuanshan Han,2,* Pan Meng,1 Qin Yang,3 Hongqing Zhao,1 Jia Ling,1 Yuhong Wang1 1Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Medical Experimental Innovation Center, The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 3Department of Pharmacy, Yueyang Hospital of Traditional Chinese Medicine, Yueyang, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhong WangInstitute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of ChinaEmail wyhwyh1007@126.comBackground: Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD).Methods: The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo.Results: The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function.Conclusion: In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.Keywords: resatorvid, breast cancer complicated with depression(BCCD), microglia(MG), TLR4/NF-κB/NLRP3 signaling pathway

Postsurgical recurrence of breast cancer is closely related to the inflammatory tumor microenvironment evoked by surgical wounds. Toll-like receptor 4 (TLR4) signaling contributes to NF- κ B activation thus secreting various inflammatory cytokines. Herein, we developed an in situ photo-crosslinked hydrogel (D/T gel) concurrently loaded with doxorubicin (DOX) and a TLR4 antagonist, resatorvid (TAK-242). Its therapeutic effect against breast cancer postsurgical relapse was accomplished through remodeling the proinflammatory tumor microenvironment. The obtained gel network exhibited ideal biodegradability and biocompatibility, which motivated dermal wound healing in the full thickness wound model in mice. Despite the initial burst release of DOX, D/T gels exhibited extended-release of both DOX and TAK-242 for up to 21 days in vitro. TAK-242 was demonstrated to inhibit the lipopolysaccharide-induced NF- κ B activation and downregulate TLR4 levels in both RAW264.7 and 4T1 cells. In a 4T1-Luc tumor postsurgical recurrence model, D/T gel significantly suppressed recurrent tumor growth by elevating the concentrations of DOX and TAK-242 at the tumor sites and remodeling the TLR4 activation-induced proinflammatory microenvironment. Overall, the D/T gel platform technology is proven to deliver therapeutics directly to the surgical wound bed, attenuating the dual inflammatory responses induced by DOX and surgical wounding thus greatly potentiating its efficacy in preventing postsurgical tumor recurrence. Postsurgical recurrence of breast cancer is closely related to the inflammatory tumor microenvironment (TME) evoked by surgical wounds. Although chemotherapeutics lead to extensive residual tumor cell necrosis, multiple inflammatory cytokines are secreted simultaneously, which are conducive to tumor recurrence. In this work, a TLR4 antagonist, TAK-242, was combined with DOX to reverse the dual inflammatory TME induced by surgical wounding and chemotherapy. To elevate the concentration of therapeutics at the tumor site, a photocrosslinked hydrogel (D/T gel) implant coloaded with TAK-242 and DOX was developed and applied on the postsurgical bed. Consequently, D/T gel attenuated the dual inflammatory responses and greatly potentiated its efficacy in preventing postsurgical tumor recurrence. [Display omitted] [ABSTRACT FROM AUTHOR]

Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage (HIBD). Although previous studies have implicated Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) in the neuroinflammatory response elicited by brain injury, the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear. We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD. Hence, we established a neonatal HIBD rat model using the Rice-Vannucci method, and injected 0.75, 1.5, or 3 mg/kg of the TLR4 inhibitor resatorvid (TAK-242) 30 minutes after hypoxic ischemia. Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema, alleviate neuronal damage and neurobehavioral impairment, and decrease the expression levels of TLR4, phospho-NF-κB p65, Beclin-1, microtubule-associated protein l light chain 3, tumor necrosis factor-α, and interleukin-1β in the hippocampus. Thus, TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway. This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University, China (approval No. 20180114-15) on January 14, 2018.

Background: Despite all advances in the treatment of ovarian cancer (OC), it remains the most lethal gynecological malignancy worldwide. There are growing amounts of evidence indicating the role of inflammation in initiating chemoresistance. Therefore, Toll-like receptor 4 (TLR4), a mediator of inflammation in cancer cells, may be a proper anticancer target.Methods: The effects of TLR4 activation by LPS was studied using MTT, colony formation, staining, scratch, and qRT-PCR assays as the first step. Then the same assays, in addition to anoikis resistance, cell cycle and annexin V/PI apoptosis tests, were used to investigate whether the inhibition of TLR4 using a small molecule inhibitor, TAK-242, could suppress the proliferation of various OC cell lines: A2780CP, 2008C13, SKOV3, and A2780S.Results: The activation of TLR4 using LPS showed enhanced proliferation and invasion in the TLR4-expressing cell line (SKOV3). Next, treatment with the inhibitor revealed that TAK-242 suppressed the inflammatory condition of ovarian cancer cells, as evident by the down-regulation of IL-6 gene expression. We also found that TAK-242 halted cancer cell proliferation by inducing cell cycle arrest and apoptosis through the modulation of genes involved in these processes. Given the fact that the overexpression of TLR4 contributes to drug resistance, it was tempting to investigate the effect of TAK-242 in a combined-modality strategy. Interestingly, we found enhanced cytotoxicity when TAK-242 was used in combination with doxorubicin.Conclusion: TAK-242 serves as an appealing therapeutic strategy in the TLR4-expressing OC cells, either in the context of monotherapy or in combination with a chemotherapeutic drug. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous "damage-associated" ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases. [ABSTRACT FROM AUTHOR]

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll-like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 [wild-type,(WT)] and/or TLR4 knockout (TLR4-/-) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-β increased by 45%, 72%, and 38%, respectively (P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions, concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice (P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4-/- and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor-alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment. [ABSTRACT FROM AUTHOR]

Background: An increase in the demand for a functional cure has accelerated research on new methods of therapy for chronic hepatitis B, which is mainly focused on restoring antiviral immunity for controlling viral infections. Previously, we had described elongation factor Tu GTP-binding domain containing 2 (EFTUD2) as an innate immune regulator and suggested that it might be an antiviral target., Methods: In this study, we generated the Epro-LUC-HepG2 cell model for screening compounds that target EFTUD2. Plerixafor and resatorvid were screened from 261 immunity and inflammation-related compounds due to their ability to highly upregulate EFTUD2. The effects of plerixafor and resatorvid on hepatitis B virus (HBV) were examined in HepAD38 cells and HBV-infected HepG2-NTCP cells., Results: The dual-luciferase reporter assays showed that the EFTUD2 promoter hEFTUD2pro-0.5 kb had the strongest activity. In Epro-LUC-HepG2 cells, plerixafor and resatorvid significantly upregulated the activity of the EFTUD2 promoter and the expression of the gene and protein. In HepAD38 cells and HBV-infected HepG2-NTCP cells, treatment with plerixafor and resatorvid strongly inhibited HBsAg, HBV DNA, HBV RNAs, and cccDNA in a dose-dependent manner. Furthermore, the anti-HBV effect was enhanced when entecavir was administered along with either of the previous two compounds, and the effect could be blocked by knocking down EFTUD2., Conclusion: We established a convenient model for screening compounds that target EFTUD2 and further identified plerixafor and resatorvid as novel HBV inhibitors in vitro . Our findings provided information on the development of a new class of anti-HBV agents that act on host factors rather than viral enzymes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Zhu C, Xiao F, Hong J, et al. EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway. J Virol. 2015;8913:6608–6618, (Copyright © 2023 Cai, Li, Hu, Xu, Yuan, Zhang, Feng, Liu, Li and Zhu.)

Toll-like receptor 4 (TLR4) is considered to play an important role in neuronal death in animal models and could be an important therapeutic target following traumatic brain injury (TBI). Resatorvid is a small molecule, commonly accepted to inhibit TLR4-mediated pathway. The purpose of this study was to investigate the neuroprotective effect of resatorvid after TBI. Our data revealed that inhibition of TLR4 by resatorvid attenuated the development of TBI in mouse model. And we found that resatorvid administration dramatically reduced neuronal apoptosis. To investigate the cellular mechanism, we evaluated the expression of transforming growth factor-β-activated kinase 1 (TAK1), which plays a crucial role in TLR4 signal transduction pathway and is activated by phosphorylation in response to TBI. In addition, enzyme-linked immunosorbent assay was used to determine the expression of tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) at 24h after injury. Our results showed that resatorvid treatment significantly reduced the protein levels of TAK1, p-TAK1, TNF-α, and IL-1β compared with vehicle treatment. Importantly, the delayed therapy (4h post injury) once daily consecutively for 5days ameliorated brain damage and improved neurological recovery, suggesting that this drug has a wide therapeutic time window. Clinically, we observed that TLR4 and TAK1 expression was significantly increased in human contusion specimens after TBI. These data provide an experimental rationale for the evaluation of TLR4 as a clinical target and therapeutic implication of resatorvid in human traumatic brain injury. [ABSTRACT FROM AUTHOR]

Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage (HIBD). Although previous studies have implicated Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) in the neuroinflammatory response elicited by brain injury, the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear. We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD. Hence, we established a neonatal HIBD rat model using the Rice-Vannucci method, and injected 0.75, 1.5, or 3 mg/kg of the TLR4 inhibitor resatorvid (TAK-242) 30 minutes after hypoxic ischemia. Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema, alleviate neuronal damage and neurobehavioral impairment, and decrease the expression levels of TLR4, phospho-NF-κB p65, Beclin-1, microtubule-associated protein l light chain 3, tumor necrosis factor-α, and interleukin-1β in the hippocampus. Thus, TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway. This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University, China (approval No. 20180114-15) on January 14, 2018., Competing Interests: None

Background: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention., Methods: A structured search of bibliographic databases for peer-reviewed research literature revealed 139 articles including our own that are presented and critically evaluated in this TLR4-directed review., Objective: To understand the molecular role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation. The specific focus of this review is on recent published evidence suggesting that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention., Results: Cumulative experimental evidence indicates that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified as a novel class of molecular therapeutics. TLR4 antagonists are in various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling that may also contribute to skin photodamage and photocarcinogenesis in human populations., Conclusion: Future research should explore the skin photoprotective and photochemopreventive efficacy of topical TLR4 antagonism if employed in conjunction with other molecular strategies including sunscreens., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)