Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages . Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. , we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

This study aims to investigate the effects of astragalus polysaccharide (APS) on diabetic retinopathy through the SHH-Gli1-AQP1 pathway. The anti-type 2 diabetes mellitus (T2DM) targets of APS were identified through comprehensive searches of drug and disease-related databases. A protein-protein interaction network was then constructed, followed by GO and KEGG enrichment analyses. Molecular docking simulations were performed to evaluate the interactions of APS and metformin with Gli1 and AQP1. An T2DM rat model was established via streptozotocin (STZ) injection and treated with metformin and varying doses of APS for 12 weeks. Histological changes in retinal cells were assessed using H&E and PAS staining. The expression levels of AQP1, Gli1, and SHH in the retina were measured using immunohistochemistry, Western blotting, immunofluorescence, and ELISA. Additionally, mRNA expression of AQP1, Gli1, and SHH was quantified by RT-qPCR. Bioinformatic analyses indicated that Gli1 and AQP1, key components of the SHH-Gli1- AQP1 signaling pathway, may be associated with T2DM. Subsequent experiments demonstrated that the STZ-induced T2DM rats exhibited significant retinal damage, which was notably mitigated by both APS and metformin treatments. Furthermore, the SHH-Gli1-AQP1 signaling pathway was found to be overactivated in STZ-induced T2DM rats. Treatment with APS and metformin significantly reduced the elevated expression levels of SHH, Gli1, and AQP1. APS effectively inhibits retinal damage of STZ-induced T2DM rats by restraining the SHH-Gli1-AQP1 signaling pathway.

To investigate whether Tasquinimod can influence cisplatin resistance in drug-resistant ovarian cancer (OC) cell lines by regulating histone deacetylase 4 (HDAC4) or p21, we explored its effects on the cell cycle, and associated mechanisms. RT-PCR and Western blot analyses, flow cytometry, CCK8 assay, and immunofluorescence were utilized to investigate the effects of Tasquinimod on gene expression, cell cycle, apoptosis, viability, and protein levels in OC cells. The results showed that Tasquinimod inhibited cell viability and promoted apoptosis in SKOV3/DDP (cisplatin) and A2780/DDP cells more effectively than DDP alone. In combination with cisplatin, Tasquinimod further enhanced cell apoptosis and reduced cell viability in these cell lines, an effect that could be reversed following HDAC4 overexpression. Tasquinimod treatment down-regulated HDAC4, Bcl-2, and cyclin D1, and CDK4 expression and up-regulated the cleaved-Caspase-3, and p21 expression in SKOV3/DDP and A2780/ DDP cells. Additionally, Tasquinimod inhibited DDP resistance in OC/DDP cells. These effects were similarly observed in OC mouse models treated with Tasquinimod. In conclusion, Tasquinimod can improve OC cells' sensitivity to DDP by down-regulating the HDAC4/p21 axis, offering insights into potential strategies for overcoming cisplatin resistance in OC.

Sepsis is a potentially fatal infectious disease that easily causes shock and numerous organ failures. The kidney is one of the most susceptible to injury. Early intervention and renal protection significantly minimize patient mortality. Oligomeric proanthocyanidin (OPC), a naturally occurring plant compound, has a high potential for renal protection. This study was aimed at exploring the potential renoprotective role of OPC in sepsis-related renal tubular injury. C57/B6 mice were intraperitoneally injected with lipopolysaccharide (LPS) to simulate sepsis-related acute kidney injury . Renal function and pathology were assessed. RNA sequencing examined OPC mechanisms against LPS-induced renal injury. Oxidative stress indicators and inflammatory cytokines in blood serum and renal tissues were evaluated. , MTT assays assess cell viability. Apoptosis cells were detected using Hoechst 33342 and propidium iodide staining. Western blot assessed PI3K/AKT and NFκB signaling pathway proteins. OPC reduced LPS-induced renal tubular injury, improved renal functions and pathological changes, restored glutathione content, superoxide dismutase activity, and catalase activity, inhibited malondialdehyde overproduction, and suppressed LPS-induced overproduction of pro-inflammatory cytokines and the decline of anti-inflammatory cytokines. OPC attenuated LPS-induced cell morphological injury, reduced cell viability loss, and recovered the changes in proteins involved in PI3K/AKT and NFκB signaling pathways in MTEC cells. OPC protects against LPSinduced renal tubular injury by counteracting oxidative stress, inhibiting inflammatory responses, activating the PI3K/AKT signaling pathway, and inhibiting the NFκB signaling pathway. It may provide a viable solution to lessen renal injury in patients with sepsis.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Geraniin, a polyphenol derived from the fruit peel of L., has been shown to possess anti-inflammatory and antioxidant properties in the cardiovascular system. The present study explored whether geraniin could protect against an isoproterenol (ISO)-induced cardiac hypertrophy model. Mice in the ISO group received an intraperitoneal injection of ISO (5 mg/kg) once daily for 9 days, and the administration group were injected with ISO after 5 days of treatment with geraniin or spironolactone. Potential therapeutic effects and related mechanisms analysed by anatomical coefficients, histopathology, blood biochemical indices, reverse transcription-PCR and immunoblotting. Geraniin decreased the cardiac pathologic remodeling and myocardial fibrosis induced by ISO, as evidenced by the modifications to anatomical coefficients, as well as the reduction in collagen I/III á1mRNA and protein expression and cross-sectional area in hypertrophic cardiac tissue. In addition, geraniin treatment reduced ISO-induced increase in the mRNA and protein expression levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α, whereas ISO-induced IL-10 showed the opposite behaviour in hypertrophic cardiac tissue. Further analysis showed that geraniin partially reversed the ISO-induced increase in malondialdehyde and nitric oxide, and the ISO-induced decrease in glutathione, superoxide dismutase and glutathione. Furthermore, it suppressed the ISO-induced cellular apoptosis of hypertrophic cardiac tissue, as evidenced by the decrease in Bcell lymphoma-2 (Bcl-2)-associated X/caspase-3/caspase-9 expression, increase in Bcl-2 expression, and decrease in TdT-mediated dUTP nick-end labeling-positive cells. These findings suggest that geraniin can attenuate ISO-induced cardiac hypertrophy by inhibiting inflammation, oxidative stress and cellular apoptosis.

Lactic acid bacteria are known to have various effects on the immune system. The type and extent of the effect differ, depending on the type of lactic acid bacteria. This study aimed to investigate the effects of Lactobacillus johnsonii bacterin on mouse-derived immune cells. Treating splenocytes with bacterin slightly increased the metabolic activity. Additionally, the expression of the activation marker CD25 and production of the Th1-type inflammatory cytokine interferon (IFN)- gamma increased. We confirmed that the increase in IFN-gamma production due to stimulation was mainly due to T and B cells among splenocytes. Treating dendritic cells (DCs) with bacterin at concentrations of 10 and 10 cfu/ ml significantly increased tumor necrosis factor-alpha, a pro-inflammatory cytokine, and interleukin-12, a cell-mediated immunity cytokine. Additionally, the expression of surface markers increased. Allogeneic mixed lymphocyte reactions showed that reduced the antigen-presenting ability of DCs. In cocultures of DCs and splenocytes, decreased cellular metabolic activity and increased cell death. upregulated the expression of programmed death ligand 1 on DCs. The findings of this study indicate that bacterin has immunomodulatory and immunostimulatory effects. While increased the expression of cytokines and surface markers of immune cells, it modulated DC-mediated immune response. Further studies are needed to determine the effects of bacterin on DCs and related immune cells.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Donepezil, an acetylcholinesterase inhibitor, is widely used for managing the symptoms of Alzheimer's disease (AD), yet its clinical response varies widely among individuals. This study aims to investigate the influence of CYP2D6 genetic variants on donepezil concentration, treatment response, and adverse effects in Korean patients with AD dementia. We conducted a longitudinal study involving 76 patients receiving either 5 mg or 10 mg of donepezil. Genetic testing identified 9 CYP2D6 alleles, categorizing patients by metabolizing abilities. Blood sampling for plasma concentrations of donepezil were performed at steady-state. Mini-Mental State Examination (MMSE) were conducted at 12, 24 and 36 months after the initiation of treatment. Adverse events were collected throughout the study period. Donepezil plasma concentrations differed significantly among metabolizer statuses (mean 56.8 ± 27.1 ng/ml in normal metabolizers vs. 69.6 ± 30.1 ng/ml in intermediate metabolizers, p = 0.042), but these differences did not affect cognitive function over three years as assessed by MMSE. Additionally, there was no significant correlation between donepezil plasma concentration and adverse events. Our study is the first to elucidate the associations between CYP2D6 genotype and the concentration, clinical response or adverse events of donepezil in Korean patients with AD dementia. Larger studies are necessary to fully understand the impact of CYP2D6 genetic variants on therapeutic outcomes with donepezil.

Echinochrome A (Ech A) isolated from marine organisms is a therapeutic effector for various cardiovascular diseases, but its precise mechanisms are unclear. This study identified the role and mechanisms mediating the effects of Ech A on the migration of vascular smooth muscle cells (VSMCs) induced by high-mobility group box 1 (HMGB1). Compared to the control cells, the migration of VSMCs stimulated with HMGB1 (100 ng/ml) was markedly increased, which was significantly attenuated in cells pretreated with MPIIIB10 (100 ng/ml), a neutralizing monoclonal antibody for osteopontin (OPN). In VSMCs stimulated with HMGB1, the increased expression of OPN mRNA and protein was accompanied by an increased OPN promoter activity. In reporter gene assays using OPN promoter-luciferase constructs, the promoter region 538-234 bp of the transcription start site containing the binding sites for activator protein 1 (AP-1) was shown to be responsible for the increased transcriptional activity by HMGB1. In addition, the binding activity of AP-1 was increased in HMGB1-stimulated cells, highlighting the pivotal role of AP-1 on OPN expression in HMGB1-stimulated VSMCs. An examination of the vascular effects of Ech A showed that the increased AP-1 binding/promoter activities and OPN expression induced by HMGB1 were attenuated in cells pretreated with Ech A (3 or 10 μM). Similarly, Ech A inhibited HMGB1-induced VSMC migration in a concentration-dependent manner. These findings suggest that Ech A inhibits VSMC migration by suppressing OPN expression. Hence, Ech A is suggested as a potential therapeutic strategy for vascular remodeling in the injured vasculatures.

The inflammasome is a cytosolic multiprotein platform that plays a key role in the inflammatory response, an essential innate immune response that protects the body from pathogens and cellular danger signals. Autophagy is a fundamental cellular mechanism that maintains homeostasis through the elimination and recycling of dysfunctional molecules and subcellular elements. Many previous studies have demonstrated a functional interplay between canonical inflammasomes that were earlier discovered and autophagy in inflammatory responses and diseases. Given the increasing evidence that non-canonical inflammasomes are unique and key factors in inflammatory responses, the functional interplay between non-canonical inflammasomes and autophagy is noteworthy. Recent studies have demonstrated that non-canonical inflammasomes and autophagy are functionally correlated with inflammatory responses and diseases. This review comprehensively discusses recent studies that have investigated the functional interplay of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4, with autophagy and autophagy-related proteins in inflammatory responses and diseases and provides insight into the development of novel anti-inflammatory therapeutics by modulating the functional interplay between non-canonical inflammasomes and autophagy.

Heart diseases are a significant contributor to global morbidity and mortality, and despite their diverse and complex mechanisms, treatment options remain limited. Maltol, a natural compound with antioxidant and anti-inflammatory activities, exhibits potential for addressing this need. This study evaluates the cardioprotective effects of maltol in isoproterenol (ISO)-induced cardiac stress models and Duchenne muscular dystrophy (DMD). Maltol's cardiac cytotoxicity was assessed in rodent (H9c2) and human (AC16) cells and compared with that of dapagliflozin to illustrate its cardiac safety. In ISO-induced stress models, maltol significantly reduced hypertrophic markers and inflammation while enhancing autophagy and antioxidant pathways. In the mdx mice, a DMD model, maltol treatment improved cardiac contractility and reduced pathogenic remodeling. Enhanced phosphorylation of phospholamban and trends toward higher SERCA2a expression indicated enhanced Ca handling, which is crucial in DMD cardiomyopathy. This study demonstrated that maltol has the potential to provide therapeutic benefits for DMD and other cardiac conditions characterized by hypertrophy and inflammation, as evidenced by its well-known antioxidant properties, low cytotoxicity, and capacity to enhance cardiac function and Ca handling.

The proliferation and migration of vascular smooth muscle cells (VSMCs) are key contributors to the development of atherosclerosis and restenosis. We investigated the impact of rosuvastatin (RSV) on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of VSMCs, with a focus on the Akt/mTOR-autophagy signaling pathways. The cytotoxicity of RSV was assessed using MTT and annexin V staining, while the proliferation and migration capabilities of PDGF-BB-induced VSMCs were evaluated using MTT and cell migration assays. Confocal microscopy was employed to examine autophagic cell images, and protein expressions were analyzed via Western blotting. Our key findings revealed that RSV inhibited PDGF-BB-induced proliferation and migration of VSMCs, significantly reducing the expression of proliferating cell nuclear antigen and matrix metalloproteinase-2, which are crucial for these processes. RSV also enhanced autophagy in PDGF-BB-stimulated cells by inducing the maturation of microtubule-associated protein light chain 3 and increasing the expression of Beclin-1, autophagy related (Atg)3, Atg5, and Atg7. The regulatory effects of RSV on PDGF-BB-induced autophagy, proliferation, and migration were associated with the suppression of the Akt/mTOR signaling pathway. These findings suggest that RSV may have potential therapeutic benefits in preventing and treating vascular diseases by targeting the Akt/mTOR pathway and inducing autophagy.

PKD1 regulates a number of cellular processes through the formation of complexes with the PKD2 ion channel or transient receptor potential classical (TRPC) 4 in the endothelial cells. Although Ca modulation by polycystins has been reported between PKD1 and TRPC4 channel or TRPC1 and PKD2, the function with TRPC subfamily regulated by PKD2 has remained elusive. We confirmed TRPC4 or TRPC5 channel activation via PKD1 by modulating G-protein signaling without change in TRPC4/C5 translocation. The activation of TRPC4/C5 channels by intracellular 0.2 mM GTPγS was not significantly different regardless of the presence or absence of PKD1. Furthermore, the C-terminal fragment (CTF) of PKD1 did not affect TRPC4/C5 activity, likely due to the loss of the N-terminus that contains the G-protein coupled receptor proteolytic site (GPS). We also investigated whether TRPC1/C4/C5 can form a heterodimeric channel with PKD2, despite PKD2 being primarily retained in the endoplasmic reticulum (ER). Our findings show that PKD2 is targeted to the plasma membrane, particularly by TRPC5, but not by TRPC1. However, PKD2 did not coimmunoprecipitate with TRPC5 as well as with TRPC1. PKD2 decreased both basal and La-induced TRPC5 currents but increased MR-mediated TRPC5 currents. Interestingly, PKD2 increased STAT3 phosphorylation with TRPC5 and decreased STAT1 phosphorylation with TRPC1. To be specific, PKD2 and TRPC1 compete to bind with TRPC5 to modulate intracellular Ca signaling and reach the plasma membrane. This interaction suggests a new therapeutic target in TRPC5 channels for improving vascular endothelial function in polycystic kidney disease.

Atherosclerosis is a major contributor to cardiovascular disease, characterized by inflammation and lipid accumulation in arterial walls, leading to plaque formation. Elevated low-density lipoprotein cholesterol is a primary risk factor for atherosclerosis. All-trans retinoic acid (ATRA), a metabolite of vitamin A, has demonstrated anti-inflammatory effects and potential in regulating vascular injury. 9-cisretinoic acid (9cRA) is an active metabolite of vitamin A and activates the retinoid X receptor. This study investigates whether potassium retinoate (PA9RA), a synthetic combination of ATRA and 9cRA, offers superior efficacy in treating atherosclerosis compared to established treatments such as clopidogrel and atorvastatin. Male ApoE mice were fed a Western-type diet and treated with PA9RA, clopidogrel, or atorvastatin for 10 weeks. The body weight, organ weight, serum biochemistry, and histopathology, including atherosclerotic lesion area and liver steatosis were assessed. PA9RA treatment led to a significant reduction in body weight and inguinal fat, with the 45 mg/kg/day dose showing marked efficacy in decreasing atherosclerotic lesion size and ameliorating liver steatosis. Histopathological evaluation revealed decreased foam cell formation and improved liver histology in PA9RA-treated groups compared to controls. Notable side effects included epidermal hyperplasia and gastric hyperplasia at high doses of PA9RA. PA9RA exhibits superior efficacy over clopidogrel and atorvastatin in ameliorating atherosclerosis and fatty liver in ApoE mice. This study highlights PA9RA's potential as a promising therapeutic agent for atherosclerosis. Further research is needed to elucidate its mechanisms of action and assess long-term safety and efficacy.

Haloperidol is a typical antipsychotic drug effective in alleviating positive symptoms of schizophrenia by blocking dopamine receptor 2 (DR2). However, it is also known to produce neuropsychiatric effects by acting on various targets other than DR. In this study, we investigated effect of haloperidol on function of 5-hydroxytryptamine (5-HT) receptor, a ligand-gated ion channel belonging to the serotonin receptor family using the whole-cell voltage clamp technique and NCB20 neuroblastoma cells. When co-applied with 5-HT, haloperidol inhibited 5-HT receptormediated currents in a concentration-dependent manner. A reduction in maximal effect (E) and an increase in EC observed during co-application indicated that haloperidol could act as a non-competitive antagonist of 5-HT receptors. Haloperidol inhibited the activation of 5-HT receptor, while also accelerating their deactivation and desensitization. The inhibitory effect of haloperidol showed no significant difference between pre- and co-application. Haloperidol did not alter the reversal potential of 5-HT receptor currents. Furthermore, haloperidol did not affect recovery from deactivation or desensitization of 5-HT receptors. It did not show a use-dependent inhibition either. These findings suggest that haloperidol can exert its inhibitory effect on 5-HT receptors by allosterically preventing opening of ion channels. This mechanistic insight enhances our understanding of relationships between 5-HT receptors and pharmacological actions of antipsychotics.

Fine particulate matter (FPM) is a major component of air pollution and has emerged as a significant global health concern owing to its adverse health effects. Previous studies have investigated the correlation between bone health and FPM through cohort or review studies. However, the effects of FPM exposure on bone health are poorly understood. This study aimed to investigate the effects of FPM on bone health and elucidate these effects and using mice. Micro-CT analysis revealed FPM exposure decreased bone mineral density, trabecular bone volume/total volume ratio, and trabecular number in the femurs of mice, while increasing trabecular separation. Histological analysis showed that the FPM-treated group had a reduced trabecular area and an increased number of osteoclasts in the bone tissue. Moreover, studies revealed that low concentrations of FPM significantly enhanced osteoclast differentiation. These findings further support the notion that short-term FPM exposure negatively impacts bone health, providing a foundation for further research on this topic.

Renal cell carcinoma (RCC) presents significant clinical challenges, highlighting the importance of understanding its molecular mechanisms. While store-operated Ca entry (SOCE) is known to play an essential role in tumorigenesis and metastasis, its specific implications across various RCC subtypes remain underexplored. This study analyzed SOCE-related mRNA profiles from the KIRC and KIRP projects in The Cancer Genome Atlas (TCGA) database, focusing on differential gene expression and overall survival outcomes. Functional studies in clear cell RCC (Caki-1) and papillary RCC cell lines (pRCC, Caki-2) revealed increased expression of Orai1 and Orai3, along with STIM1, exhibited in both subtypes, with decreased STIM2 and increased Orai2 expression in pRCC. Notably, Orai3 expression had a gender-specific impact on survival, particularly in females with pRCC, where it inversely correlated with STIM2 expression. Functional assays showed Orai3 dominance in Caki-2 and Orai1 in Caki- 1. Interestingly, 2-APB inhibited SOCE in Caki-1 but enhanced it in Caki-2, suggesting Orai3 as the primary SOCE channel in pRCC. Knockdown of Orai1 and Orai3 reduced cell migration and proliferation regulating focal adhesion kinase (FAK) and Cyclin D1 in both cell lines. These findings highlight the critical roles of Orai1 and Orai3 in RCC metastasis, with Orai3 linked to poorer prognosis in females with pRCC. This study offers valuable insights into RCC diagnostics and potential therapeutic strategies targeting ORAI channels and STIM proteins.

Auricular vagus nerve stimulation (aVNS) is one of the promising neuromodulation techniques due to its non-invasiveness, convenience, and effectiveness. aVNS has been suggested as a potential treatment for neurodegenerative diseases showing impaired cerebrospinal fluid (CSF) dynamics. Improving CSF flow has been proposed as a key mechanism of the therapeutic effect on neurodegenerative diseases. However, aVNS parameters have been set empirically and the effective parameter that maximize the effect remains elusive. Here we show that 30 minutes of low-frequency aVNS increased arterial vasomotion events and enhanced cortical CSF influx along the branches of middle cerebral arteries. By using two photon imaging or widefield fluorescence microscopy with plasma and CSF tracers for visualizing blood vessels and perivascular spaces, arterial vasomotion and cortical CSF influx dynamics were acquired. The low-frequency (2 Hz) aVNS, but not middleand high-frequency (40 and 100 Hz) aVNS, significantly increased the number of vasomotion events compared to the sham group. Accordingly, in the CSF imaging, 2 Hz of aVNS markedly enhanced the CSF influx. Our findings demonstrate that lowfrequency aVNS is the effective parameter in respect to modulating vasomotion and CSF influx, resulting in brain clearance effect.

Schwann cells are the most abundant cells in the peripheral nervous system, maintaining the development, function and regeneration of peripheral nerves. Defects in these Schwann cells injury response potentially contribute to the pathogenesis of diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus. The protein p66shc is essential in regulating oxidative stress responses, autophagy induction and cell survival, and is also vital in the development of DPN. In this study, we hypothesized that p66shc mediates high glucose-induced oxidative stress and autophagic dysfunction. In Schwann cells treated with high glucose; p66shc expression, levels of reactive oxygen species, autophagy impairment, and early apoptosis were elevated. Inhibition of p66shc gene expression by siRNA reversed high glucose-induced oxidative stress, autophagy impairment, and early apoptosis. We also demonstrated that the levels of p66shc was increased, while autophagy-related proteins p62 and LC3 (LC3-II/I) were suppressed in the sciatic nerve of streptozotocin-induced diabetes mice. P66shc-deficient mice exhibited the improvement in autophagy impairment after diabetes onset. Our findings suggest that the p66 plays a crucial role in Schwann cell dysfunction, identifying its potential as a therapeutic target.

Platelet-derived growth factors (PDGFs) ligands and their corresponding receptors, PDGF receptor (PDGFR)α and PDGFRβ, play a crucial role in controlling diverse biological functions, including cell growth, viability and migration. These growth factors bind to PDGFRs, which are receptor tyrosine kinases present on the surface of target cells. The interaction between PDGFs and PDGFRs induces receptor dimerization and subsequent activation through auto-phosphorylation, which in turn triggers a cascade of intracellular signaling pathways. PDGF/PDGFR signaling is essential for maintaining normal physiological functions, including tissue regeneration and growth. However, dysregulation of this signaling pathway leads to pathological conditions, including fibrosis, atherosclerosis, and cancer development in various organs. The pathological impact of PDGF/PDGFR signaling primarily stems from its capacity to promote excessive cell proliferation, enhanced migration, and increased extracellular matrix deposition, resulting in tissue overgrowth, scarring, and abnormal vessel formation. These processes are integral to the pathogenesis of fibrotic, neoplastic, and vascular disorders. Therefore, understanding these pathways is crucial for developing targeted treatments designed to inhibit PDGF/PDGFR signaling in these diseases. This review delves into the dual role of PDGF/PDGFR signaling in both physiological and pathophysiological contexts across different organs and provides insights into current pharmacological therapies designed to target the PDGF signaling pathway. INTRODUCTION Platelet-derived growth factors (PDGFs) are key signaling molecules that interact with specific cell to modulate various cellular responses. Upon binding to their receptors (PDGFRs), PDGFs initiate dimerization and tyrosine phosphorylation, which activates downstream signaling pathways. The PDGF signaling network comprises four ligands-PDGF-A, PDGF-B, PDGFC, and PDGF-D, that interact with two receptors, PDGFRα and PDGFRβ [1-6]. PDGFRα exhibits broader ligand specificity, binding to PDGF-A, PDGF-B, PDGF-C homodimers, and PDGFAB heterodimers, whereas PDGFRβ specifically binds to PDGFB and PDGF-D homodimers. Under both physiological and pathol.