α7nAChR-mediated astrocytic activation: a novel mechanism of Xiongzhi Dilong decoction in ameliorating chronic migraine.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpha 7 nicotinic acetylcholine receptor (α7nAChR)-mediated astrocytic activation is closely related to central sensitization of chronic migraine (CM). Xiongzhi Dilong decoction (XZDL), originated from Xiongzhi Shigao decoction of Yi-zong-jin-jian, has been confirmed to relieve CM in experiment and clinic. However, its underlying mechanism for treating CM has not been elucidated. AIM OF THE STUDY: To reveal the underlying mechanisms of XZDL to alleviate CM in vivo focusing mainly on α7nAChR-mediated astrocytic activation and central sensitization in TNC. MATERIALS AND METHODS: CM rat model was established by subcutaneous injection of nitroglycerin (NTG) recurrently, and treated with XZDL simultaneously. Migraine-like behaviors of rats (ear redness, head scratching, and cage climbing) and pain-related reactions (mechanical hind-paw withdrawal threshold) of rats were evaluated before and after NTG injection and XZDL administration at different points in time for nine days. The immunofluorescence single and double staining were applied to detect the levels of CGRP, c-Fos, GFAP and α7nAChR in NTG-induced CM rats. ELISA kits were employed to quantify levels of TNF-α, IL-1ß, and IL-6 in medulla oblongata of CM rats. The expression levels of target proteins were examined using western blotting. Finally, methyllycaconitine citrate (MLA, a specific antagonist of α7nAChR) was applied to further validate the mechanisms of XZDL in vivo. RESULTS: XZDL significantly attenuated the pain-related behaviors of the NTG-induced CM rats, manifesting as constraints of aberrant migraine-like behaviors including elongated latency of ear redness and decreased numbers of head scratching and cage climbing, and increment of mechanical withdrawal threshold. Moreover, XZDL markedly lowered levels of CGRP and c-Fos, as well as inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in CM rats. Furthermore, XZDL significantly enhanced α7nAChR expression and its co-localization with GFAP, while markedly inhibited the expression of GFAP and the activation of JAK2/STAT3/NF-κB pathway in the TNC of CM rats. Finally, blocking α7nAChR with MLA reversed the effects of XZDL on astrocytic activation, central sensitization, and the pain-related behaviors in vivo. CONCLUSION: XZDL inhibited astrocytic activation and central sensitization in NTG-induced CM rats by facilitating α7nAChR expression and suppressing JAK2/STAT3/NF-κB pathway, implying that the regulation of α7nAChR-mediated astrocytic activation represents a novel mechanism of XZDL for relieving CM.

Enhancement of Corrosion and Wear Resistance of Ni-P Coatings Stems from the Synergistic Effects of Cr3C2 and Heat Treatment.

This study describes the preparation of Ni-P-Cr3C2 composite coatings using pulsed electrodeposition, with varying Cr3C2 concentrations (0, 1, 2, 3, 4, and 5 g/L). Subsequently, the Ni-P-Cr3C2 composite coatings are heat-treated at different temperatures (200, 400, and 600 °C) using the characteristic of Cr3C2 oxidizing to Cr2O3 at high temperatures. The Ni-P coatings, Ni-P-Cr3C2 composite coatings, and heat-treated-state Ni-P-Cr3C2 composite coatings are compared and discussed. The results show that the hardness, wear resistance, and corrosion resistance of the composite coatings are optimized when the Cr3C2 content is 3 g/L and the heat-treatment temperature is 400 °C. This is due to the presence of oxides such as Cr2O3 on the surface of the composite coatings after heat treatment at 400 °C. By efficiently enhancing the coating's densification to the substrate, these oxides raise the composite coating's resistance to corrosion and wear. The Ni-P-Cr3C2 composite coating in its heat-treated makeup at 400 °C is found to have long-term corrosion resistance in the 3.5 wt % NaCl solution immersion test. This study provides a new idea in the field of corrosion.

Gastrodin relieves Parkinson's disease-related motor deficits by facilitating the MEK-dependent VMAT2 to maintain dopamine homeostasis.

BACKGROUND: Dysfunction of dopamine homeostasis (DAH), which is regulated by vesicular monoamine transporter 2 (VMAT2), is a vital cause of dopamine (DA) neurotoxicity and motor deficits in Parkinson's disease (PD). Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-D-glucoside; GTD), a natural active compound derived from Gastrodia elata Blume, can be used to treat multiple neurological disorders, including PD. However, whether GTD regulates VMAT2-mediated DAH dysfunction in PD models remains unclear. PURPOSE: To explore whether GTD confers dopaminergic neuroprotection by facilitating DA vesicle storage and maintaining DAH in PD models. METHODS: Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and PC12 cells with 1-methyl-4-phenyl-pyridinium (MPP+) to induce PD characteristics. Multiple behavioural tests were performed to evaluate the motor functions of the mice. HPLC was used to measure DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Transmission electron microscopy was used to observe synaptic vesicles. Molecular docking and molecular dynamics were used to determine the binding affinity of GTD to the target protein. Reserpine (Res, a VMAT2 inhibitor) and PD0325901 (901, a MEK inhibitor) were employed to investigate the mechanism of GTD. Western blotting and immunohistochemistry were used to assess the expression of the target proteins. RESULTS: GTD attenuated motor deficits and dopaminergic neuronal injury, reversed the imbalance of DAH, and increased VMAT2 levels and vesicle volume in MPTP-induced mice. GTD ameliorated cell damage, ROS release, and dysfunction of DAH in MPP+-induced PC12 cells. Moreover, the neuroprotective effects of GTD were reversed by Res in vitro and in vivo. Furthermore, GTD can activate the MEK/ERK/CREB pathway to upregulate VMAT2 in vitro and in vivo. Interestingly, 901 reversed the effects of GTD on VMAT2 and dopaminergic neuronal impairment. CONCLUSION: GTD relieved PD-related motor deficits and dopaminergic neuronal impairment by facilitating MEK-depended VMAT2 to regulate DAH, which offers new insights into its therapeutic potential.

Enhancement of the Wear Resistance and Corrosion Resistance of Electroplated Ni-W-B Coatings Using PDA-Functionalized VC.

In this study, vanadium carbide (VC) was used as the raw material to synthesize PDA-functionalized VC (P-VC). VC and P-VC were added as nanoreinforced materials to the Ni-W-B coating. The effects of the two nanomaterials on the morphology, wear resistance, and corrosion resistance of the Ni-W-B coatings were investigated and compared. The experimental results show that the surface of the Ni-W-B/P-VC coating is denser and more uniform than that of the Ni-W-B and Ni-W-B/VC coatings, and there are no obvious defects on the surface. According to the hardness test, the Ni-W-B/P-VC coating reaches the highest microhardness of 887.1 HV. According to the friction and wear tests, the Ni-W-B/P-VC coating has the shallowest scratches, the lowest average friction coefficient (COF = 0.274), and the lowest wear rate (9.578 × 10-8 mm2/N). The corrosion resistance is the best, the corrosion rate is 0.0456 mm/y, and the impedance value Rt reaches 14,501 Ω·cm2.

Evaluating cardiac disorders associated with triazole antifungal agents based on the US Food and Drug Administration Adverse Event reporting system database.

Introduction: Triazole antifungal agents are widely used to treat and prevent systemic mycoses. With wide clinical use, the number of reported adverse events has gradually increased. The aim of this study was to analyze the cardiac disorders associated with TAAs (fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole) based on data from the US Food and Drug Administration Adverse Event Reporting System FDA Adverse Event Reporting System. Methods: Data were extracted from the FAERS database between the first quarter of 2004 and third quarter of 2022. The clinical characteristics in TAA-associated cardiac AE reports were analyzed. Disproportionality analysis was performed to evaluate the potential association between AEs and TAAs using the reporting odds ratio (ROR) and proportional reporting ratio (PRR). Results: Among 10,178,522 AE reports, 1719 reports were TAA-associated cardiac AEs as primary suspect drug. Most reports were related to fluconazole (38.34%), voriconazole (28.56%) and itraconazole (26.76%). Itraconazole (N = 195, 42.39%) and isavuconazole (N = 2, 14.29%) had fewer serious outcome events than three other drugs including fluconazole, voriconazole, and posaconazole. 13, 11, 26, 5 and 1 signals were detected for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively. The number of new signals unrecorded in the drug label was 9, 2, 13, 2 and 0 for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively. Conclusion: Isavuconazole might be the safest of the five TAAs for cardiac AEs. TAA-associated cardiac disorders may result in serious adverse outcomes. Therefore, in addition to AEs on the drug label, we should pay attention to new AEs unrecorded on the drug label during the clinical use of TAAs.

A shock flash breaking out of a dusty red supergiant.

Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.

Integrative multi-omics analysis reveals the critical role of the PBXIP1 gene in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, and its strongest risk factor is aging. A few studies have explored the relationship between aging and AD, while the underlying mechanism remains unclear. We assembled data across multi-omics (i.e., epigenetics, transcriptomics, and proteomics, based on frozen tissues from the dorsolateral prefrontal cortex) and neuropathological and clinical traits from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Aging was assessed using six DNA methylation clocks (including the Horvath clock, Hannum clock, Levine clock, HorvathSkin clock, Lin clock, and Cortical clock) that capture mortality risk in literature. After accounting for age, we first identified a gene module (including 263 genes) that was related to the integrated aging measure of six clocks, as well as three neuropathological traits of AD (i.e., ß-amyloid, Tau tangles, and tangle density). Interestingly, among 20 key genes with top intramodular connectivity of the module, PBXIP1 was the only one that was significantly associated with all three neuropathological traits of AD at the protein level after Bonferroni correction. Furthermore, PBXIP1 was associated with the clinical diagnosis of AD in both ROSMAP and three independent datasets. Moreover, PBXIP1 may be related to AD through its role in astrocytes and hippocampal neurons, and the mTOR pathway. The results suggest the critical role of PBXIP1 in AD and support the potential and feasibility of using multi-omics data to investigate mechanisms of complex diseases. However, more validations in different populations and experiments in vitro and in vivo are required in the future.

TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA.

The mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.

Differences in tissue distribution ability of evodiamine and dehydroevodiamine are due to the dihedral angle of the molecule stereo-structure.

Introduction: This researcher focused at the evodiamine and dehydroevodiamine tissue distribution and structure-pharmacokinetics (PK) relationship after intravenous injection in mice. Methods: Using a transmembrane transport experiment, the permeability of evodiamine and dehydroevodiamine on Caco-2 cells was evaluated. The tissue distribution and pharmacokinetics (PK) of evodiamine and dehydroevodiamine in mice were studied. To comprehend the connection between structure and tissue distribution, physicochemical property evaluations and molecular electrostatic potential (MEP) calculations were performed. Results: Dehydroevodiamine's Papp values in vitro were 10-5 cm/s, whereas evodiamine's were 10-6 cm/s. At a dose of 5 mg/kg, the brain concentration of dehydroevodiamine was 6.44 times more than that of evodiamine. By MEP or physicochemical measures, the permeability difference between evodiamine and dehydroevodiamine is unaffected. The dihedral angle of the stereo-structure appears to be the main cause of the difference in tissue distribution ability between evodiamine and dehydroevodiamine. Discussion: Dehydroevodiamine has a dihedral angle of 3.71° compared to 82.34° for evodiamine. Dehydroevodiamine can more easily pass through the phospholipid bilayer than evodiamine because it has a more planar stereo-structure. Dehydroevodiamine is therefore more likely to pass cross the blood-brain barrier and enter the brain in a tissue-specific manner.

Transarterial Chemoembolization Combined With Apatinib Plus PD-1 Inhibitors for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

INTRODUCTION: The aim of this study was to compare transarterial chemoembolization (TACE) combined with apatinib and PD-1 inhibitors (TACE-AP) with TACE combined with apatinib alone (TACE-A) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and to explore the prognostic factors affecting the survival of patients. METHODS: This retrospective study analyzed data of patients with HCC with PVTT who were treated with TACE-AP or TACE-A between December 2018 and June 2021. The primary end points of the study were progression-free survival (PFS) and overall survival (OS), and the secondary end points were objective response rate (ORR) and adverse events (AEs). Propensity score matching (PSM) and stabilized inverse probability weighting (sIPTW) analyses were used to reduce patient selection bias, and Cox regression analysis was used to analyze prognostic factors affecting patient survival. RESULTS: Sixty-nine and 40 patients were included in the TACE-A and TACE-AP groups, respectively. After PSM and IPTW analyses, the median PFS and median OS in the TACE-AP group were significantly higher than those in the TACE-A group (PFS: after PSM, 6.9 vs 4.0 months, P < 0.001, after IPTW, 6.5 vs 5.1 months, P < 0.001; OS: after PSM, 14.6 vs 8.5 months P < 0.001, after IPTW, 16.1 vs 10.5 months, P < 0.001). After PSM and IPTW analyses, the tumor ORR in the TACE-AP group was significantly higher than that in the TACE-A group (PSM, 53.6% vs 17.9%, P = 0.005; IPTW, 52.5% vs 28.6%, P = 0.013). All treatment-related AEs were observed to be tolerated. Multivariate Cox regression analysis showed that the main prognostic factors affecting the survival of patients were tumor number, PVTT type, alpha-fetoprotein, and treatment mode. DISCUSSION: In the treatment of patients with HCC with PVTT, TACE-AP significantly improved PFS, OS, and ORR, and the AEs were safe and controllable.

The multi-BRCT domain protein DDRM2 promotes the recruitment of RAD51 to DNA damage sites to facilitate homologous recombination.

DNA double-strand breaks (DSBs) are the most toxic form of DNA damage in cells. Homologous recombination (HR) is an error-free repair mechanism for DSBs as well as a basis for gene targeting using genome-editing techniques. Despite the importance of HR, the HR mechanism in plants is poorly understood. Through genetic screens for DNA damage response mutants (DDRMs), we find that the Arabidopsis ddrm2 mutant is hypersensitive to DSB-inducing reagents. DDRM2 encodes a protein with four BRCA1 C-terminal (BRCT) domains and is highly conserved in plants including bryophytes, the earliest land plant lineage. The plant-specific transcription factor SOG1 binds to the promoter of DDRM2 and activates its expression. In consistence, the expression of DDRM2 is induced by DSBs in a SOG1-dependent manner. In support, genetic analysis suggests that DDRM2 functions downstream of SOG1. Similar to the sog1 mutant, the ddrm2 mutant shows dramatically reduced HR efficiency. Mechanistically, DDRM2 interacts with the core HR protein RAD51 and is required for the recruitment of RAD51 to DSB sites. Our study reveals that SOG1-DDRM2-RAD51 is a novel module for HR, providing a potential target for improving the efficiency of gene targeting.

Influence of Preoperative Serum Albumin on Acute Kidney Injury after Aortic Surgery for Acute Type A Aortic Dissection: A Retrospective Cohort Study.

There are relatively few articles on the relationship between serum albumin and acute kidney injury (AKI). Therefore, the objective of this research was to study the relationship between serum albumin and AKI in patients who were undergoing surgery for acute type A aortic dissection. METHODS: We retrospectively collected data from 624 patients attending a Chinese hospital between January 2015 and June 2017. The target independent variable was serum albumin measured before surgery after hospital admission, and the dependent variable was AKI, defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: The mean age of these 624 selected patients was 48.5 ± 11.1 years, and almost 73.7% were male. A nonlinear association was detected between serum albumin and AKI; the turning point was 32 g/L. The risk of AKI decreased gradually as the serum albumin level increased up to 32 g/L (adjusted OR = 0.87; 95% CI 0.82-0.92; p < 0.001). When the serum albumin level exceeded 32 g/L, the level of serum albumin was not associated with the risk of AKI (OR = 1.01, 95% CI 0.94-1.08; p = 0.769). CONCLUSIONS: The findings suggest that preoperative serum albumin below 32 g/L was an independent risk factor for AKI in patients undergoing surgery for acute type A aortic dissection. TRIAL REGISTRATION: A retrospective cohort study.

Identification of the interference spectra of edible oil samples based on neighborhood rough set attribute reduction.

Due to numerous edible oil safety problems in China, an automatic oil quality detection technique is urgently needed. In this study, rough set theory and Fourier transform spectrum are combined for proposing a digital identification method for edible oil. First, the Fourier transform spectra of three different types of edible oil samples, including colza oil, waste oil, and peanut oil, are measured. After the input spectra are differentially and smoothly processed, the characteristic wavelength bands are selected with neighborhood rough set attribution reduction (NRSAR). Moreover, the classification models are established based on random forest (RF) and extreme learning machine (ELM) algorithms. Finally, confusion matrix, classification accuracy, sensitivity, specificity, and the distribution of judgment are calculated for evaluating the classification performances of different models and determining the optimal oil identification model. The results show that by using the third-order difference pre-processing method, 193 wavelength bands in the visible range can be reduced to 10 characteristic wavelengths, with a compression ratio of over 88.61%. Using the established NRS-RF and NRS-ELM models, the total identification accuracies are 91.67% and 93.33%, respectively. In particular, the identification accuracy of peanut oil using the NRS-ELM model reaches up to 100%, whereas the identification accuracies obtained using the principal component analysis (PCA)-based models that are commonly used in information processing (PCA-RF and PCA-ELM) are 81.67% and 90.00%, respectively. As compared with feature extraction methods, the proposed NRSAR shows directive advantages in terms of precision, sensitivity, specificity, and the distribution of judgment. In addition, the execution time is also reduced by approximately 1/3. Conclusively, the NRSAR method and NRS-ELM the model in the spectral identification of edible oil show favorable performance. They are expected to bring forth insightful oil identification techniques.

Inhibiting mitochondrial inflammation through Drp1/HK1/NLRP3 pathway: A mechanism of alpinetin attenuated aging-associated cognitive impairment.

Mitochondrial inflammation triggered by abnormal mitochondrial division and regulated by the Drp1/HK1/NLRP3 pathway is correlated with the progression of aging-associated cognitive impairment (AACI). Alpinetin is a novel flavonoid derived from Zingiberaceae that has many bioactivities such as antiinflammation and anti-oxidation. However, whether alpinetin alleviates AACI by suppressing Drp1/HK1/NLRP3 pathway-inhibited mitochondrial inflammation is still unknown. In the present study, D-galactose (D-gal)-induced aging mice and BV-2 cells were used, and the effects of alpinetin on learning and memory function, neuroprotection and activation of the Drp1/HK1/NLRP3 pathway were investigated. Our data indicated that alpinetin significantly alleviated cognitive dysfunction and neuronal damage in the CA1 and CA3 regions of D-gal-treated mice. Moreover, D-gal-induced microglial activation was markedly reduced by alpinetin by inhibiting the Drp1/HK1/NLRP3 pathway-suppressed mitochondrial inflammation, down-regulating the levels of p-Drp1 (s616), VDAC, NLRP3, ASC, Cleaved-caspase 1, IL-18, and IL-1ß, and up-regulating the expression of HK1. Furthermore, after Drp1 inhibition by Mdivi-1 in vitro, the inhibitory effect of alpinetin on Drp1/HK1/NLRP3 pathway was more evident. In summary, the current results implied that alpinetin attenuated aging-related cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation, suggesting that the inhibition of the Drp1/HK1/NLRP3 pathway is one of the mechanisms by which alpinetin attenuates AACI.

Sarsasapogenin, a principal active component absorbed into blood of total saponins of Anemarrhena, attenuates proliferation and invasion in rheumatoid arthritis fibroblast-like synoviocytes through downregulating PKM2 inhibited pathological glycolysis.

Increased glycolytic in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) not only contributes to early-stage disease pathogenesis but leads to sustained proliferation of FLS. Given the importance of PKM2 in glycolysis and apoptosis, PKM2 is considered a potential therapeutic and drug discovery target in RA. Total saponins of anemarrhena (TSA), a class of steroid saponins, originated from Anemarrhena asphodeloides Bge. In this study, we verified that 200 mg/kg TSA could significantly alleviate inflammation and the pathological characteristics of RA and inhibit synovial hyperplasia in AA rats. We confirmed that sarsasapogenin (SA) was the principal active ingredient absorbed into the blood of TSA by the UPLC/Q Exactive MS test. Then we used TNF-α-induced MH7A to get the conclusion that 20 µM SA could effectively inhibit the glycolysis by inhibiting the activity of PKM2 tetramer and glucose uptake. Moreover, 20 µM SA could suppress proliferation, migration, invasion, and cytokine release of FLS, interfere with the growth cycle of FLS, and induce FLS apoptosis by depressing the phosphorylation of PKM2. At last, In-1, a potent inhibitor of the PKM2 was used to reverse verify the above results. Taken together, the key mechanisms of SA on RA treatment through downregulating the activity of PKM2 tetramer and phosphorylation of PKM2 inhibited pathological glycolysis and induced apoptosis to exert inhibition on the proliferation and invasion of RA FLS.

Inhibition Ras/MEK/ERK pathway: An important mechanism of Baihu Jia Guizhi Decoction ameliorated rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Alleviating rheumatism by inhibiting synovitis is a routine treatment for rheumatoid arthritis (RA). Baihu Jia Guizhi Decoction (BHJGZ) is a classic prescription and has a long history of application for treating RA with a good anti-inflammatory action. However, the underlying molecular mechanisms have not been fully elucidated. AIM OF THE STUDY: This work aimed to decipher the potential mechanism of BHJGZ against RA focusing on Ras/MEK/ERK pathway. MATERIALS AND METHODS: Based on the prediction of network pharmacology, the inhibition action of BHJGZ on Ras/MEK/ERK pathway was firstly validated in vivo and in vitro. Moreover, the affinity with the ingredients of BHJGZ in serum and the targets of Ras/MEK/ERK pathway were evaluated. Finally, the efficacy of BHJGZ for relieving RA was assessed in AA rats. RESULTS: The Ras/MEK/ERK pathway was predicted by network pharmacology as one of important mechanisms of BHJGZ to treat RA. The high expression of Ras protein in synovitis of AA rats was significantly reduced by the treatment with BHJGZ, and the activation of Ras/MEK/ERK pathway in vivo and in vitro was also markedly inhibited (p < 0.05 or p < 0.01). Moreover, the level of p-ERK/ERK, IL-6 and TNF-α in vitro were further suppressed after Ras or MEK was inhibited by mirdametinib or lonafarnib respectively (p < 0.01). Furthermore, the results of molecular docking showed a good affinity and stable binding with the ingredients of BHJGZ in serum and multiple key proteins of the Ras/MEK/ERK pathway. Finally, paw swelling, paw circumference and pathological changes of joint synovitis were significantly reduced by BHJGZ in AA rats (p < 0.05). CONCLUSION: The inhibition of Ras/MEK/ERK pathway is one of crucial mechanisms of BHJGZ for ameliorating synovitis of RA.

Integration of transdermal chemistry and network pharmacology to decipher the mechanism of ShexiangZhuifeng analgesic plaster to treat rheumatoid arthritis.

BACKGROUND: Transdermal patches are an effective form of treatment for rheumatoid arthritis (RA), and they have a number of benefits, including patient compliance, accessibility, and low systemic toxicity. ShexiangZhuifeng Analgesic Plaster (SZAP), a patch made up of many traditional medicines, has been successfully utilized in numerous clinical trials to treat RA. However, information about anti-RA processes and transdermal active components is still emerging. PURPOSE: Our objectives were to identify the transdermal active components of SZAP and investigate its anti-RA mechanisms, primarily focused on joint inflammation. METHODS: The collagen-induced arthritis (CIA) rats were created first, and then the arthritis score, Paw thickness, and morphology feature of joint synovial were assessed after 7 days of therapy with SZAP. Moreover, the Franz diffusion cell and UPLC-MS technologies were combined to identify and measure the transdermal active ingredients of SZAP. Furthermore, network pharmacology was utilized to anticipate the putative the mechanism of SZAP for treating RA. Finally, the results of network pharmacology were validated using LPS-induced RAW 264.7 cells and CIA rats. RESULTS: SZAP significantly reduced paw thickness, arthritic score and pathological characteristics of joint synovitis in (CIA) rats. Additionally, 12 transdermal active components of SZAP were identified, and network pharmacology prediction results suggested that SZAP may alleviate joint synovial inflammation by blocking the Akt/mTOR/HIF-1 pathway. Our investigations' findings demonstrated that SZAP dramatically reduced the concentrations of excess cytokines (IL6, VEGF, and TNF-α), as well as the protein overexpression of the AKT/mTOR/HIF- pathway (HIF-1, p-AKT, and p-mTOR), whereas its anti-inflammation effect was reversed once AKT or mTOR was activated. CONCLUSION: By blocking the AKT/mTOR/HIF-1 pathway, SZAP can lessen the release of inflammatory mediators, which reduces joint synovial inflammation associated with RA. The pharmacological evaluation of TCM transdermal drug delivery formulations like SZAP may be amenable to the integration of transdermal chemistry and network pharmacology approaches.

The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity.

T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.