Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy worldwide, accounting for more than 90% of all oral cancers, and is characterized by high invasiveness and poor long-term prognosis. Its etiology is multifactorial, involving tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. Oral leukoplakia and erythroplakia are the main precancerous lesions lesions, with oral leukoplakia being the most common. Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways. Post-translational modifications (such as ubiquitination and deubiquitination) play key roles in regulating these pathways by controlling protein stability and activity. Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways. The ubiquitination/deubiquitination process mainly involves E3 ligases (E3s) that catalyze substrate ubiquitination, deubiquitinating enzymes (DUBs) that remove ubiquitin chains, and the 26S proteasome complex that degrades ubiquitinated substrates. Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumor-related proteins, thereby driving OSCC initiation and progression. Therefore, understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components. Here, we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway, Wnt/β-catenin pathway, Hippo pathway, and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways, along with potential drug targets. PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70% of OSCC cases. It is modulated by E3s (e.g., FBXW7 and NEDD4) and DUBs (e.g., USP7 and USP10): FBXW7 and USP10 inhibit signaling, while NEDD4 and USP7 potentiate it. Aberrant activation of the Wnt/β‑catenin pathway leads to β‑catenin nuclear translocation and induction of cell proliferation. This pathway is modulated by E3s (e.g., c-Cbl and RNF43) and DUBs (e.g., USP9X and USP20): c-Cbl and RNF43 inhibit signaling, while USP9X and USP20 potentiate it. Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis. This pathway is modulated by E3s (e.g., CRL4^DCAF1 and SIAH2) and DUBs (e.g., USP1 and USP21): CRL4^DCAF1 and SIAH2 inhibit signaling, while USP1 and USP21 potentiate it. Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance. This pathway is modulated by E3s (e.g., TRAF6 and LUBAC) and DUBs (e.g., A20 and CYLD): A20 and CYLD inhibit signaling, while TRAF6 and LUBAC potentiate it. Targeting these E3s and DUBs provides directions for OSCC drug research. Small-molecule inhibitors such as YCH2823 (a USP7 inhibitor), GSK2643943A (a USP20 inhibitor), and HOIPIN-8 (a LUBAC inhibitor) have shown promising antitumor activity in preclinical models; PROTAC molecules, by binding to surface sites of target proteins and recruiting E3s, achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors, for example, PU7-1-mediated USP7 degradation, offering new strategies to overcome traditional drug limitations. Currently, NX-1607 (a Cbl-b inhibitor) has entered phase I clinical trials, with preliminary results confirming its safety and antitumor activity. Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.

Objective Vascular dementia(VD)is a clinical syndrome caused by various cerebrovascular diseases,including ischemic,hemorrhagic,and acute and chronic hypoxic cerebrovascular diseases,leading to impaired brain function and affecting patients'cognitive ability,daily life,and work abilities.Vascular dementia is a preventable and reversible form of dementia,second only to Alzheimer's disease as the second common cause of dementia.At present,the relevant pathogenesis of vascular dementia is not clear,and there is no clear treatment method.However,its pathogenesis may be related to neuroinflammation,oxidative stress,neuronal damage and white matter lesions.Its main risk factors include genetic factors,hypercholesterolemia,diabetes,hypertension,etc.Neuroinflammatory response plays a major role in the process of secondary brain injury caused by cerebral ischemia,and inflammatory factors lead to an inflammatory cascade reaction that exacerbates damage to the nervous system.Inhibiting the inflammatory pathway and reducing the expression of inflammatory factors can improve the symptoms of vascular dementia patients and animal models,indicating that neuroinflammation may play an important role in the pathogenesis of vascular dementia.This article explores the effects of Buyang Huanwu Decoction on inflammatory factors from the perspective of summarizing relevant literature in recent years.It mainly reviews the pharmacological effects of Buyang Huanwu Decoction on treating vascular dementia,the relationship between inflammatory factor levels and vascular dementia,and the prevention and treatment of vascular dementia by regulating inflammatory factor levels.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

The excipient processing is an essential part of traditional Chinese medicine processing, and understanding its scientific connotations is a critical scientific issue that urgently needs resolution. Building upon a foundation where the composition of traditional Chinese medicine substances is fundamentally clear, this paper applies the techniques and methods of chemoinformatics to the study of the excipient processing mechanism. Relevant information on traditional Chinese medicines processed with four kinds of excipients (wine, vinegar, salt and honey) was collected, including properties, taste, meridian tropism, chemical components, etc. Molecular descritors and skeletons corresponding to each chemical component were calculated using chemoinformatics to characterize the properties and structural features of the components. Characteristic components associated with the four excipients (wine, vinegar, salt and honey) were explored through multivariate statistical analysis and Murcko skeleton analysis. Further analysis, taking honey-processed Astragali Radix as an example, the focus was on the impact of the processing excipient honey on the solubility and permeability of its characteristic pharmacologically active components (isoflavones). It was discovered that the excipient honey can increase their solubility and permeability, emphasizing that the impact of processing excipients on the pharmacological classification properties is a key breakthrough in elucidating the mechanism of excipient processing. In summary, this study analyzed the characteristic components associated with the processing excipients "wine, vinegar, salt and honey" based on their composition characteristics, providing data support for the research on the mechanism of excipient processing from a biopharmaceutical perspective.

Biomacromolecule drugs have been increasingly used in clinical practice due to their distinct advantages, including precise targeting, small dose, high safety and activity. However, owing to their high molecular weight, strong hydrophilicity, and poor stability in the gastrointestinal tract, the oral bioavailability of the biomacromolecule drugs remains extremely poor. As a novel and innovative technology for active drug delivery, gastrointestinal microneedles hold immense potential in the oral delivery of biomacromolecule drugs because of their low-invasive nature and high permeation enhancement effects. This review primarily summarizes the actuating force, design strategies, fabrication techniques, and applications of gastrointestinal microneedles for the oral delivery of biomacromolecule drugs. Additionally, the challenges and further perspectives in the development this technology are presented, aiming to promote the subsequent research and clinical translation of gastrointestinal microneedles, and to provide a new efficient and safe strategy for oral delivery of biomacromolecule drugs.

OBJECTIVE To investigate the effect of pachymic acid （PA） on renal function and fibrosis in chronic renal failure （CRF） rats and its potential mechanism based on the Ras homolog gene family member A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） signaling pathway. METHODS Using male SD rats as subjects， the CRF model was established by 5/6 nephrectomy； the successfully modeled rats were divided into model group， PA low-dose， medium-dose and high-dose groups （5， 10， 20 mg/kg PA）， high-dose PA+ROCK pathway activator lysophosphatidic acid （LPA） group （20 mg/kg PA+1 mg/kg LPA）， with 15 rats in each group. Another 15 rats were selected as the sham operation group with only the kidney exposed but not excised. The rats in each drug group were gavaged and/or injected with the corresponding liquid via the caudal vein， once a day， for 12 consecutive weeks. During the experiment， the general condition of rats was observed in each group. After the last administration， the serum renal function indexes （blood urea nitrogen， serum creatinine， uric acid） of rats in each group were detected， the renal histopathological changes were observed； the renal tubule injury score and the area of renal fibrosis were quantified. The levels of oxidative stress indexes [malondialdehyde （MDA）， superoxide dismutase （SOD）] and inflammatory factors （tumor necrosis factor-α， interleukin-1β， interleukin-6）， the positive expression rates of connective tissue growth factor （CTGF） and collagen Ⅰ were detected as well as the expression levels of pathway-related proteins （RhoA， ROCK1） and fibrosis- related proteins （transforming growth factor-β1， bare corneum homologs 2， α-smooth muscle actin） were determined. RESULTS Compared with the sham operation group， the rats in model group had reduced diet， smaller body size， listless spirit and sluggish response， reduced and atrophied glomeruli， dilated renal tubules with chaotic structure， and a large number of inflammatory cells infiltrated interstitium； the serum levels of renal function indexes， renal tubule injury score， renal fibrosis area proportion， the levels of MDA and inflammatory factors， the positive expression rates of CTGF and collagen Ⅰ， and the expression levels of pathway-related proteins and fibrosis-related proteins in renal tissues were significantly increased， while SOD level was significantly decreased （P＜0.05）. Compared with the model group， the general condition and pathological injuries of kidney tissue of rats in PA groups were improved to varying degrees，and the above quantitative indexes were significantly improved in a dose-dependent manner （P＜0.05）. LPA could significantly reverse the improvement effect of PA on the above indicators （P＜0.05）. CONCLUSIONS PA can improve renal function and alleviate renal fibrosis in CRF rats， which may be related to inhibiting the activation of RhoA/ROCK signaling pathway.

Objective To analyze the correlations of the expressions of miR-4500 and nerve growth factor(NGF)in breast cancer patients with preoperative magnetic resonance(MR)signs.Methods A total of 105 patients with breast cancer admitted to our hospital were selected,the mRNA expression levels of miR-4500 and NGF in breast cancer tissues and adjacent tissues of patients were detected by qRT-PCR,and the positive expression rates of NGF in breast cancer tissues and adjacent tissues were determined by immunohistochemistry method.The correlations of the expressions of miR-4500 and NGF in breast cancer tissues with clinicopathological features and MR signs of patients were analyzed.The targeting relationship between miR-4500 and NGF was predicted by the bioinformatics website,and the correla-tion between the expressions of the two was analyzed.Results Compared with the adjacent tissues,the expression level of miR-4500 in breast cancer tissue decreased(P<0.05),while the level of NGF mRNA and the positive expression rate of NGF increased(P<0.05).There was no significant difference in age,pathological type,tumor classification,parenchymal background,apparent diffusion coefficient or enhancement curve among different expressions of miR-4500 and NGF(P>0.05).The histological grade,lymph node metastasis,tumor diameter,tumor morphology,ring-like enhancement,and peritu-moral brain edema were related to the expressions of miR-4500 and NGF(P<0.05).The bioinformatics website prediction showed that miR-4500 and NGF had binding sites,and the expressions of miR-4500 and NGF mRNA in breast cancer tissues were negatively correlated(r=-0.576,P<0.05).Conclusion The expression of miR-4500 in breast cancer tissue is low,and the expression of NGF is high,which are correlated with the preoperative MR signs in patients,providing a molecu-lar basis for MR signs.

AIM To investigate the variation rules of main secondary metabolites in Hedysari Radix before and after rubbing strip.METHODS UPLC-MS/MS was adopted in the content determination of formononetin,ononin,calycosin,calycosin-7-glucoside,medicarpin,genistein,luteolin,liquiritigenin,isoliquiritigenin,vanillic acid,ferulic acid,γ-aminobutyric acid,adenosine and betaine,after which cluster analysis,principal component analysis and orthogonal partial least squares discriminant analysis were used for chemical pattern recognition to explore differential components.RESULTS After rubbing strip,formononetin,calycosin,liquiritigenin and γ-aminobutynic acid demonstrated increased contents,along with decreased contents of ononin,calycosin-7-glucoside and vanillic acid.The samples with and without rubbing strip were clustered into two types,calycosin-7-glucoside,formononetin,γ-aminobutynic acid,vanillic acid,calycosin-7-glucoside and formononetin were differential components.CONCLUSION This experiment clarifies the differences of chemical constituents in Hedysari Radix before and after rubbing strip,which can provide a reference for the research on rubbing strip mechanism of other medicinal materials.

Objective To observe the therapeutic effect and mechanism of Baoyuan Decoction for chronic heart failure model rat.Methods SD rats were randomly divided into blank group,model group,Baoyuan Decoction group,Captopril group,Baoyuan Decoction+CCT020312[protein kinase R-like endoplasmic reticulum kinase(PERK)activator]group,15 rats in each group.Except for the blank group,the rats in the other groups were induced by Adriamycin to construct a chronic heart failure model.After corresponding drug intervention,cardiac function indexes[left ventricular end-diastolic diameter(LVEDD),left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),brain natriuretic peptide(BNP),cardiac troponin I(cTnI)],inflammation-related factors[tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β)],oxidative stress factors[malondialdehyde(MDA),superoxide dismutase(SOD)]were detected in each group.Changes in apoptosis-related indicators[B-cell lymphoma 2(Bcl-2),B-cell lymphoma 2-associated X protein(Bax),Caspase-3]and PERK/transcription activator 4(ATF4)signaling pathway-related proteins glucose-regulated protein 78(GRP78),PERK,ATF4,C/EBP homologous protein(CHOP)levels.Results Compared with the blank group,LVEDD,BNP,cTnI,TNF-α,IL-1β,MDA levels,protein expression levels of Bax,Caspase-3,GRP78,PERK,ATF4,CHOP in the model group were significantly increased,LVEF,LVFS,SOD levels and Bcl-2 protein expression level were significantly decreased(all P＜0.05).Compared with the model group and Baoyuan Decoction+CCT020312 group,LVEDD,BNP,cTnI,TNF-α,IL-1β,MDA levels,protein expression levels of Bax,Caspase-3,GRP78,PERK,ATF4,CHOP in Baoyuan Decoction group and Captopril group were significantly decreased,LVEF,LVFS,SOD levels and Bcl-2 protein expression level were significantly increased(all P＜0.05).Compared with the Captopril group,there was no significant change in the above indexes(except CHOP protein expression level)in the Baoyuan Decoction group(P＞0.05).Conclusion Baoyuan Decoction can delay the progression of chronic heart failure rats,and its mechanism may be related to inhibiting the PERK/ATF4 signaling pathway to alleviate cardiomyocyte apoptosis,further reducing the degree of inflammatory response and oxidative stress,thereby promoting the repair of cardiac function and myocardial injury.

Chronic atrophic gastritis(CAG)is a common intractable gastric disease in clinic,which belongs to the gastric precancerous lesions.Professor LIU Feng-Bin and his team have performed the exploration and practice in the field of CAG for more than 30 years,and they proposed that the evolution of the traditional Chinse medicine(TCM)pathogenesis of inflammation-to-tumor transition(ITT)in CAG was characterized by spleen deficiency being the root cause,qi stagnation,blood stasis and dampness retention being the branch cause,and stasis and toxin being the aggravating factors.Deificiency of the spleen and stomach is the initial factor of CAG,which influences the whole process of the disease.Qi stagnation,blood stasis and dampness retention are the triggering and aggravating factors for the ITT in CAG.The formation of blood stasis and toxin is the key to the progression and transition of CAG.Treatment of ITT in CAG should be based on the results of syndrome differentiation and gastroscopic findings by staging therapy.Before treatment,disease dianosis and syndrome differentiation should be made,and macro and micro syndrome differentiation should be carried out for assistance.Therapy of strengthening the spleen and supporting healthy qi should be implemented throughout the whole process of the disease.The early stage of CAG has the features of gastric mucosa with mild to moderate atrophy and with or without mild intestinal epithelial hyperplasia,the pathogenesis of early CAG is characterized by weakness of the spleen and stomach and is accompanied with the pathological factors of qi stagnation,damp-retention and blood stasis,and the basic treatment should adopt the therapies of strengthening the spleen and clearing heat,regulating qi and activating blood stasis.The advanced stage of CAG has the features of severe atrophic gastric mucosa with or without moderate to severe intestinal epithelial and/or mild to moderate intraepithelial neoplasia,the pathogenesis is characterized by weakness of the spleen and stomach,phlegm blended with blood stasis,and stasis-toxin in the gastric collaterals,and the basic treatment should adopt the therapies of supporting healthy qi and dissipating masses,and unblocking the collaterals and removing toxin,so as to construct an intact line to blocking the ITT in CAG with traditional Chinese medicine.