Objective To design and synthesize PROTAC degraders targeting the SARS-CoV-2 main protease （M^pro）based on PROTAC technology. Methods Compound 3w was used as the M^pro ligand, and the indole N atom in the solvent-exposed region was selected as the linker attachment site. A series of M^pro PROTACs were designed and synthesized by conjugating compound 3w with the CRBN ligand pomalidomide through alkane linkers of different lengths. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. Western Blot analysis was employed to evaluate their degradation activity and explore its mechanism in M^pro-HEK-293T cells. Results Four novel M^pro PROTACs（A1-A4）were successfully synthesized. The most potent compound A4 demonstrated M^pro degradation activity with a DC₅₀ value of 5.2 μmol/L, and its degradation mechanism was validated. Conclusion A novel class of M^pro PROTAC degraders were successfully designed and synthesized, and their protein degradation capability and mechanism of action were demonstrated. These results provided lead compounds for the research and development of antiviral degraders against SARS-CoV-2.

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.

Objective To explore the mechanism of action of lamotrigine in the treatment of major depressive disorder(MDD).Methods Information on the drug targets of lamotrigine and the therapeutic targets of MDD were collected for intersection target gene analysis and protein-protein interaction screening.Various biological pathways related to lamotrigine in treatment of MDD were determined through gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.The screened core targets were preliminarily validated using molecular docking technology.Further validation of Mendelian randomization was conducted using genome-wide association analysis data from gamma-aminobutyric acid recep tor-associated protein-like 1(GABARAPL1)and MDD in the OpenGWAS database.Results The biological pathways related to lamotrigine in treatment of MDD were identified,which included gamma-aminobutyric acid(GABA)ergic synapses,nicotine addiction,glutamatergic synapses,endogenous cannabinoid signaling.Molecular docking showed that the docking energy of lamotrigine with GABRA1,GABRB2,GABRA6,GABRD,GABRG2,GABRG1,GABRA5,GABRA4,GABRB3,and GABRA2 receptors was-5.8 kCal·mol-1.Among them,the GABRB3 receptor showed the strongest docking energy with lamotrigine,which was-9.5 kCal·mol-1.In the genome-wide association analysis data of GABARAPL1,303 single nucleotide polymorphisms were associated with GABARAPL1(P＜5 × 106).15 single nucleotide polymorphisms were screened and retained for Mendelian randomization analysis,and the results showed that GABA receptors may be an important therapeutic target for MDD.Conclusion The treatment of MDD with lamotrigine may be achieved by acting on GABA receptors,which provided a research basis for the clinical application of lamotrigine in treating MDD.

Objective To observe the multi-system toxicity of Tripterygium glycosides tablets in rats with type Ⅱ collagen-induced arthritis(CIA).Methods Healthy SD rats were randomly divided into normal group,model group and experimental group,with 10 rats in each group.In addition to the normal group,the other groups were established collagen-induced arthritis model.After the first immunization,the normal group and the model group were given an equal volume of 0.3％sodium carboxymethyl cellulose solution,and the experimental group was given 72 mg·kg-1·d-1 Tripterygium glycosides solution,once a day for 6 weeks.On the 42 nd day,the blood routine of each group was detected and the organ index was calculated.The levels of liver,kidney function and sex hormones in rats were detected by enzyme-linked immunosorbent assay.The histopathological changes of liver,kidney,ovary and testis were observed by hematoxylin-eosin(HE)staining.Results The testicular indexes of the normal group,the model group and the experimental group were(0.81±0.05)％,(0.97±0.06)％and(0.81±0.12)％;the estradiol contents were(63.90±16.19),(55.42±7.23)and(40.04±5.97)pg·mL-1;the testosterone contents were(1 290.96±257.94),(1 198.43±190.77)and(912.62±61.72)pg·mL-1,respectively.There were statistically significant differences in the above indexes between the model group and the experimental group(P＜0.01,P＜0.05).HE pathological results showed that Tripterygium glycosides tablets could cause abnormal histopathological changes of ovary and testis in CIA model rats.Conclusion Continuous administration of 8-fold clinical equivalent dose of Tripterygium glycosides tablets for 6 weeks can cause damage to the reproductive system of CIA rats.

Quercetin can mediate the activation of mitogen-activated protein kinase(MAPK)signaling pathways to prevent osteoporosis(OP).This paper comprehensively discusses the interrelationship between MAPK and osteoporosis-related cells based on the latest domestic and international research.Additionally,it elucidates the research progress of quercetin in mediating the MAPK signaling pathway for OP prevention.The aim is to provide an effective foundation for the clinical prevention and treatment of OP and the in-depth development of quercetin.

Objective To elucidate utilization patterns,cost and safety of Bruton's tyrosine kinase inhibitors(BTKi)in the real world.Methods A retrospective cohort was designed and constructed using real-world BTKi data from a single lymphoma center.Descriptive analysis was performed to describe the demographic and clinical characteristics of the population.Medicine utilization and cost were quantified by defined daily doses(DDDs)and defined daily dose cost(DDDc),respectively.A generalized estimating equation(GEE)was used to explore the potential influencing factors of platelet aggregation rate(PAR).Results The study cohort included 193 patients[median age,65 years;77(39.90％)women],most of whom received ibrutinib(n=109,56.48％),and 77.20％patients combined BTKi with chemotherapy or targeted therapy.The implementation of national negotiation policy had a large impact on medicine utilization and cost.The DDDs difference between the two BTKis was reduced from 18.55 to 1.41 times.The DDDc for ibrutinib decreased from 1 619.99 Yuan to 567.00 Yuan,and that for zanubrutinib from 706.25 Yuan to 340.00 Yuan was already lower than ibrutinib.Interruptions were more readily observed in patients treated with ibrutinib,and hematological toxicity was the main adverse drug event(ADE)leading to treatment interruption.Besides,the GEE model showed that combining BTKi with antiplatelet medication significantly decreases the PAR[β=-34.35％,95％confidence interval(CI):-41.60％--27.11％,P＜0.001].Compared to zanubrutinib,ibrutinib also notably reduces the PAR(β=-12.38％,95％CI:-24.50％--0.27％,P＜0.05).Conclusion After the implementation of national negotiation policy,there is no significant difference in the clinical preference for two BTKis.Compared with ibrutinib,zanubrutinib showed an advantage in terms of economic profile,treatment interruptions caused by ADE,and the effect on PAR.

Objective To explore the effect of tilianin combined with aerobic training on cognitive function of rats with Alzheimer's disease(AD).Methods Rats were divided into 7 groups:blank group,model group,control group,low dose experimental group,medium dose experimental group,high dose experimental group and combination group,12 rats in each group.The rats in blank group were sham operated,and other groups were AD model rats established by bilateral hippocampal injection of amyloid-beta peptide 1-42(A(31-42).One week after modeling,the rats in control group and combination group were trained on the treadmill,and the rats in other groups were fed quietly.The rats in blank group,model group and control group were given 0.5％carboxymethyl cellulose sodium(CMC)2 mL.The rats in low,medium and high dose experimental groups were given intragastric administration of 5,10 and 20 mg·kg-1·d-1tilianin 2 mL.The rats in combined group were given 20 mg·kg-1·d-1 tilianin 2 mL by gavage.The drug was given for 6 weeks.Cognitive function was evaluated by Morris water maze test.The level of Beta-site APP cleaving enzyme protein 1(BACE1)mRNA in hippocampus was measured by quantitative reverse transcription polymerase chain reaction.The phosphorylation level of nuclear factor-κB(NF-κB)p65 in hippocampus was detected by Western blot.Results The escape latencies of blank group,model group,control group,low dose experimental group,medium dose experimental group,high dose experimental group and combination group were(20.16±2.06),(60.45±6.55),(46.52±2.90),(42.80±3.15),(41.19±2.54),(35.66±2.82)and(28.49±1.97)s;the relative expression of BACE1 mRNA were 1.00±0.06,7.88±0.49,6.02±0.38,4.96±0.57,3.01±0.21,1.98±0.17 and 1.48±0.11;the relative phosphorylation levels of NF-κB p65 were 0.11±0.03,1.46±0.11,0.89±0.10,0.71±0.06,0.37±0.05,0.29±0.02 and 0.15±0.01.Compared between model group and blank group,comparison between low,medium,high dose experimental group and model group,comparison between combination group and high dose experimental group all showed statistically significant differences(all P＜0.05).Conclusion Tilianin combined with aerobic training can improve the cognitive function of AD rats,and its mechanism may be related to the inhibition of inflammation mediated by NF-κB signal pathway.

ObjectiveExisting artificial vision devices can be divided into two types: implanted devices and extracorporeal devices, both of which have some disadvantages. The former requires surgical implantation, which may lead to irreversible trauma, while the latter has some defects such as relatively simple instructions, limited application scenarios and relying too much on the judgment of artificial intelligence (AI) to provide enough security. Here we propose a system that has voice interaction and can convert surrounding environment information into tactile commands on head and neck. Compared with existing extracorporeal devices, our device can provide a larger capacity of information and has advantages such as lower cost, lower risk, suitable for a variety of life and work scenarios. MethodsWith the latest remote wireless communication and chip technologies, microelectronic devices, cameras and sensors worn by the user, as well as the huge database and computing power in the cloud, the backend staff can get a full insight into the scenario, environmental parameters and status of the user remotely (for example, across the city) in real time. In the meanwhile, by comparing the cloud database and in-memory database and with the help of AI-assisted recognition and manual analysis, they can quickly develop the most reasonable action plan and send instructions to the user. In addition, the backend staff can provide humanistic care and emotional sustenance through voice dialogs. ResultsThis study originally proposes the concept of “remote virtual companion” and demonstrates the related hardware and software as well as test results. The system can not only achieve basic guide functions, for example, helping a person with visual impairment to shop in supermarkets, find seats at cafes, walk on the streets, construct complex puzzles, and play cards, but also can meet the demand for fast-paced daily tasks such as cycling. ConclusionExperimental results show that this “remote virtual companion” is applicable for various scenarios and demands. It can help blind people with their travels, shopping and entertainment, or accompany the elderlies with their trips, wilderness explorations, and travels.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

With the increasing proportion of human papilloma virus(HPV)infection in the pathogenic factors of oro-pharyngeal cancer,a series of changes have occurred in the surgical treatment.While the treatment mode has been im-proved,there are still many problems,including the inconsistency between diagnosis and treatment modes,the lack of popularization of reconstruction technology,the imperfect post-treatment rehabilitation system,and the lack of effective preventive measures.Especially in terms of treatment mode for early oropharyngeal cancer,there is no unified conclu-sion whether it is surgery alone or radiotherapy alone,and whether robotic minimally invasive surgery has better func-tional protection than radiotherapy.For advanced oropharyngeal cancer,there is greater controversy over the treatment mode.It is still unclear whether to adopt a non-surgical treatment mode of synchronous chemoradiotherapy or induction chemotherapy combined with synchronous chemoradiotherapy,or a treatment mode of surgery combined with postopera-tive chemoradiotherapy.In order to standardize the surgical treatment of oropharyngeal cancer in China and clarify the indications for surgical treatment of oropharyngeal cancer,this expert consensus,based on the characteristics and treat-ment status of oropharyngeal cancer in China and combined with the international latest theories and practices,forms consensus opinions in multiple aspects of preoperative evaluation,surgical indication determination,primary tumor re-section,neck lymph node dissection,postoperative defect repair,postoperative complication management prognosis and follow-up of oropharyngeal cancer patients.The key points include:① Before the treatment of oropharyngeal cancer,the expression of P16 protein should be detected to clarify HPV status;② Perform enhanced magnetic resonance imaging of the maxillofacial region before surgery to evaluate the invasion of oropharyngeal cancer and guide precise surgical resec-tion of oropharyngeal cancer.Evaluating mouth opening and airway status is crucial for surgical approach decisions and postoperative risk prediction;③ For oropharyngeal cancer patients who have to undergo major surgery and cannot eat for one to two months,it is recommended to undergo percutaneous endoscopic gastrostomy before surgery to effectively improve their nutritional intake during treatment;④ Early-stage oropharyngeal cancer patients may opt for either sur-gery alone or radiation therapy alone.For intermediate and advanced stages,HPV-related oropharyngeal cancer general-ly prioritizes radiation therapy,with concurrent chemotherapy considered based on tumor staging.Surgical treatment is recommended as the first choice for HPV unrelated oropharyngeal squamous cell carcinoma(including primary and re-current)and recurrent HPV related oropharyngeal squamous cell carcinoma after radiotherapy and chemotherapy;⑤ For primary exogenous T1-2 oropharyngeal cancer,direct surgery through the oral approach or da Vinci robotic sur-gery is preferred.For T3-4 patients with advanced oropharyngeal cancer,it is recommended to use temporary mandibu-lectomy approach and lateral pharyngotomy approach for surgery as appropriate;⑥ For cT1-2N0 oropharyngeal cancer patients with tumor invasion depth＞3 mm and cT3-4N0 HPV unrelated oropharyngeal cancer patients,selective neck dissection of levels ⅠB to Ⅳ is recommended.For cN+HPV unrelated oropharyngeal cancer patients,therapeutic neck dissection in regions Ⅰ-Ⅴ is advised;⑦ If PET-CT scan at 12 or more weeks after completion of radiation shows intense FDG uptake in any node,or imaging suggests continuous enlargement of lymph nodes,the patient should undergo neck dissection;⑧ For patients with suspected extracapsular invasion preoperatively,lymph node dissection should include removal of surrounding muscle and adipose connective tissue;⑨ The reconstruction of oropharyngeal cancer defects should follow the principle of reconstruction steps,with priority given to adjacent flaps,followed by distal pedicled flaps,and finally free flaps.The anterolateral thigh flap with abundant tissue can be used as the preferred flap for large-scale postoperative defects.