The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction(HFpEF)and HFpEF complicated with atrial fibrillation(HFpEF-AF)in Chinese patients and explore the related factors.Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou Uni-versity from 2009 to 2020 were selected and assigned to a HFpEF-AF group(n =267)and a HFpEF group(n = 568)according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic(ROC)curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated.Results There was no difference in the HFA-PEFF score between the two groups(P =0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group(P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high perform-ance in diagnosing all HFpEF patients,with the area under the curve(AUC)of 0.892 and 0.922 and the opti-mal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in di-agnosing HFpEF-AF(AUC of approximately 1.000)and low performance in diagnosing HFpEF(AUC of 0.885).Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

Objective To investigate the safety of rigid scleral contact lenses in correcting ametropia.Methods A total of 96 patients(192 eyes)with myopia between-20.00 and 0 D and astigmatism between 0 and 3.5 D were included in this perspective study.They were divided into an experimental group(wearing rigid scleral contact lenses)and a control group[wearing rigid corneal contact lenses(RGP)],with 48 patients in each group.Eye indicators including best correc-ted visual acuity(BCVA),corneal endothelial cell density,hexagonal cell ratio,tear film break-up time(BUT),intraocu-lar pressure(IOP),corneal fluorescence staining score,conjunctival congestion score,and ciliary congestion score were measured and compared between the two groups before wearing,on the day of wearing,and 1 week,1 month,and 3 months after wearing lenses,and eye changes were observed.Results The BCVA of patients in the two groups was grea-ter than or equal to 1.00 before wearing lenses and within 3 months after wearing lenses.Compared with before wearing lenses,the corneal endothelial cell density in the experimental group slightly decreased,and the hexagonal cell ratio slightly increased at 3 months after wearing lenses,but the differences were not statistically significant(both P＞0.05).Before wearing lenses and at 3 months after wearing lenses,the corneal endothelial cell density and the hexagonal cell ratio in the experimental group were slightly higher than those in the control group,but the differences were not statistically significant(both P＞0.05).There were no significant differences in BUT and IOP between the experimental group and the control group before wearing,on the day of wearing,and 1 week,1 month,and 3 months after wearing lenses(all P＞0.05).There were no significant differences in corneal fluorescence staining score and conjunctival and ciliary congestion ratings between the experimental group and the control group before wearing lenses and at 3 months after wearing lenses(all P＞0.05).At 3 months after wearing lenses,no conjunctival or corneal edema was observed in the experimental group.Con-clusion Rigid scleral contact lenses and RGP are safe and effective in correcting ametropia;thus,they can be applied widely.

Objective:To determine the content of the released nickel ion through the 7 extraction media to extract the Ni-Ti wires and to plot the curve of the released nickel ion so as to identify a leaching medium that can be substituted for blood for in vitro Ni release evaluation. Methods:The release of Ni through microwave digestion/inductively coupled plasma mass spectrometry (ICP-MS) in the goat serum was determined. Because of the high content of Ni release, it could be determined by diluting the extraction medium, and other extraction media could be determined directly. Ni release standard curves were plotted by the release amount and different time point variables. Though the different extraction media Ni release curves confirm the specificity of extraction media instead of blood.Results:By analyzing the Ni release curves of seven leaching media, it was found that none of these seven extraction media was suitable for the evaluation of Ni release in in vitro leaching media. Considering the safety of the leaching medium and the simplicity of preparation, hydrochloric acid solution was chosen as the leaching medium, but the concentration needed to be diluted accordingly. Finally, a hydrochloric acid solution was created as an alternative to blood for the in vitro study of Ni release from Ni-Ti alloy cardiovascular products, with a volume fraction of 0.005%. Conclusions:The in vitro leaching medium that can replace blood was found to be hydrochloric acid for the time being, but its concentration was too high, resulting in too much Ni release as well, which deviated from the actual situation. Therefore, the hydrochloric acid solution was diluted step by step, and the Ni release curve was examined until it was close to the clinical release level, and the actual concentration was determined, thus laying a solid foundation for the subsequent evaluation of the safety and risk.

Objective To investigate the hemodynamic characteristics of carotid artery models with different degrees of artificial arterial stenosis based on hemodynamic numerical simulation,and to analyze causes of internal carotid artery stenosis and the diseases due to the stenosis from the perspective of hemodynamics.Methods Two-dimensional CT data of healthy individuals were collected from Affiliated Hospital of Inner Mongolia Minzu University,and the three-dimensional model of carotid artery was reconstructed from the two-dimensional CT data using medical modeling software MIMICS20.0.Subsequently,the obtained carotid artery model was imported to 3-Matic Medical software and interfered with various degrees of artificial internal carotid artery stenosis at the same location to obtain the models with 25%,50%and 75%internal carotid artery stenosis.After format conversion,boundary condition setting and mesh generation,the models were imported to computational fluid dynamics software FLUENT14.5 for the hemodynamic numerical simulation and analysis of the carotid artery and two-phase blood flow.Results The comparison of the blood streamlines and velocity vector maps of 3 different degrees of internal carotid artery stenosis at the same location revealed that with the increase of stenosis severity,the phenomenon of blood vortex flow at the carotid sinus decreases rapidly,but obvious vortex flow appeared above and below the internal carotid artery stenosis,and the blood flow was selectively deflected.During the internal carotid artery stenosis from 25%to 50%and then to 75%,the pressure on the wall of internal carotid artery was always low,and the pressure on the wall of internal carotid artery was gradually increased,forming a high pressure area.There was high shear stress area at the stenosis,and the low shear stress ranges above and below the stenosis were obviously larger.Conclusion The technology of using computer software to obtain models with artificial stenosis is convenient and efficient.When the internal carotid artery stenosis increases from 25%to 50%and then to 75%,the blood flow of the carotid artery changes obviously,obvious vortex flow appears in the internal carotid artery,and the mechanical properties of the wall of the carotid artery also change.

ObjectiveTo investigate the pharmacological effect and metabolic mechanism of Linderae Radix on the intrauterine adhesion （IUA） rat model. MethodAn IUA rat model was induced by mechanical injury and infection. Molecular biology and pharmacology techniques were employed to evaluate the inhibitory effect of Linderae Radix extract （LAE） on fibrosis in IUA. Serum metabolomics analysis based on gas chromatography-mass spectrometry （GC-MS） was conducted to explore the metabolic regulation mechanism of LAE. ResultAnimal experiments showed that LAE significantly improved the morphology and structural damage of uterine tissue cells in the IUA rat model， promoted endometrial proliferation， vascular regeneration， and morphological recovery， inhibited the mRNA expression of transforming growth factor-β₁ （TGF-β₁）， Smad2， and Smad3， and increased the expression of Smad7 mRNA to suppress fibrosis. Additionally， LAE significantly suppressed the levels of estrogen （E₂）， follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， and tumor necrosis factor-α （TNF-α） expression （P<0.01）， thereby improving the uterine microenvironment. Metabolomics analysis revealed significant metabolic abnormalities in the serum of IUA rats compared with the results in the normal group， and nine differential metabolites were identified. LAE effectively ameliorated these metabolic abnormalities， primarily by influencing six differential metabolites， including five shared metabolites among the nine identified markers： L-aspartic acid， L-pyroglutamic acid， L-serine， glucose， and L-norvaline. Pathway enrichment analysis indicated that the aminoacyl-tRNA biosynthesis pathway was the main affecting mechanism. ConclusionIn combination with the pharmacological research results， LAE effectively improved uterine damage and inhibited fibrosis in the IUA rat model. Its mechanism may involve the inhibition of the aminoacyl-tRNA biosynthesis pathway and the improvement of the microenvironment.

Objective To investigate the incidence trend, clinical characteristics and prognosis of lung cancer in Ma'anshan area. Methods The data of 398 lung cancer patients admitted to the Department of Respiratory and Critical Care Medicine, Maanshan People's Hospital in Ma'anshan area from January 2018 to May 2022 were selected, and the composition ratio of age, sex, histology and outcome data and its change trend over time were analyzed. Results The minimum age of lung cancer patients in this area was 35 years old, the maximum age was 92 years old, and the average age was (69.94 ± 9.76) years old . The patients were mainly from 70 to 79 years old, followed by 60 to 69 years old and >80 years old . The number of patients was decreasing year by year . The patients with squamous cell carcinoma transferred from 60 to 69 years old to 70 to 79 years old, and adenocarcinoma mainly concentrated in 70 to 79 years old . The incidence of squamous cell carcinoma increased (P=0.006), while that of adenosquamous carcinoma decreased (P=0.005) . The improved discharge rate of lung cancer was increasing year by year (P<0.001) , and the cured discharge rate (P=0.044) was decreasing year by year. The improved discharge rate of men was increasing year by year (P=0.039) , while the improved discharge rate of women was decreasing and then increasing, and the improved discharge rate in 2020 was the lowest (P=0.027) . The mortality increased with age (P=0.002). Conclusion From 2018 to 2022, the number of patients in Ma'anshan area will decrease year by year . The patients were mainly in the 70-79 age group . The incidence rate of adenocarcinoma was the highest , while the incidence rate and age of squamous cell carcinoma were on the rise . The overall improvement discharge rate is increasing year by year , and the cure discharge rate is decreasing year by year. The improvement discharge rate for men is increasing year by year , and vice versa for women.

Objective:To investigate the correlation between Piwi-interacting RNA (piRNA) and diabetic nephropathy (DN).Methods:The differential expression profiles of piRNAs in renal tissues of patients with DN (experimental group) and renal tissues adjacent to tumors of patients with renal tumors (control group) were detected by high-throughput sequencing. The biological function of differentially expressed piRNAs was described by gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis. Real-time fluorescence quantitative PCR was used to detect the serum expression level of target piRNAs in patients with DN. Spearman correlation analysis was used to analyze the correlation between serum target piRNAs and clinical indexes of patients with DN.Results:The results of high throughput sequencing showed that there were 127 differentially expressed piRNAs between DN group and control group, with screening condition of |log 2(fold changes)|≥2 and P<0.05. Among them, there were 99 up-regulated piRNAs and 28 down-regulated piRNAs. The top 5 up-regulated piRNAs were piRNA-hsa-161686, piRNA-hsa-349255, piRNA-hsa-355720, piRNA-hsa-151229 and piRNA-hsa-154959, respectively. The top 5 down-regulated piRNAs were piRNA-hsa-1929960, piRNA-hsa-174194, piRNA-hsa- 148658, piRNA-hsa-172594 and piRNA-hsa-172421, respectively. The PCR verification results of 3 up-regulated genes and 3 down-regulated genes with low P values and high expression levels showed that serum expression level of piRNA-hsa-77976 was significantly down-regulated in patients with DN ( P=0.028), which was consistent with that of sequencing, while the expression levels of other genes were inconsistent with the sequencing results or had no statistical significance. Bioinformatics analysis results predicted that significantly differentially expressed piRNAs might participate in the regulation of DN through Rap1, Ras, PI3K-Akt and axon guiding pathways. The results of correlation analysis showed that the expression level of piRNA-hsa-77976 was negatively correlated with blood urea nitrogen ( r=-0.584, P=0.028), serum creatinine ( r=-0.637, P=0.014), cystatin C ( r=-0.738, P=0.003) and β2 microglobulin ( r=-0.822, P<0.001), and positively correlated with estimated glomerular filtration rate ( r=0.661, P=0.010). Conclusion:The differential expression of piRNA is closely related to DN, and may be used as a new biomarker for the diagnosis and prognosis of DN.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.