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.

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.

Objective: To investigate the correlation between heart rate index (HRI), systolic blood pressure(SBP) peak-to-SBPrest ratio (SBPR) and peak oxygen consumption (peakVO₂) in patients with chronic heart failure (CHF), and discuss the possibility of using HRI and SBPR collected during exercise to assess the exercise tolerance of CHF patients in the absence of gas analysis. Methods: In this cross-sectional study, a total of 547 patients with CHF who underwent cardiopulmonary exercise test(CPET) in Tongji Hospital Heart Rehabilitation Center Affiliated to Tongji University from March 2007 to December 2018 were collected retrospectively, focusing on their clinical data including age, gender, type of heart failure,BMI as well as data collected during their CPETs, such as peakVO₂, HRI and SBPR. Spearman univariate correlation analysis was used for statistical analysis, to unveil the correlations between peakVO₂ and those parameters, and multiple linear regression analysis was also conducted. Results: A total of 547 CHF patients conducting CPET were included in this research, of which 447 were male, at age of 63(56, 69). Univariate analysis indicates that HRI, SBPR and peakVO₂ showed significant positive correlation (r=0.323, 0.263, respectively, all P<0.001); Age and peak VO₂ showed significant negative correlation(r=-0.207, P<0.001); Male patients showed peakVO₂ higher than female(r=-0.229, P<0.001); PeakVO₂ of heart failure with reduced ejection fraction(HFrEF) was lower than heart failure with mid-range ejection fraction(HFmrEF)and heart failure with preserved ejection fraction(HFpEF) (r=0.181, P<0.001). Body mass index (BMI) had no significant correlation with peakVO₂ (P>0.05). Multivariate linear regression analysis showed that the HRI, SBPR were positively correlated with peakVO₂(t=7.68, 5.08, respectively, all P<0.05), while age and BMI showed negative correlation with peakVO₂(t=-5.43, -0.31, respectively, all P<0.05). PeakVO₂ of male was higher than female(t=-6.03, P<0.05), and peakVO₂ of HFrEF was lower than those of HFmrEF and HFpEF(t=3.17, 4.48, respectively, all P<0.05). A linear equation (F=33.52, adjusted R²=0.29) could be constructed: peakVO₂=10.65(male) or 8.53(female)+4.26HRI+3.31SBPR-0.07age-0.13BMI+0(HFrEF) or 1.05 (HFmrEF) or 1.62(HFpEF). Conclusion: HRI and SBPR are positively correlated with peakVO₂. In the absence of gas analysis, it is possible to apply HRI and SBPR during exercise to predict exercise tolerance in patients with CHF.
Chronic Disease ; Cross-Sectional Studies ; Female ; Heart Failure ; Heart Rate ; Humans ; Male ; Oxygen Consumption/physiology* ; Prognosis ; Retrospective Studies ; Stroke Volume/physiology*

OBJECTIVE: This study aimed to compare the effects of water storage treatment and thermal cycling on the shear bond strength (SBS) of three self-adhesive dual-cure resin cements. METHODS: Six cubic zirconia specimens with side length of 2 cm were obtained by cutting and sintering. Three self-adhering dual-cure resin cements (i.e., Clearfil SAC, RelyX U200, and Multilink Speed) were selected. According to their bonding modes, they were divided into three groups: direct bonding group (direct coating with resin cement), adhesive group (applying universal adhesives and then coating with resin cement), and primer group (applying Z-Prime Plus and then coating with resin cement). According to experimental conditions, each group was divided into two subgroups: subgroup a (water storage at 37 ℃ for 24 h) and subgroup b (thermalcycling for 5 000 times). SBS data were analyzed by one-way ANOVA by using SPSS 19.0 software (P<0.05). The fractured zirconia surface was observed under a stereomicroscope. RESULTS: After water storage for 24 h, the SBS of the adhesive group and the primer group of the three resin cements was higher than that of the direct adhesive group (P<0.05), but the difference in SBS between the adhesive group and the primer group was not significant (P>0.05). After thermalcycling, the SBS of the three types of resin cements decreased (P<0.05); the SBS of the adhesive group was higher than that of the direct adhesive group and the primer group (P<0.05). Fracture mode analysis revealed that the type Ⅲ fracture mode evidently increased after the thermalcycling treatment compared with the water storage treatment. CONCLUSIONS The universal adhesives and the primer can improve the SBS of self-adhesive dual-cure resin cement in water storage at 37 ℃ for 24 h. The universal adhesives had a better bonding durability than the zirconia primer.
Ceramics ; Dental Bonding ; Dental Cements ; Dental Stress Analysis ; Materials Testing ; Resin Cements ; Shear Strength ; Surface Properties ; Zirconium

OBJECTIVEThis study aimed to determine the effects of copper content on the corrosion resistance of CoCrMoCu alloy and its in vitro antibacterial performance.

METHODSCoCrMoCu specimens with different Cu contents (2%, 3%, 5%, and 7%) were prepared by vacuum melting method. CoCrMo without Cu served as control. The corrosion resistance of the specimens was measured by electrochemistry. The antibacterial effects of the specimens on Staphylococcus aureus and Escherichia coli were analyzed by coating-film method.

RESULTSCompared with CoCrMo without Cu, the addition of 2%-5% Cu to CoCrMo improved the pitting and uniform corrosion of CoCrMo alloy and decreased the corrosion current density. The antibacterial performance of CoCrMoCu alloy increased with increased Cu content. The antibacterial rate of alloy was 99% when Cu content exceeded 5%.

CONCLUSIONSCu addition had a statistically significant influence on the corrosion resistance and antibacterial performance of CoCrMoCu. CoCrMoCu has better corrosion resistance and antibacterial performance when Cu content is 5%.

Objective: To evaluate the safety, efficacy and tolerability of China-made sildenafil citrate (Jinge) in the treatment of ED. METHODS: We conducted a multi-center, randomized, double-blind and placebo-controlled clinical trial among 222 ED patients in five urological or andrological clinics of China. The patients were randomly assigned to receive sildenafil citrate (SC, n = 111) or placebo (n = 111) for 8 weeks. We obtained and analyzed the demographic and clinical characteristics of the patients, the scores of International Index of Erectile Function (IIEF), the success rate of sexual intercourse, and the incidence of adverse events. RESULTS: No statistically significant differences were found between the patients of the SC and those of the placebo group in the mean age (［47.2±11.32］ yr vs ［46.67±13.08］ yr, P>0.05), psychological etiology (27.93% vs 23.42%, P>0.05), organic etiology (21.62% vs 29.73%, P>0.05) or mixed etiology (50.45% vs 46.85%, P>0.05), nor in height, weight, nationality, or history of smoking, drinking or allergy. Compared with the placebo controls, the SC-treated patients showed significant increases in the excellence rate of effectiveness (29.91% vs 78.90%, P<0.01), success rate of sexual intercourse (29.16% vs 63.87%, P<0.01), and total effectiveness rate (34.58% vs 77.98%, P<0.01). The effectiveness rates on organic, psychogenic and mixed types ED were remarkably higher in the SC group (64.52%, 83.33%, and 82.14%) than in the placebo control (46.15%, 21.21%, and 25.00%) (P<0.01). Mild or temporary adverse events were observed in 32 cases in the SC group as compared with 13 in the placebo control. CONCLUSIONS China-made sildenafil citrate is an effective, safe and well-tolerated drug for ED of different etiologies in the Chinese population.
Aged ; China ; Coitus ; Double-Blind Method ; Drug Compounding ; Erectile Dysfunction ; drug therapy ; etiology ; Humans ; Male ; Phosphodiesterase 5 Inhibitors ; therapeutic use ; Sildenafil Citrate ; therapeutic use ; Smoking ; Treatment Outcome

OBJECTIVETo investigate the relationship between renal clear cell carcinoma and type 2 diabetes mellitus (DM).

METHODSTwo hundreds and sixty-four patients with renal clear cell carcinoma and four hundred controls who suffered from non-urinary system, non-neoplastic or non-hormone-related disorders, were enrolled from January 2008 to December 2012. The incidence of diabetes between the 2 groups and the relationship between renal clear cell carcinoma and duration of diabetes were compared, moreover, renal clear cell carcinoma patients with DM were compared with patients without DM for their clinical features, laboratory examinations and histological characteristics.

RESULTSThe comparison of renal clear cell carcinoma group and control group: the incidence of DM in the two groups were 19.7% and 12.8% respectively, and the difference was significant (χ(2) = 5.86, P < 0.05, OR = 1.68). In the renal clear cell carcinoma group, the proportion of patients with DM diagnosed within 2-4 years was 4.92%, which were significant higher than those in the control group 1.70% (χ(2) = 5.49, P < 0.05, OR = 2.91). And men with diabetes had high occurrence risk 86% of renal clear cell carcinoma (OR = 1.86, 95%CI: 1.09-3.15). The comparison of diabetes patients subgroup and non-diabetic patients subgroup in renal clear cell carcinoma group: in respect of clinical features, greatest tumor diameter in the two subgroups were (4.9 ± 2.3) cm and (4.2 ± 2.1) cm respectively, and the difference was significant (t = 1.96, P < 0.05). However, there was no significant difference in terms of age, gender and cancer location between the two subgroups (P > 0.05). In respect of laboratory examinations, serum creatinine in the two subgroups were (72 ± 20) µmol/L and (65 ± 17) µmol/L, and the difference was significant (t = 2.34, P < 0.05); serum urea nitrogen in the 2 subgroups were (7.1 ± 2.1) mmol/L and (6.0 ± 1.5) mmol/L respectively, and the difference was significant too (t = 1.47, P < 0.05). In respect of histological characteristics, the proportion of well differentiated clear cell carcinoma were 80.8% and 81.1% respectively, and the difference was significant (χ(2) = 4.23, P < 0.05). The proportion of stage II were 25.0% and 27.8% respectively and the difference was significant (χ(2) = 4.08, P < 0.05).

CONCLUSIONSDM is closely related with renal clear cell carcinoma and DM may be a possible risk factor for the tumor. And for elderly patients with diabetes who appear waist discomfort or hematuria, a careful examination of kidney is important to make early diagnosis, give timely treatment and improve survival prognosis.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Renal Cell ; complications ; Case-Control Studies ; Diabetes Mellitus, Type 2 ; complications ; Female ; Humans ; Incidence ; Kidney Neoplasms ; complications ; Male ; Middle Aged ; Prognosis

OBJECTIVETo evaluate the application of ultrasonography in diagnosis and treatment of the upper arm radial neuritis.

METHODSFrom 2005.12 to 2011.7, 10 patients of the upper arm radial neuritis were selected and included 6 males and 4 females with an average age of 32 years old ranging from 20 to 40 years. The course of disease ranged from 4 months to 2 years. All patients feel pain on the outside of upper arm. Medical examination showed Tinel's sign masculine, and the muscle force included extension of wrist and fingers were reduced. Upper arm radial neuritis were diagnosed by clinical sign and medical examination. All patients underwent ultrasonography examination, electrophysiology examination and operation. The ultrasonography were compared to the results of electrophysiology examination,and ultrasonography were compared to intra-operative findings and pathology examination.

RESULTSThe ultrasound images showed average diameter of affected limb radial nerve were (0.29+/-0.04) cm, average area were (0.23+/-0.05) cm2, and all of these were greater than uninjured side. Ultrasonograghic findings and orientation of radial neuritis were consistent with intra-operative findings,and the results of ultrasonography were consistent with the results of pathology examination.

CONCLUSIONUltrasonography examination provide morphological evidence for the diagnosis and treatment of the upper arm radial neuritis.

Adult ; Female ; Humans ; Male ; Neuritis ; diagnostic imaging ; pathology ; physiopathology ; therapy ; Radial Nerve ; diagnostic imaging ; Ultrasonography

BACKGROUNDRecently there has been a great deal of interest in the role of serum uric acid (SUA) in atrial fibrillation (AF). The objective of this study was to establish whether there is a relationship between levels of SUA and recurrence of paroxysmal AF after catheter ablation.

METHODSThree hundred and thirty patients diagnosed with paroxysmal AF were analyzed. Patients were categorized into quartiles on the basis of their pre-operative SUA measurement and follow-up, and Kaplan-Meier estimation with a Log-rank test was used for the analysis of the influence of SUA on the recurrence of AF. Pre-procedural clinical variables were correlated with the clinical outcome after ablation using multivariate Logistic analysis. A Cox proportional hazards model was used to estimate the relationship between SUA and the recurrence of AF.

RESULTSAfter a mean follow-up of (9.341 ± 3.667) (range 3.0 - 16.3) months, recurrence rates from the lowest SUA quartile to the highest SUA quartile were 16.0%, 26.4%, 28.3%, and 29.3% respectively (P = 0.014). After adjustment for gender, body mass index (BMI), hypertension, serum levels of high sensitivity C-reactive protein (hsCRP), triglyceride (TG), left atrial diameter (LA), estimated glomerular filtration rate (eGFR), and SUA, there was an increased risk of recurrence in subjects in the highest SUA quartile compared with those in the lowest quartile (hazard ratio 2.804, 95% confidence interval 1.466 - 5.362, P = 0.002). Following multivariate Logistical analysis, SUA was found to be an independent predictor of recurrence (hazard ratio 1.613, 95% confidence interval 1.601 - 1.625, P = 0.014).

CONCLUSIONIn a retrospective study of patients with paroxysmal AF undergoing catheter ablation, elevated preoperative SUA levels were associated with a higher rate of recurrence of AF.

Aged ; Atrial Fibrillation ; blood ; surgery ; Catheter Ablation ; Electrophysiology ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Uric Acid ; blood

OBJECTIVETo introduce the experience in the treatment of lower eyelid pouches orbital rim.

METHODSAn incision was made along the margin of lower eyelid and dissection was performed under the orbicularis muscle to expose the orbital septum and periosteum of lower orbital rim. The fat released from orbital septum was transposed just below the lower orbital rim and fixed on the periosteum. If lacrimal groove deformity was not corrected completely, the musculocutaneous flap, which may be excised beside the incision, was kept to correct the deformities further with only the muscle portion.

RESULTS72 cases with lower eyelid pouches complicated with lacrimal groove deformities were treated with transposition of orbital fat and orbicularis muscular flaps. Satisfactory results were achieved in all the patients after a follow-up period of 3-6 months.

CONCLUSIONIt is an effective and feasible technique to correct lacrimal groove deformities with transposition of orbital fat and orbicularis muscular flaps.

Adipose Tissue ; transplantation ; Aged ; Blepharoplasty ; methods ; Eyelids ; surgery ; Humans ; Orbit ; Periosteum ; surgery