Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results. To fundamentally overcome these issues and accelerate drug discovery, a new combined-structure RBFE (CS-FEP) calculation strategy was proposed, which solved the existing issues by constructing a new alchemical pathway, smoothed the alchemical transformation, increased the phase-space overlap between adjacent states, and thus significantly increased the convergence and accelerated the relative binding free energy calculations. This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1 (PDE1). Starting from a PDE1 inhibitor (compound 9, IC₅₀ = 16.8 μmol/L), the CS-FEP guided hit-to-lead optimizations resulted in a promising lead (11b and its mesylate salt formulation 11b-Mesylate, IC₅₀ = 7.0 nmol/L), with ∼2400-fold improved inhibitory activity. Further experimental studies revealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.

Lipid-based nanocarrier is a classic drug delivery system with great biocompatibility and biodegradability. It can effectively reduce the toxicity of anti-tumor and anti-infective drugs in clinical practice. However, it has not yet met the clinical demand for enhanced therapeutic efficacy, and the clinical application is still very limited. The complex in vivo delivery process of lipid-based nanomedicine and the reciprocal interactions with body lead to unexpected changes in in vivo performance of nanomedicine and seriously hinder clinical translation. Therefore, the in-depth study of the relationships among intrinsic properties of lipid-based nanomedicine, the in vivo delivery process, and the regulatory mechanisms will not only provide guidance for the rational design of nanocarriers, but also promote the clinical translation and precision medicine of new lipid-based nanomedicine. In this review, we summarize the in vivo delivery process, regulating factors and intervention strategies for the in vivo delivery of lipid-based nanomedicine.

OBJECTIVE: To investigate the effect of total hip arthroplasty(THA) with the prosthesis of 127° small neck stem angle and 135° large neck stem angle. METHODS: From January 2014 to June 2016, 84 patients with THA were selected, including 44 males and 40 females, aged 45 to 72(53.4±8.1) years old, 68 patients with necrosis of the femoral head(32 on the left and 36 on the right), 16 patients with serious osteoarthritis of the hip caused by other reasons, and the course of disease was 9 to 36 (24.0±5.5) months. Forty-two patients in each group were evaluated by Harris score, visual analog score(VAS), length measurement of lower limbs, biomechanical evaluation of different angles of the neck stem. The complications and quality of life 24 months after operation were compared. RESULTS: Two patients in each group were lost, the rest were followed up for 30 to 36 (33.0±1.6)months. The Harris score and the length of both lower limbs were measured before and 1, 6, 12, 24 months after operation. The difference of Harris score and the length of both lower limbs in the two groups was significantly improved compared with that before operation( CONCLUSION THA with large and small neck stem angle prosthesis can better recover the function of hip joint, but large neck stem angle can reduce the degree of postoperative pain and improve the quality of life of patients.
Aged ; Arthroplasty, Replacement, Hip ; Female ; Hip Joint/surgery* ; Hip Prosthesis ; Humans ; Male ; Middle Aged ; Quality of Life ; Retrospective Studies ; Treatment Outcome

Background:Clinical outcomes of undifferentiated arthritis (UA) are diverse,and only 40 ％ of patients with UA develop rheumatoid arthritis (RA) after 3 years.Discovering predictive markers at disease onset for further intervention is critical.Therefore,our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development.Methods:We performed a prospective,multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals.Clinical and serological parameters were obtained at recruitment.Follow-up was undertaken in all patients every 12 weeks for 2 years.Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression.Results:A total of 234 patients were recruited in this study,and 17 (7.3％) patients failed to follow up during the study.Among the 217 patients who completed the study,83 (38.2％) patients went into remission.UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9％ vs.16.8％,x2=8.228,P=0.008),anti-cyclic citrullinated peptide (CCP) antibodypositivity (66.7％ vs.10.7％,x2 =43.897,P ＜ 0.001),and double-positivity rate of RF and anti-CCP antibody (38.1％ vs.4.1％,x2 =32.131,P ＜ 0.001) than those who did not.Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017,95％ confidence interval:5.803-55.938;P ＜ 0.001).Conclusion:As an independent predictor of RA,anti-CCP antibody should be tested at disease onset in all patients with UA.

OBJECTIVETo explore the effects of integrative medicine (IM) rehabilitation protocolon motor function, activity of daily living, and quality of life (QOL) in hemiplegia patients after stroke.

METHODSTotally 120 patients with post-stroke hemiplegia were allocated to four groups using sealed envalope drawing, i.e., the rehabilitation group, the Chinese medical treatment group, the acupuncture group, and the comprehensive rehabilitation group, 30 cases in each group. Based on routine rehabilitative training, patients in the Chinese medical treatment group, the acupuncture group, and the compre-hensive rehabilitation group received standardized treatment based on syndrome typing, Shi's Consciousness-Restoring Resuscitation acupuncture, Chinese herbs + acupuncture comprehensive rehabilitatino protocol, respectively. The treatmet cycle consisted of 4 weeks with 24-week follow-ups. Fugl-Meyer motor assessment (FMA), Modified Barthel Index (MBI), and Stroke-Specific Quality of Life Scale(SS-QQL), and safety assessment were taken as main effect indices before treatment, at week 4 of treatment, at week 12 and 24 of follow-ups, respectively.

RESULTSThere was no statistical difference in FMA score, MBI score, SS-QOL score among the four groups before treatment (P > 0.05). These scores were significantly improved in the four groups at week 4 of treatment, week 12 and 24 of follow-ups, respectively (P < 0.05). Besides, FMA score and SS-QOL score were significantly improved in the comprehensive rehabilitation group at each corresponding time point, as compared with other treatment groups (P < 0.05).

CONCLUSIONSThe comprehensive protocol could significantly improve motor function, activity of daily living in hemiplegia patients after stroke, and further improve their QOL. Its effect was better than other single treatment.

Activities of Daily Living ; Acupuncture Therapy ; Hemiplegia ; rehabilitation ; Humans ; Integrative Medicine ; methods ; Medicine, Chinese Traditional ; Motor Skills ; Quality of Life ; Stroke Rehabilitation ; Treatment Outcome

OBJECTIVETo study the analgesia mechanism of needle-knife lysis in spinal cord and other parts of central nervous system by comparing the changes of Leu-Enkephalin (L-ENK) content in different parts of centrium of rats undergone needle-knife lysis and electro-acupuncture respectively.

METHODSSixty healthy SD rats were randomly devided into normal control group, model group, needle-knife lysis (NKL) group and electro-acupuncture (EA) group. 4% papain solution mixed with 0.3 mol/L cysteine solutin in the ratio of 1:1, paused for 0.5 h,injected the mixture, 20 microl each time,into the left knee joint cavities of rats in model, NKL, EA groups at the 1st, 4th, 7th day. After 4 weeks in NKL group and EA group were treated with needle-knife lysis and electro-acupuncture, respectively. Three weeks after treatment, samples of spinal cord of the swollen part of rat waists and rat brains were taken from and the content of L-ENK of medulla oblongata, midbrain, pituitary gland, and hippocampus were measured.

RESULTSL-ENK content of model group increased higher than that of normal control group in spinal cord, hippocampus and midbrain (P < 0.01); there were no significant difference between normal control group and modle group on L-ENK in medulla oblongata and thalamus (P > 0.05). After intervening of NKL or EA, L-ENK content of NKL group increased higher in hippocampus than that of model group and EC group (P < 0.05); but L-ENK content of NKL group in midbrain was lower than that of model group (P < 0.05).

CONCLUSIONNeedle-knife lysis has characteristic of regulation for the L-ENK content in different parts of central nervous system of rats with knee osteoarthritis, and analgesic effect of needle-knife was possibly related with regulation of center L-ENK.

Acupuncture Therapy ; methods ; Animals ; Central Nervous System ; chemistry ; Electroacupuncture ; Enkephalin, Leucine ; analysis ; Female ; Male ; Osteoarthritis, Knee ; metabolism ; therapy ; Rats ; Rats, Sprague-Dawley