Loss of the Protein Cystathionine ß-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis.

BACKGROUND/AIMS: Renal tubulointerstitial fibrosis (TIF) is the common pathway of progressive chronic kidney disease. Inflammation has been widely accepted as the major driving force of TIF. Cystathionine ß-synthase (CBS) is the first and rate-limiting enzyme in the transsulfuration pathway. CBS is considered to play protective role in liver and pulmonary fibrosis, but its role in TIF remains unknown. The purpose of this study was to investigate the potential role and mechanism of CBS in renal inflammation and TIF. METHODS: Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of collagen I, collagen III, fibronectin, CD3, CD68, IL-1ß, TNF-α were measured in sham operation and unilateral ureteral obstruction (UUO) rats. Proteomics and gene array analysis were performed to screen differentially expressed molecules in the development of renal inflammation and TIF in UUO rats. The expression of CBS was detected in patients with obstructive nephropathy and UUO rats. We confirmed the expression of CBS using western blot and real-time PCR in HK-2 cells. Overexpression plasmid and siRNA were transfected specifically to study the possible function of CBS in HK-2 cells. RESULTS: Abundant expression of CBS, localized in renal tubular epithelial cells, was revealed in human and rat renal tissue, which correlated negatively with the progression of fibrotic disease. Expression of CBS was dramatically decreased in the obstructed kidney from UUO rats as compared with the sham group (SHM). In addition, knocking down CBS exacerbated extracellular matrix (ECM) deposition, whereas CBS overexpression attenuated TGF-ß1-induced ECM deposition in vitro. Inflammatory and chemotactic factors were also increased in CBS knockdown HK-2 cells stimulated by IL-1ß. CONCLUSIONS: These findings establish CBS as a novel inhibitor in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.

Cloning and Direct Evolution of a Novel 7-O-Glycosyltransferase from Cucurbita moschata and Its Application in the Efficient Biocatalytic Synthesis of Luteolin-7-O-glucoside.

Luteolin-7-O-glucoside(L7G), a glycosylation product of luteolin, is present in a variety of foods, vegetables, and medicinal herbs and is commonly used in dietary supplements due to its health benefits. Meanwhile, luteolin-7-O-glucoside is an indicator component for the quality control of honeysuckle in the pharmacopoeia. However, its low content in plants has hindered its use in animal pharmacological studies and clinical practice. In this study, a novel 7-O-glycosyltransferase CmGT from Cucurbita moschata was cloned, which could efficiently convert luteolin into luteolin-7-O-glucoside under optimal conditions (40 °C and pH 8.5). To further improve the catalytic efficiency of CmGT, a 3D structure of CmGT was constructed, and directed evolution was performed. The mutant CmGT-S16A-T80W was obtained by using alanine scanning and iterative saturation mutagenesis. This mutant exhibited a kcat/Km value of 772 s-1·M-1, which was 3.16-fold of the wild-type enzyme CmGT. Finally, by introducing a soluble tag and UDPG synthesis pathway, the strain BXC was able to convert 1.25 g/L of luteolin into 1.91 g/L of luteolin-7-O-glucoside under optimal conditions, achieving a molar conversion rate of 96% and a space-time yield of 27.08 mg/L/h. This study provides an efficient method for the biosynthesis of luteolin-7-O-glucoside, which holds broad application prospects in the food and pharmaceutical industry.

Design, synthesis, and biological activity of 9-O-cinnamoylberberines as novel lipid-lowering agents.

Berberine possesses a wide spectrum of lipid regulation, and yet it has poor physicochemical property and cytotoxicity as a drug candidate. In order to alleviate the problems, a total of twenty-one 9-O-cinnamoylberberines and twenty 9-O-cinnamoyltetrahydroberberines were designed, synthesized, and evaluated by in vitro cell viability experiment and four classical lipid-lowering assays involving with total cholesterol, triglyceride, low density lipoprotein cholesterol, and high density lipoprotein cholesterol. A structure-activity relationship study of these compounds resulted in the discovery of two promising candidate molecules (5p and 7u). Compound 5p displayed the most potent inhibitory effect for TG formation, with the inhibitory rates of 40.5% and 76.8% in 3T3-L1 cells and HepG2 cells, respectively. Compound 7u exhibited the most promoting activity for the production of HDLC, with the increasing rates of 52.6% and 70.5% in both models, respectively. These two attractive compounds can be further investigated as new lipid-lowering agents in follow-up researches.

The Impact of Psychological Health on Patient Recovery After Arthroplasty.

Purpose: The purpose of this study was to determine the relationship between psychological health and postoperative recovery and satisfaction in patients undergoing total joint arthroplasty (TJA). Methods: We prospectively enrolled patients undergoing TJA from July 2019 to December 2020. A psychological evaluation was conducted according to the Hospital Anxiety and Depression Scale (HADS). Based on the preoperative HADS scores, we grouped the patients into two groups: the symptomatic group and the asymptomatic group. Data on the Harris Hip Score (HHS), Knee Society Knee Scoring System (KSS), Forgotten Joint Score-12 (FJS-12), Short Form-12 (SF-12), and Numeric Rating Scale (NRS) for pain in these two groups were collected preoperatively and postoperatively. Then, these data were analyzed by Statistical Package for Social Sciences (SPSS) version 19. Results: The final cohort consisted of 80 patients. Patients undergoing TJA had significantly decreased HADS and NRS scores and improved HHS, KSS, SF-12, and FJS-12 scores (all p < 0.001). Compared with the symptomatic group, the asymptomatic group showed better postoperative recovery (p < 0.05), especially after total knee arthroplasty (TKA) (p < 0.05). Good postoperative recovery positively impacted the patients' postoperative psychological state. Conclusion: Finally, the psychological state can affect recovery after TJA, and successful TJA can help improve patients' psychological states, especially after TKA.

A comparison of short-stem prostheses and conventional stem prostheses in primary total hip arthroplasty: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: In total hip arthroplasty (THA), short-stem prostheses (SS) were designed to achieve better preservation of proximal femoral bone stock and stability than conventional stem prostheses (CS), however these effects are controversial. We aimed perform a systematic review and meta-analysis to evaluate the effectiveness of SS and CS in primary THA. METHODS: Relevant randomized controlled trials (RCTs) involving the comparison of SS and CS in primary THA were screened using the electronic databases PubMed, Embase and Web of Science. Data were analyzed with the RevMan 5.3 software program and evaluated with mean difference (MD), risk ratio (RR) and 95% confidence intervals (CIs) by random or fixed-effect models. RESULTS: Sixteen RCTs involving 1,233 patients (1,486 hips) were included. Compared with CS, the incidence of thigh pain was significantly reduced with Proxima SS (RR 0.13, 95% CI, 0.03-0.51; P=0.004). Bone mineral density (BMD) with femoral neck-preserved SS [SS (I)] showed less decrease in Gruen zone 1 (MD 14.60, 95% CI, 10.67-18.54; P<0.00001) and Gruen zone 7 (MD 9.72, 95% CI, 5.21-14.23; P<0.0001) than CS. However, the changes of BMD were not significantly different between the SS without femoral neck preservation group [SS (II)] and the CS group. In addition, no significant differences were found in the revision rate, Harris Hip Score (HHS), or maximum total point motion (MTPM) between the SS and CS groups. CONCLUSIONS: The results of this study showed that compared with CS, Proxima SS decreased the incidence of thigh pain and that SS (I) provided better proximal bone remodeling than CS. But the revision rates, HHS, and MTPM between SS and CS were similar. However, the findings of this meta-analysis require further verification in high-quality RCTs.

Review of the Biomolecular Modification of the Metal-Organ-Framework.

Metal-organ frameworks (MOFs), as a kind of novel artificial material, have been widely studied in the field of chemistry. MOFs are capable of high loading capacities, controlled release, plasticity, and biosafety because of their porous structure and have been gradually functionalized as a drug carrier. Recently, a completely new strategy of combining biomolecules, such as oligonucleotides, polypeptides, and nucleic acids, with MOF nanoparticles was proposed. The synthetic bio-MOFs conferred strong protection and endowed the MOFs with particular biological functions. Biomolecular modification of MOFs to form bridges for communication between different subjects has received increased attention. This review will focus on bio-MOFs modification methods and discuss the advantages, applications, prospects, and challenges of using MOFs in the field of biomolecule delivery.

Targeted Delivery of Curcumin to Polyethylene-Induced Osteolysis by Magnetically Guided Zoledronate-Anchored Poly Lactic-Co-Glycolic Acid Nanoparticles via Repressing NF-κB Signaling.

Aseptic loosening induced by periprosthetic osteolysis (PPO) is the leading complication of total joint arthroplasty (TJA) and results in patients having to receive revision surgery. However, there is still no efficient drug to prevent or even slow the pathological process. Herein, we report novel dual-targeted, curcumin-loaded Poly lactic-co-glycolic acid nanoparticles (ZSCNPs) to inhibit polyethylene-induced osteolysis. These ZSCNPs have good biocompatibility and excellent bone binding affinity. Under external magnetic field guidance, the ZSCNPs can specifically target osteolytic sites with sustained curcumin release, efficiently suppress the effect of IκB kinase, subsequently inhibit activation of the nuclear factor-kappa B (NF-κB) signaling pathway, and ultimately prevent osteoclast formation and particle-induced osteolysis. Therefore, these novel dual-targeted, drug-loaded nanoparticles could be applied as a useful strategy for targeted treatment of PPO after TJA.

A Comparative Study of Patients' Subjective Feelings Toward Total Hip Arthroplasty with Patient-Specific Instruments and Traditional Total Hip Arthroplasty.

OBJECTIVE: To determine whether differences exist in patients' subjective feelings, daily life, and surgical satisfaction between those who underwent surgery for developmental dysplasia of the hip (DDH) using patient-specific instruments (PSIs) and those who underwent traditional surgical total hip arthroplasty (THA). METHODS: We selected 30 adult patients with various types of DDH who underwent surgery during 2016-2017 at our hospital. The patients were divided into PSI surgery group and the traditional surgery group. All patients underwent follow-up, and we collected data on the Harris Hip Score, Oxford University Hip Score (OHS), Forgotten Joint Score (FJS-12), Visual Analogue Scale (VAS) score, patient satisfaction score, intraoperative surgical time, amount of bleeding and postoperative complications incidence for both groups. We then performed statistical analyses on the data. RESULTS: The Harris Hip Score, OHS, VAS score, patient satisfaction score, and mean bleeding volume did not differ statistically significantly (t-tests, P > 0.05). No statistically significant differences were found between surgical groups in the incidence of complication and sub-trochanteric osteotomy, or in the surgical side (chi-square tests, P > 0.05). For the experimental group, the FJS-12 score was 80.0 ± 12.0, and for the control group the score was 68.5 ± 16.1. The operative time of the experimental group was 138.4 ± 32.2 min, while that of the control group was 88.9 ± 26.8 min. The values of these data differed significantly (t-tests, P < 0.05). CONCLUSIONS: The novel PSI designed by our group has certain advantages for the short-term subjective feelings of patients after THA, but it may cause prolonged operative times.

Near-infrared-induced IR780-loaded PLGA nanoparticles for photothermal therapy to treat breast cancer metastasis in bones.

Nanodrug-based cancer therapy, especially when treating bone metastases, faces the problem of limited therapeutic efficacy. In this work, we reported a photothermally triggered nanomaterial based on IR780-entrapped poly-lactide-co-glycolide (PLGA) nanoparticles (IR780@PLGA NPs) for the photothermal therapy of bone metastases of breast cancer, in which IR780 converted light into heat to play a role in "burning" the tumors. Anti-tumor therapy studies showed the impressive effectiveness of IR780@PLGA NPs in the photothermal therapy (PTT) of bone metastases. As a result, the IR780@PLGA NPs show a great potential for controlling the bone metastases of breast cancer.

Involvement of hydrogen sulfide in the progression of renal fibrosis.

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.