Tocilizumab Exerts Anti-Tumor Effects on Colorectal Carcinoma Cell Xenografts Corresponding to Expression Levels of Interleukin-6 Receptor.

The use of tocilizumab against the interleukin-6 receptor (IL-6R) has been demonstrated as inhibiting the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels remains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as human CRC xenograft models with anti-IL-6R antibody (tocilizumab) therapy. The IL-6R expression levels, histology of CRC growth/invasiveness, and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels showed better responsiveness in tocilizumab therapy than in the treated HT-29 group. Likewise, therapeutic effects of tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, invasiveness with MMP-9 proteinase expressions, and ERK 1/2 and STAT3 signaling transduction in the SW480 treatment group were superior to the HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, tocilizumab may serve as a targeted and promising anti-CRC therapy.

Versatile Effects of GABA Oolong Tea on Improvements in Diastolic Blood Pressure, Alpha Brain Waves, and Quality of Life.

Emerging evidence has demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human study was to investigate the therapeutic effects of daily GO tea consumption on improvements in blood pressure, relaxation-related brain waves, and quality of life (QOL) over a period of 28 consecutive days. Total polyphenols, major catechins, and free amino acids were analyzed via an HPLC assay. Changes in heart rate, blood pressure, α brain waves (index of relaxation), and the eight-item QOL score were investigated on days 0, 7, 14, 21, and 28. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, the daily consumption of GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p < 0.05 for both). For participants with pre-hypertension, GO tea could effectively reduce heart rate and systolic and diastolic blood pressure on day 28 (p < 0.05). At the end of the study, incremental changes in alpha brain waves and QOL scores were also demonstrated (p < 0.05 for both). This study suggests that GO tea might potentially serve as a natural source for alternative therapy to improve blood pressure, stress relief, and QOL.

The favorable outcome of Bernese periacetabular osteotomy for the hip osteoarthritis in multiple epiphyseal dysplasia.

BACKGROUND: Multiple epiphyseal dysplasia (MED) is a rare congenital bone dysplasia. Patients with MED develop secondary hip osteoarthritis as early as the third to the fourth decade. Currently, there is no consensus on the prevention of the progressive hip osteoarthritis secondary to MED. The Bernese periacetabular osteotomy (PAO) is a joint-preserving surgery to reshape acetabulum and extend femoral head coverage. However, there is no documentary evidence for the effect of the procedure on MED hips. PATIENTS AND METHODS: We analyzed the preliminary outcomes following the Bernese PAO in 6 MED hips. The average age at the time of surgery was 14.3 years (range from 11.4 to 17.2 years). For our study interest of time efficiency, radiographic parameters were analyzed preoperatively and 1 year postoperatively. The hip function was evaluated by the Harris Hip Score (HHS) before and after surgery. RESULTS: The mean follow-up time was 1.7 years. The mean lateral center-edge angle increased from 3.8° to 47.1° (p = 0.02), anterior center-edge angle increased from 7.3° to 35.1° (p = 0.02), and acetabulum index decreased from 27.8° to 14.6° (p = 0.04). The femoral head coverage ratio increased from 66.8% to 100% (p = 0.02). The post-operative anteroposterior pelvic radiograph demonstrated all preoperative broken Shenton lines were reversed. The mean HHS improved from 67.3 to 86.7 (p = 0.05). CONCLUSION: Bernese PAO is a feasible treatment for hip disorders in MED patients. It reshapes acetabular and femoral morphology efficiently. In our study, the preliminary results showed the procedure not only improved radiographic outcomes but also hip function.

Synergistic Chemopreventive Effects of a Novel Combined Plant Extract Comprising Gallic Acid and Hesperidin on Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third most common cancer with a high mortality rate worldwide. Although gallic acid and hesperidin exert anticancer activity, synergistic effects of gallic acid and hesperidin against CRC remain elusive. This study aims to investigate the therapeutic mechanism of a novel combination of gallic acid and hesperidin against CRC cell growth, including cell viability, cell-cycle-associated proteins, spheroid formation, and stemness. METHODS: Gallic acid and hesperidin derived from Hakka pomelo tea (HPT) were detected by colorimetric methods and high-performance liquid chromatography using ethyl acetate as an extraction medium. CRC cell lines (HT-29 and HCT-116) treated with the combined extract were investigated in our study for cell viability (trypan blue or soft agar colony formation assay), cell cycle (propidium iodide staining), cell-cycle-associated proteins (immunoblotting), and stem cell markers (immunohistochemistry staining). RESULTS: Compared with other extraction methods, HPT extraction using an ethyl acetate medium exerts the most potent effect on inhibiting HT-29 cell growth in a dose-dependent manner. Furthermore, the treatment with combined extract had a higher inhibitory effect on CRC cell viability than gallic acid or hesperidin alone. The underlying mechanism was involved in G1-phase arrest and Cip1/p21 upregulation that could attenuate HCT-116 cell proliferation (Ki-67), stemness (CD-133), and spheroid growth in a 3D formation assay mimicking in vivo tumorigenesis. CONCLUSION: Gallic acid and hesperidin exert synergistic effects on cell growth, spheroids, and stemness of CRC and may serve as a potential chemopreventive agent. Further testing for the safety and effectiveness of the combined extract in large-scale randomized trials is required.

Prophylactic Effects of Purple Shoot Green Tea on Cytokine Immunomodulation through Scavenging Free Radicals and NO in LPS-Stimulated Macrophages.

Polyphenols and flavonoids from non-fermented green tea and fully-fermented black tea exhibit antioxidant abilities that function as natural health foods for daily consumption. Nonetheless, evidence regarding prophylactic effects of purple shoot tea on immunomodulation remains scarce. We compared the immunomodulatory effects of different tea processes on oxidative stress and cytokine expressions in lipopolysaccharide (LPS)-stimulated macrophages. Major constituents of four tea products, Taiwan Tea Experiment Station No.12 (TTES No. 12) black and green tea and purple shoot black and purple shoot green tea (TB, TG, PB and PG, respectively), were analyzed to explore the prophylactic effects on expressions of free radicals, nitric oxide (NO), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in LPS-activated RAW264.7 cell models. PG contained abundant levels of total polyphenols, flavonoids, condensed tannins and proanthocyanidins (371.28 ± 3.83; 86.37 ± 1.46; 234.67 ± 10.1; and 24.81 ± 0.75 mg/g, respectively) contributing to excellent free radical scavenging potency. In both the LPS-activated inflammation model and the prophylactic model, all tea extracts suppressed NO secretion in a dose-dependent manner, especially for PG. Intriguingly, most tea extracts enhanced expressions of IL-6 in LPS-stimulated macrophages, except PG. However, all teas disrupted downstream transduction of chemoattractant MCP-1 for immune cell trafficking. In the prophylactic model, all teas inhibited inflammatory responses by attenuating expressions of IL-6 and TNF-α in a dose-dependent manner, especially for TG and PG. Our prophylactic model demonstrated PG exerts robust effects on modulating LPS-induced cytokine expressions of MCP-1, IL-6 and TNF-α through scavenging free radicals and NO. In light of the prophylactic effects on LPS-related inflammation, PG effectively scavenges free radicals to modulate cytokine cascades that could serve as a functional beverage for immunomodulation.

Participation of lipopolysaccharide in hyperplasic adipose expansion: Involvement of NADPH oxidase/ROS/p42/p44 MAPK-dependent Cyclooxygenase-2.

Obesity is a world-wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro-inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS-modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase-2 (COX-2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS-stimulated gene expression of COX-2 together with the phosphorylation of p47phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase-dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS-mediated COX-2 expression and preadipocyte proliferation. Moreover, LPS-induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX-2 or PEG2 receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK-dependent COX-2 expression.

Translational Medicine in Uremic Vascular Calcification: Scavenging ROS Attenuates p-Cresyl Sulfate-Activated Caspase-1, NLRP3 Inflammasome and Eicosanoid Inflammation in Human Arterial Smooth Muscle Cells.

We formerly proved that uremic vascular calcification (UVC) correlates tightly with oxidative elastic lamina (EL) injury and two cell fates (apoptosis and osteocytic conversion) in smooth muscle cells (SMC) of chronic kidney disease (CKD) patients and eliminating p-cresyl sulfate (PCS)-activated intracellular ROS ameliorates the MAPK signaling pathway in a human arterial SMC (HASMC) model. Nonetheless, whether ROS scavenger attenuates PCS-triggered inflammasome activation and eicosanoid inflammation in the UVC process remains unknown. Patients with lower extremity amputation were categorized into CKD and normal control group according to renal function. We used immunohistochemistry stain to analyze UVC in arterial specimens, including oxidative injury (8-hydroxy-2'-deoxyguanosine (8-OHdG) and internal EL disruption), cytosolic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX2), interleukin-1 beta (IL-1ß), caspase-1 and NLRP3. To simulate the patho-mechanism of human UVC, the therapeutic effects of ROS scavenger on PCS-triggered inflammatory pathways was explored in a HASMC model. We found CKD patients had higher circulating levels of PCS and an increase in medial arterial calcification than the control group. In CKD arteries, the severity of UVC corresponded with expressions of oxidative EL disruption and 8-OHdG. Furthermore, coupling expressions of cPLA2 and COX2 were accentuated in CKD arteries, indicative of eicosanoid inflammation. Notably, tissue expressions of IL-1ß, caspase-1 and NLRP3 were enhanced in parallel with UVC severity, indicative of inflammasome activation. From bedside to bench, ROS scavenger attenuates PCS-activated expressions of cPLA2/COX2, pro-caspase-1 and NLRP3 in the HASMC model. UVC as an inevitable outcome is predictive of death in CKD patients. Nonetheless, UVC remain pharmacoresistant despite the evolution of treatment for mineral-parathyroid hormone-vitamin D axis. Beyond the mineral dysregulation, the stimulation of pro-oxidant PCS alone results in eicosanoid inflammation and inflammasome activation. Concerning the key role of Caspase-1 in pyroptosis, cell fates of HASMC in uremic milieu are not limited to apoptosis and osteogenesis. In view of this, reducing ROS and PCS may act as a therapeutic strategy for UVC-related cardiovascular events in CKD patients.

A Long-Term Study of Alignment Correction Following Proximal Femoral Varus Osteotomy and Pemberton Osteotomy in Children With Legg-Calvé-Perthes Disease and Developmental Dysplasia of the Hip.

Proximal femoral varus osteotomy (PFVO) is a common procedure performed in children with developmental dysplasia of the hip (DDH) and Legg-Calvé-Perthes disease (LCPD). However, the long-term effect on angular deformities of the knees and ankles following PFVO remains controversial. This study investigated the relationship between PFVO and alignment changes in the knee and ankle after the procedure. Twenty-five patients undergoing PFVO procedure with a minimum 4-year evaluation period were enrolled in the study, including 14 unilateral LCPD and 11 unilateral DDH. The standing scanogram examinations were collected before the operation, immediately following surgery, after a 1-year follow-up, after a 3-year follow-up, and at the final visit to the clinic. The radiographic parameters included leg length, femoral neck-shaft angle (FNSA), femorotibial angle (FTA), mechanical axis deviation (MAD), tibiotalar angle (TTA), and mechanical lateral distal femoral angle (mLDFA). At the final examination, FNSA demonstrated insignificant change between the operative and non-operative limbs in the DDH group. Compared with the postoperative result, FNSA significantly improved in the LCPD group (p = 0.039). Both groups did not develop statistical significance in TTA, mLDFA, MAD, and leg length discrepancy after more than a 5-year follow-up. From a biomechanical perspective that the foot passes more medial to the knee under the center of leg mass, varus knee was prone to develop. In order to correct the mechanical axis, the knee reverted to a valgus position gradually. Our study indicates that patients with LCPD or DDH receiving PFVO and Pemberton osteotomy narrow the gap of angular growth in knees and ankles between the operative and non-operative limbs after a long-term follow-up.

Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease-Mineral and Bone Disorder.

The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder (CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (µCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of caspase-related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).

Fat-Bone Relationship in Chronic Kidney Disease-Mineral Bone Disorders: Adiponectin Is Associated with Skeletal Events among Hemodialysis Patients.

BACKGROUND: The risk of skeletal events is rising in parallel with the burden of chronic kidney disease and mineral bone disorder (CKD-MBD), whilst the role of the fat-bone axis in CKD-MBD remains elusive. Adiponectin derived from adipocytes has emerged as a valid biomarker of low bone mineral density and increased marrow adiposity. We aimed to explore the association between adiponectin and bone fracture (BF) risks in patients with maintenance hemodialysis (MHD). METHODS: Serum concentrations of adiponectin and bio-clinical data were determined at study entry. The Cox proportional hazard regression analyses were used to assess unadjusted and adjusted hazard ratios (aHRs) of adiponectin and various clinical predictors for BF risks. The predictive accuracy of adiponectin for BF events was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Age and serum concentrations of adiponectin, phosphate, and intact parathyroid hormone were significantly associated with higher risks of BF. With respect to the risk of BF events, the cumulative event-free survival curves differed significantly between the high and low concentration groups of adiponectin (p = 0.02). In multivariable analysis, higher adiponectin levels were associated with an incremental risk of BF (adjusted hazard ratios (aHRs): 1.08 (95% confidence interval (CI): 1.01-1.15, p < 0.05). The ROC analysis of adiponectin cutoff point concentration (18.15 ug/mL) for prediction of BF showed 0.66 (95% CI = 0.49 to 0.84). CONCLUSION: Adiponectin was associated with an incremental risk of BF that could serve as a potential predictor of BF in MHD patients. In the high-risk population with hyperphosphatemia, an elevated adiponectin level could alert clinicians to the urgent need to correct mineral dysregulation and undertake further bone survey.

Circulating p-Cresyl Sulfate, Non-Hepatic Alkaline Phosphatase and Risk of Bone Fracture Events in Chronic Kidney Disease-Mineral Bone Disease.

Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, are at a considerably high risk of bone fracture events. Experimental data indicate that uremic toxins intricately involved in bone-related proteins exert multi-faced toxicity on bone cells and tissues, leading to chronic kidney disease-mineral and bone disorder (CKD-MBD). Nonetheless, information regarding the association between p-cresyl sulfate (PCS), non-hepatic alkaline phosphatase (NHALP) and skeletal events remains elusive. We aim to explore the association between PCS, NHALP and risk of bone fracture (BF) in patients with hemodialysis. Plasma concentrations of PCS and NHALP were ascertained at study entry. Cox proportional hazard regression analyses were used to determine unadjusted and adjusted hazard ratios (aHRs) of PCS for BF risk. In multivariable analysis, NHALP was associated with incremental risks of BFs [aHR: 1.06 (95% CI: 1.01-1.11)]. The association between the highest PCS tertile and BF risk remained robust [aHR: 2.87 (95% CI: 1.02-8.09)]. With respect to BF events, the interaction between NHALP and PCS was statistically significant (p value for the interaction term < 0.05). In addition to mineral dysregulation and hyperparathyroidism in hemodialysis patients, higher circulating levels of PCS and NHALP are intricately associated with incremental risk of BF events, indicating that a joint evaluation is more comprehensive than single marker. In light of the extremely high prevalence of CKD-MBD in the hemodialysis population, PCS may act as a pro-osteoporotic toxin and serve as a potential surrogate marker for skeletal events.

Effect of Neferine on DNCB-Induced Atopic Dermatitis in HaCaT Cells and BALB/c Mice.

Atopic dermatitis (AD) is a chronic and persistent inflammatory skin disease characterized by eczematous lesions and itching, and it has become a serious health problem. However, the common clinical treatments provide limited relief and are accompanied by adverse effects. Therefore, there is a need to develop novel and effective therapies to treat AD. Neferine is a small molecule compound isolated from the green embryo of the mature seeds of lotus (Nelumbo nucifera). It has a bisbenzylisoquinoline alkaloid structure. Relevant studies have shown that neferine has many pharmacological and biological activities, including anti-inflammatory, anti-thrombotic, and anti-diabetic activities. However, there are very few studies on neferine in the skin, especially the related effects on inflammatory skin diseases. In this study, we proved that it has the potential to be used in the treatment of atopic dermatitis. Through in vitro studies, we found that neferine inhibited the expression of cytokines and chemokines in TNF-α/IFN-γ-stimulated human keratinocyte (HaCaT) cells, and it reduced the phosphorylation of MAPK and the NF-κB signaling pathway. Through in vivo experiments, we used 2,4-dinitrochlorobenzene (DNCB) to induce atopic dermatitis-like skin inflammation in a mouse model. Our results show that neferine significantly decreased the skin barrier damage, scratching responses, and epidermal hyperplasia induced by DNCB. It significantly decreased transepidermal water loss (TEWL), erythema, blood flow, and ear thickness and increased surface skin hydration. Moreover, it also inhibited the expression of cytokines and the activation of signaling pathways. These results indicate that neferine has good potential as an alternative medicine for the treatment of atopic dermatitis or other skin-related inflammatory diseases.

A Growth Differentiation Factor 15-Based Risk Score Model to Predict Mortality in Hemodialysis Patients.

BACKGROUND: The risk of cardiovascular (CV) and fatal events remains extremely high in patients with maintenance hemodialysis (MHD), and the growth differentiation factor 15 (GDF15) has emerged as a valid risk stratification biomarker. We aimed to develop a GDF15-based risk score as a death prediction model for MHD patients. METHODS: Age, biomarker levels, and clinical parameters were evaluated at study entry. One hundred and seventy patients with complete information were finally included for data analysis. We performed the Cox regression analysis of various prognostic factors for mortality. Then, age, GDF15, and robust clinical predictors were included as a risk score model to assess the predictive accuracy for all-cause and CV death in the receiver operating characteristic (ROC) curve analysis. RESULTS: Age, GDF15, and albumin were significantly associated with higher all-cause and CV mortality risk that were combined as a risk score model. The highest tertile of GDF-15 (>1707.1 pg/mL) was associated with all-cause mortality (adjusted hazard ratios (aHRs): 3.06 (95% confidence interval (CI): 1.20-7.82), p < 0.05) and CV mortality (aHRs: 3.11 (95% CI: 1.02-9.50), p < 0.05). The ROC analysis of GDF-15 tertiles for all-cause and CV mortality showed 0.68 (95% CI = 0.59 to 0.77) and 0.68 (95% CI = 0.58 to 0.79), respectively. By contrast, the GDF15-based prediction model for all-cause and CV mortality showed 0.75 (95% CI: 0.67-0.82) and 0.72 (95% CI: 0.63-0.81), respectively. CONCLUSION: Age, GDF15, and hypoalbuminemia predict all-cause and CV death in MHD patients, yet a combination scoring system provides more robust predictive powers. An elevated GDF15-based risk score warns clinicians to determine an appropriate intervention in advance. In light of this, the GDF15-based death prediction model could be developed in the artificial intelligence-based precision medicine.

Preliminary Results of Subtalar Arthroereisis with Vulpius Procedure for Symptomatic Flatfoot in Patients with Type I Osteogenesis Imperfecta.

In this retrospective study, we aim to assess the safety and feasibility of adapting subtalar arthroereisis (SA) for type I osteogenesis imperfecta (OI) patients with symptomatic flatfoot. From December 2013 to January 2018, six type I OI patients (five girls and one boy, 12 feet) with symptomatic flexible flatfoot were treated with SA and the Vulpius procedure. All the patients were ambulatory and skeletally immature with failed conservative treatment and unsatisfactory life quality. The median age at the time of surgery was 10 years (range 5-11), and the median follow-up period was 55 months (range 33-83). All functional and radiographic parameters improved (p < 0.05) after the procedure at the latest follow-up. The median American Orthopaedic Foot and Ankle Society ankle-hindfoot scale improved from 68 (range 38-80) to 95 (range 71-97). All of the patients ambulated well without significant complications. The weight-bearing radiographs showed maintained correction of the tarsal bone alignment with intact bony surfaces adjacent to implants during the post-operative follow-up period. This is the very first study on symptomatic flatfoot in pediatric patients with type I OI. Our data suggest that SA is a potentially viable approach, as functional improvements and maintained radiographic correction without significant complication were observed.

Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301-1307) reduced mitochondrial ROS generation; (Am J Physiol-Renal Physiol. 2011. 301, F1218-F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427-436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285-297) blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs-mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast-osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast-osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = -0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/ß-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid-bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast-osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease.

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)-produced in the liver by colonic microorganisms-cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)-a gut microbe-dependent metabolite of dietary L-carnitine and choline-is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.

Endosinotarsal device exerts a better postoperative correction in Meary's angle than exosinotarsal screw from a meta-analysis in pediatric flatfoot.

For pediatric flexible flatfoot, the subtalar extra-articular screw arthroereisis (SESA) and endosinotarsal device are the most popular techniques in current practice. Nevertheless, scarce literature is available comparing the outcomes between these two techniques. Thus, we aimed to provide a meta-analysis for the radiographic and clinical outcomes, respectively. A systemic search for correction of pediatric flexible flatfoot using subtalar arthroereisis was conducted mainly in Pubmed and Scopus, and the search was completed on 31 Dec., 2019. The standardized mean differences (SMD) of postoperative versus preoperative calcaneal pitch and Meary's angle were defined as the primary outcomes, whereas the preoperative versus posteoperative AOFAS (American Orthopaedic Foot and Ankle Society) as the secondary outcome. The meta-analysis included 12 comparative studies comprising 2063 feet in total. The quantitative analysis showed a marked improvement in Meary's angle of endosinotarsal cone implant group (SMD: 4.298; 95% CI 2.706-5.889) than exosinotarsal screw group (SMD: 1.264; 95% CI 0.650-1.877). But no significant difference was noted between both groups in calcaneal pitch and AOFAS. The exosinotarsal screw and endosinotarsal device are both effective arthroereisis implant for pediatric flexible flatfoot. While considering the correction of Meary's angle, the endosinotarsal device is better than exosinotarsal screw.

Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells.

Osteogenesis in human arterial smooth muscle cell (HASMC) is a key feature of uremic vascular calcification (UVC). Concerning pro-oxidant properties of p-cresyl sulfate (PCS), the therapeutic effect of reactive oxygen species (ROS) scavenger on PCS triggered inflammatory signaling transduction in osteogenesis was investigated in this translational research. Based on severity level of chronic kidney disease (CKD), arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, oxidative injury and osteogenesis along with PCS concentrations. To mimic human UVC, HASMC model was used to explore whether PCS-induced ROS could trigger mitogen-activated protein kinase (MAPK) pathways with nuclear factor-κB (NF-κB) translocation that drive context-specific gene/protein expression, including Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). In parallel with PCS accumulation, CKD arteries corresponded with UVC severity, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine), Runx2 and ALP. PCS directly phosphorylated extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 (pERK/pJNK/pP38) and modulated NF-κB translocation to promote expressions of Runx2 and ALP in HASMC. Notably, intracellular ROS scavenger attenuated pERK signaling cascade and downstream osteogenic differentiation. Collectively, our data demonstrate PCS induces osteogenesis through triggering intracellular ROS, pERK/pJNK/pP38 MAPK pathways and NF-κB translocation to drive Runx2 and ALP expressions, culminating in UVC. Beyond mineral dysregulation, osteocytic conversion in HASMC could be the stimulation of PCS. Thus PCS may act as a pro-osteogenic and pro-calcific toxin. From the perspective of translational medicine, PCS and intracellular ROS could serve as potential therapeutic targets for UVC in CKD patients.

Therapeutic Targeting of Aristolochic Acid Induced Uremic Toxin Retention, SMAD 2/3 and JNK/ERK Pathways in Tubulointerstitial Fibrosis: Nephroprotective Role of Propolis in Chronic Kidney Disease.

The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL/6 mice, mimicking human CKD. The kidney sizes/masses, renal function indicators, plasma concentrations of PCS/IS, tissue expressions of TIF, α-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-ß (TGF-ß) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed α-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2/3-dependent pathways but also SMAD-independent JNK/ERK activation in the signaling cascades of TGF-ß family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-ß signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.