Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking.

Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1-40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment.

Renal protective effects of astragaloside IV, in diabetes mellitus kidney damage animal models: A systematic review, meta-analysis.

Astragaloside IV (ASIV) is the essential active component of astragalus that has diverse biological activities. Previous research has suggested its potentially beneficial effects on diabetic nephropathies. However, its effects and protective mechanism remain unclear. In this study, we conducted a preclinical systematic review to evaluate the efficacy and potential mechanisms of ASIV in reducing kidney damage in diabetes mellitus (DM) models. Studies were searched from nine databases until January 2020. A random-effects model was used to calculate combined standardised mean difference estimates and 95 % confidence intervals. Risk of bias of studies was assessed using the Systematic Review Center for Laboratory Animal Experimentation risk of bias tool 10-item checklist. RevMan 5.3 software was used for statistical analysis. Twenty-three studies involving 562 animals were included in the meta-analysis. Studies quality scores ranged from 2 to 5. The ASIV group induced a marked decrease in serum creatinine (P < 0.00001), blood urea nitrogen (P < 0.00001), 24-h urine protein (P < 0.00001) and pathological score (P < 0.001) compared with the control group. The determined potential mechanisms of ASIV action were relieving oxidative stress, delaying renal fibrosis, anti-apoptosis and anti-inflammatory action. We conclude that ASIV exerts renal protective effects in animals with DM through multiple signalling pathways.

Performance of Multiparametric Models in Patients With Brugada Syndrome: A Systematic Review and Meta-Analysis.

Background: Multiparametric models have shown better risk stratification in Brugada syndrome. Recently, these models have been validated in different populations. Aims: To perform a systematic review and meta-analysis of the predictive performance of three validated multiparametric models (Delise model, Sieria model, and Shanghai score). Methods: We searched PubMed, Embase, MEDLINE, Web of Science, and Ovid for studies validating the risk multiparametric model. A Sieria score > 2 and Shanghai score ≥ 4 were considered to indicate higher risk. Performance estimates were summarized using a random-effects model. Results: Seven studies were included, with sample sizes of 111-1,613. The follow-up duration was 3.3-10.18 years. The Sieria model had a pooled area under the curve (AUC), sensitivity, and specificity of 0.71 [95% confidence interval (CI): 0.67-0.75], 57% (95% CI: 35-76), and 71% (95% CI: 62-79), respectively. The Shanghai score had an AUC of 0.63-0.71, 68.97-90.67% sensitivity, and 43.53-63.43% specificity. The AUC of the Delise model was 0.77-0.87; however, the optimal cut-off was not identified. Conclusions: The three models exhibited moderate discriminatory ability for Brugada syndrome. The Sieria model has poor sensitivity and moderate specificity, whereas the Shanghai score has poor specificity and moderate sensitivity.

Surgical Correction of Kyphosis in Patients With Camptocormia Associated With Parkinson's Disease: A Case Report and Review of the Literature.

Background: Camptocormia is a postural deformity that is characterized by a markedly flexed lumbar spine, with symptoms that worsen with walking and standing. Here, we report a case of camptocormia associated with Parkinson's disease. Case description: A 70-year-old man with a 7-year history of Parkinson's disease presented with a fall injury that caused lower back pain for 3 months and was aggravated for 2 months. He had been diagnosed with a compression fracture after the fall and had undergone percutaneous kyphoplasty at a local hospital. MRI showed non-union of the L1 vertebra and compression fracture of L2. The patient underwent posterior osteotomy, canal decompression, and internal fixation of the T10-L3 intervertebral plate with bone graft fusion. Postoperative examination showed that the lumbar lordosis was corrected and sensation was restored in both lower extremities. However, after 1 month, the fixation was loosened and a correction surgery was performed at our hospital. At the most recent follow-up at 1.5 years, the patient was found to be in good general health and did not complain of lower back discomfort. He was also actively exercising according to the rehabilitation regimen and had resumed social life. Conclusion: This is a rare case of camptocormia in a Parkinson's patient that highlights the need for careful evaluation of whether internal spinal fixation surgery is beneficial in such patients.

Ferroptosis-related genes are candidate diagnostic and prognostic biomarkers for skin cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is a disease with the highest mortality rate among skin cancers. As a new type of programmed cell death, ferroptosis has been confirmed to be related to the occurrence and development of a variety of cancers. At present, the expression and prognostic value of ferroptosis-related genes (FRGs) in SKCM are still unclear. In this study, we selected seven FRGs that were differentially expressed in SKCM and related to the patient's prognosis through the databases. Further studies have shown that these genes are closely related to immune cell infiltration and immune checkpoints. All in all, these seven FRGs may be potential targets for clinical diagnosis, prognosis and treatment of SKCM patients.

ShenKang Injection Attenuates Renal Fibrosis by Inhibiting EMT and Regulating the Wnt/ß-Catenin Pathway.

Shenkang Injection (SKI) is a traditional Chinese medicine injection commonly used in the clinical treatment of chronic kidney disease. Although it has been confirmed that SKI has anti-kidney fibrosis effects, the underlying mechanism remains unclear. To investigate the effects of SKI on epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin pathway and explore its potential anti-fibrosis mechanism. A unilateral ureteral obstruction (UUO) model was induced by ligating the left ureter of male SD rats. A total of 24 rats were randomly divided into the following four groups: sham group, model group, SKI group, and benazepril group. The rats in each group were treated for 28 days, and renal function was evaluated by blood urea nitrogen (BUN) and serum creatinine (Scr). The degree of renal fibrosis was assessed by hematoxylin and eosin (HE) and Masson staining. Extracellular matrix (ECM) deposition was evaluated by immunohistochemistry. Real-time fluorescent quantitative PCR (RT-qPCR) and western blotting were used to detect the expression of genes and proteins in the Wnt/ß-catenin signaling pathway. Further studies were performed in vitro using HK-2 cells treated with TGF-ß1. At 28 days postoperation, the levels of BUN and Scr expression were significantly increased in the UUO group. SKI and benazepril reduced the levels of BUN and Scr, which displayed protective renal effects. Pathological staining showed that compared with the sham operation group, the renal parenchymal structure was severely damaged, the number of glomeruli was reduced, and a large amount of collagen was deposited in the kidney tissue of the UUO group. SKI treatment reduced morphological changes. Immunohistochemistry showed that compared with the sham operation group, the content of collagen I and FN in the kidney tissue of the UUO group were significantly increased, whereas the SKI content was decreased. In addition, compared with the UUO group, the levels of Wnt1, active ß-catenin, Snail1, and PAI-1 expression were reduced in the SKI group, suggesting that SKI may reduce renal fibrosis by mediating the Wnt/ß-catenin pathway. Further in vitro studies showed that collagen I, FN, and α-SMA levels in HK-2 cells were significantly increased following stimulation with TGF-ß1. SKI could significantly reduce the expression of collagen I, FN, and α-SMA. A scratch test showed that SKI could reduce HK-2 migration. In addition, by stimulating TGF-ß1, the levels of Wnt1, active ß-catenin, snail1, and PAI-1 were significantly upregulated. SKI treatment could inhibit the activity of the Wnt/ß-catenin signaling pathway in HK-2 cells. SKI improves kidney function by inhibiting renal fibrosis. The anti-fibrotic effects may be mediated by regulation of the Wnt/ß-catenin pathway and EMT inhibition.

Emerging role of TWEAK-Fn14 axis in lupus, a disease related to autoimmunity and fibrosis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment.

Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.

Association of FcγRIIA-R/H131 polymorphism and systemic lupus erythematosus lupus nephritis risk: A meta-analysis.

AIM: Previous studies have discussed association of FcγRIIA-R/H131 polymorphism and systemic lupus erythematosus (SLE), lupus nephritis (LN) risk. However, conclusions were inconsistent. METHODS: A meta-analysis was performed in this study with allelic contrast (allele R vs H), additive model (genotype RR vs HH), recessive model (genotype RR vs RH + HH), and dominant model (genotype RR + RH vs HH). RESULTS: A total of 33 studies discussed the correlation between FcγRIIA-R/H131 polymorphism and SLE, involving 5652 SLE patients and 6322 controls. Allele R was significantly related to SLE in the overall population (odds ratio [OR] = 1.238, P < .001), Asian (OR = 1.237, P < .001) and European population (OR = 1.212, P = .012). Additive, recessive and dominant models were correlating with SLE in the overall population (OR = 1.448, P < .001; OR = 1.303, P < .001; OR = 1.310, P < .001), Asian population (OR = 1.640, P = .001; OR = 1.437, P < .001; OR = 1.344, P = .005), respectively. In addition, 22 studies evaluated relation of FcγRIIA-R/H131 polymorphism with LN, involving 2065 patients with LN, and 2023 patients without LN. Results showed that allele R and the other 3 models related to LN susceptibility in the overall population when discussing differences of polymorphism between patients with/without LN. We further compared differences of polymorphism between patients with LN and controls, showing that additive and recessive models related to LN risk in the overall population, Asian, European and North American populations. CONCLUSION: In summary, FcγRIIA-R/H131 polymorphism is associated with SLE and LN.

A review on the efficacy and mechanism of action of Shenkang injection against chronic kidney disease.

Chronic kidney disease (CKD) is one of the most common conditions which significantly increases the risk for serious health outcomes. Epidemiological investigations have shown that CKD has become a serious global health problem. At present, there are no treatments for CKD, thus the need for an effective and safe treatment for this condition. Shenkang Injection (SKI), which is an herbal medication in Chinese Medicine, has been used in the management and treatment of CKD and has achieved favorable therapeutic effects. The purpose of this paper is to review the clinical efficacy, mechanism of action, and safety profile of SKI when used in CKD, and to provide comprehensive potential evidence for its clinical application.

The polymorphisms of osteopontin gene and plasma osteopontin protein levels with susceptibility to colorectal carcinoma.

Osteopontin (OPN) plays an important role in the development and progression of some tumors. The polymorphisms of OPN probably change its expression and contribute to interindividual differences of susceptibility to some cancers. The purpose of the present study was to explore the association of rs9138 (+1239; 3'UTR: 3'untranslated regions) and rs1126616 (+750; exon 7) polymorphisms located in the OPN gene with colorectal carcinoma (CRC) susceptibility and to investigate the correlation of the polymorphisms, plasma levels of the OPN protein, clinicopathologic parameters, tumor markers, and lipid. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The plasma levels, tumor markers, and lipid were measured by enzyme-linked immunosorbent assay. The results indicated that genotype AA and AC of rs9138 and CC and CT of rs1126616 were associated with increased risk of CRC. The allelic frequencies of rs9138A, rs1126616C, and the haplotype (A-C) were associated with increased risk of CRC. Although there was no significant difference of plasma levels in various genotypes, increased plasma protein expression in CRC patients compared with controls was found. Our results suggested that the rs9138 and rs1126616 of OPN were associated with CRC risk, and the OPN protein in plasma may be a potential tumor marker of CRC.