Construction of the Au Nanoparticle/Graphene Oxide/Au Nanotube (AuNP/GO/AuNT) Sandwich Membrane for Surface-Enhanced Raman Scattering Sensing.

Au nanotube-based composite membrane served as surface-enhanced Raman scattering (SERS) substrate with an ultralarge aspect ratio possesses an excellent flexibility and widely tunable surface plasmon resonance, and by introducing graphene oxide (GO) as a spacer layer, the SERS enhancement of the composite membrane is obviously better than those from the individual blocks of the Au nanotubes (AuNTS) membrane and the Au nanoparticle/graphene oxide (AuNP/GO) membrane. Such a "sandwich" (AuNP/GO/AuNT) structured membrane has a high SERS sensitivity and a wide tunability by controlling the size of Au nanoparticles and the thickness of graphene oxide, and the detection limits of the AuNP/GO/AuNT substrate for R6G and NBA are as low as 10-12 and 10-7 M, respectively; the large enhancement is attributed to the adsorption and chemical mechanism of graphene oxide and the physical mechanism of the Au nanoparticles and nanotubes (the electromagnetic field coupling between them).

A mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery.

Intravesical therapy (IT) is widely used to tackle various urological diseases. However, its clinical efficacy is decreased by the impermeability of various barriers presented on the bladder luminal surface, including the urinary mucus layer and the densely packed tissue barrier. In this study, we report a mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery. Upon intravesical instillation, its poloxamer 407 (PLX) hydrogel gelated and adhered to the urothelium to prolong its intravesical retention. The urea afterwards diffused into the hydrogel, thus generating a concentration gradient. Urease-powered membrane nanomotors (UMN) without asymmetric surface engineering could catalyze the urea and migrate down this concentration gradient to deeply and unidirectionally penetrate the urothelial barrier. Moreover, the intravesical hybrid system-delivered gemcitabine could effectively inhibit the bladder tumor growth without inducing any side effect. Therefore, our mucoadhesive-to-penetrating nanomotors-in-hydrogel system could serve as an alternative to IT to meet the clinical need for more efficacious therapeutics for urological diseases.

C-reactive protein inhibits C3a/C3aR-dependent podocyte autophagy in favor of diabetic kidney disease.

Numerous studies have reported the pathogenic roles of C-reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b-9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp-/- , and huCRPtg rats with STZ-diabetic DKD. The Crp-/- rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp-/- rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP-overexpression and CRP-knockout cell lines were established and used to demonstrate that CRP suppresses C3a-induced podocyte autophagy under high-glucose conditions. We further verified that the inhibition of C3a-induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.

Effect of intraoperative anastomotic reinforcement suture on the prevention of anastomotic leakage of double-stapling anastomosis for laparoscopic rectal cancer: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The use of sutures to strengthen the anastomosis after rectal cancer surgery to reduce the possibility of anastomotic leakage has been debated. The aim of this systematic review and meta-analysis was to investigate the influence of intraoperative anastomotic reinforcing sutures on anastomotic leakage of double-stapling anastomosis for laparoscopic rectal cancer surgery. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was performed to identify literature examining anastomotic leak as the primary outcome to compare studies of laparoscopic surgery for rectal cancer using the double-stapling anastomosis technique with or without intraoperative anastomotic reinforcement with sutures. RESULTS: A total of 1122 rectal cancer patients from 5 nonrandomized studies were included in the research. In the combined trial, intraoperative anastomotic reinforcement sutures significantly reduced the incidence of anastomotic leakage in patients who underwent laparoscopic rectal cancer surgery (OR, 0.32; 95% CI, 0.19-0.55; p < 0.0001). With or without intraoperative anastomotic reinforcing sutures, the incidence of postoperative reoperation for anastomotic leak did not differ substantially (OR, 0.32; 95% CI, 0.08-1.21, p = 0.09). Moreover, the surgery was prolonged due to anastomotic reinforcement with sutures (OR, 6.64; 95% CI, - 6.18 to 19.47, p = 0.31). CONCLUSIONS: Intraoperative anastomotic reinforcement with sutures may be associated with a lower incidence of anastomotic leakage. The amount of research evidence is limited because most of the studies analyzed did not include patients with factors such as neoadjuvant therapy or prophylactic stomas. Therefore, additional multicenter randomized controlled studies with larger size samples are needed to support the validity of the approach.

Widely tunable surface plasmon resonance and uniquely superior SERS performance of Au nanotube network films.

Three-dimensional Au network films with flexibility and transferability were fabricated based on sputtering deposition onto electrospun nanofibers as a template. The films are constructed using long Au nanotubes that are cross-linked with each other and that have dense nanoparticles on the tube wall surface. The surface plasmon resonance (SPR) peaks for the films are tunable in a wide range, from visible light to the near-infrared region, by tuning the inner diameter and/or wall thickness of the nanotubes. Such structured film exhibits significant surface-enhanced Raman scattering (SERS) activity with good signal uniformity and stability, and possesses great potential in thein situdetection of trace organic pollutants on a solid surface by simple transferring. This study provides a Au film with a unique structure and widely tunable SPR forin situSERS sensing and other needs.

6-Gingerol suppresses tumor cell metastasis by increasing YAPser127 phosphorylation in renal cell carcinoma.

According to the World Health Organization, the incidence and mortality rates of renal cell carcinoma (RCC) are rapidly increasing worldwide. Serious side effects caused by immune therapy and resistance to targeted drug therapy are urgent clinical problems facing kidney treatment. There is increasing global interest in developing natural products with a reduced number of side effects as adjunctive therapeutic options for RCC. Ginger is a spice and herbal remedy used worldwide, and 6-gingerol is a major pharmacologically active ingredient in ginger. In our study, we found that 6-gingerol suppressed RCC cell migration and metastasis in vitro and in vivo. Moreover, reduction in MMP2, Slug, and Vimentin protein levels was observed following 6-gingerol treatment of 786-O and ACHN cells. Furthermore, we revealed the mechanisms underlying the ability of 6-gingerol to inhibit RCC cell migration and metastasis. 6-Gingerol increased yes-associated protein (YAP)ser127 phosphorylation and reduced YAP levels in cell nuclei. We also used a series of loss-of-function and gain-of-function experiments to support our results. Western blot results showed that MMP2, Slug, and Vimentin protein expression was downregulated in YAP-silenced cells and upregulated in YAP-overexpressing cells. Transwell data demonstrated that YAP suppressed RCC migration ability. Immunofluorescence images showed that 6-gingerol decreased YAP levels, leading to disordered F-actin and a reduction in cell lamellipodia. Overall, our results indicated that 6-gingerol is a potential antimetastatic compound for use in kidney therapy.

The miR-218/GAB2 axis regulates proliferation, invasion and EMT via the PI3K/AKT/GSK-3ß pathway in prostate cancer.

Altered expression of microRNA (miRNA) is associated with the occurrence and metastasis of various tumors. We previously found that miR-218 inhibits tumor angiogenesis through the RICTOR/VEGFA axis in prostate cancer (PCa). In this study, we determined that miR-218 also had a negative effect on cell growth, migration, and invasion ability in PCa. Our data showed that miR-218 bound to the Grb2-associated binding protein 2 (GAB2) 3'-UTR region and inhibited GAB2 expression. As a novel downstream target of miR-218, GAB2 has been reported to be involved in the occurrence and development of various human tumors, but its role in the progression and metastasis of PCa has not been addressed. We demonstrated for the first time that the expression of GAB2 in the PCa cell lines was increased, while knocking down GAB2 significantly inhibited cell growth, metastatic ability and EMT process in PCa. In addition, the recovery of GAB2 could reverse the changes in the biological function of PCa cells caused by the ectopic expression of miR-218. Mechanistically, miR-218-mediated GAB2 transcriptional suppression significantly inhibited the activity of the PI3K/AKT/GSK-3ß pathway, whose abnormal activation was found to be related to the malignant progression of PCa. Taken together, our findings suggest that the miR-218/GAB2 axis may become a novel prognostic indicator and potential therapeutic target in PCa.

Evaluation of anti-cancer potency of silibinin on murine renal carcinoma RenCa cells in an animal model with an intact immune system.

Silibinin is a flavonoid extract isolated from milk thistle and has been proved to be a promising chemotherapeutic drug for cancer. However, most of those studies were performed on the human cancer cells, where the effects of silibinin could only be observed on an animal model with a deficient immune system. RenCa cells were isolated from a murine spontaneous renal cell carcinoma, which resembles many features of human renal cell carcinoma, and have been used to establish animal models with a sound immune response. Herein, we investigated the anti-cancer effects of silibinin on RenCa cells, revealing that it inhibited cell viability in both dose- and time-dependent manners. Silibinin slightly triggered apoptosis and significantly induced G2-M cell cycle arrest by downregulating cyclin B1 and CDK1 and increasing expression of p21. Furthermore, silibinin significantly inhibited the growth of RenCa cell xenografts in vivo. In addition, we found that silibinin reduced programmed cell death 1 ligand 1 expression of RenCa cells in vivo and in vitro. Our findings demonstrate that silibinin can inhibit the growth of mouse tumor cells in an animal model with an intact immune system, and silibinin may decrease the immunosuppression effect of tumor cells. Our results provide new evidence for evaluation of Silibinin application in cancer therapy.

G Protein γ subunit 7 loss contributes to progression of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common urinary neoplasm, looking for useful candidates to establish scientific foundation for the therapy of ccRCC is urgent. We downloaded genomic profiles of GSE781, GSE6244, GSE53757, and GSE66271 from the Gene Expression Omnibus (GEO) database. GEO2R was used to analyze the derivative genes, while hub genes were screened by protein-protein interactions and cytoscape. Further, overall survival, gene methylation, gene mutation, and gene expression were all analyzed using bioinformatics tools. Colony formation and cell-cycle assay were used to detect the biological function of GNG7 in vitro. We found that GNG7 was downregulated in ccRCC tissues and negatively associated with overall survival in ccRCC patients. We also found that promoter methylation and frequent gene mutation were responsible for GNG7 gene suppression. GNG7 low expression was related to upregulation of enhancer of zeste homolog 2 and downregulation of disabled homolog 2-interacting protein. Further, Gene Set Enrichment Analysis results showed that mTOR1, E2F, G2M, and MYC pathways were all significantly altered in response to GNG7 low expression. In vitro, A498 and 786-O cells in which GNG7 expression was silenced, exhibited a lower G1 phase when compared to the negative control cells. Taken together, our findings suggest that GNG7 is a tumor suppressor gene in ccRCC progression and represents a novel candidate for ccRCC treatment.

A multicenter case-control study on screening of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in han chinese.

Uterine leiomyoma (UL) is an estrogen-responsive benign tumor in the female reproductive system and the main risk of hysterectomy for women. However, gene polymorphism of estrogen-metabolizing enzymes may lead to the different susceptibility to UL. We detected 10 single mucleotide polymorphisms in three key estrogen metabolite enzymes (COMT, CYP1A1, CYP1B1) in a Chinese Han population consisting of 800 patients and 800 healthy women from five different medical centers. The genetic polymorphism of rs3087869 (IVS1+2329C>T) (OR 3.200, 95% CI 1.614-6.345) and rs4680 (Val158Met) (OR 5.675, 95% CI 2.696-11.942) loci on COMT, rs1048943 (Ile462Val) (OR 4.629, 95% CI 2.216-9.672) and rs4646422 (Gly45Asp) (OR 3.240, 95% CI 1.624-6.461) loci on CYP1A1 and rs1065827 (Ala119Ser) (OR 5.635, 95% CI 2.990-10.619) locus on CYP1B1 were the risk factors to UL development and rs1056836 (Leu432Val) (OR 0.188, 95% CI 0.061-0.575) locus on CYB1B1 may be the protective factor to UL. The results provide a theoretical basis for genetic screening and early intervention to UL-susceptible populations.

Microwave De-Icing Efficiency Improvement of Asphalt Mixture with Structural Layer Optimization and Heat-Resistance Design.

The application of microwave de-icing technology in road engineering is constrained by its low energy utilization rate, which can be attributed to low heat production rates and ineffective heat dissipation to the underlying pavement. In this work, asphalt mixtures are designed as an upper layer (heating layer) and a lower layer (thermal-resistance layer). Magnetite slag was selected as a microwave-sensitive source for generating heat, and expanded perlite powder was incorporated into the lower layer as a thermal resistance material. Structural layer optimization and thermal-resistance layer design of the asphalt mixture were carried out by changing the thickness of the upper and lower layers to further improve the heat production rates. The design effectiveness is comprehensively evaluated by factors such as the changing law of the average surface temperature of mixtures, ice-melting time, and cost-effectiveness analyses. The results show that EP possesses better thermal stability, lower microwave energy conversion ability and more excellent heat-resistance potential compared with mineral powder. The heat-resistance layer with EP can prevent heat from being conducted to the lower layer and promote it to concentrate on the specimen surface, which can endow the microwave heating efficiency of specimens to be further improved by up to 26.97% and the de-icing time reduced by 10%, ascribed to the heat-resistance design. Furthermore, the collaborative design of the structural layer optimization and heat-resistance layer can increase energy utilization efficiency and save microwave-absorbing materials while ensuring excellent microwave de-icing efficiency.

A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.

Properties, Microstructure Development and Life Cycle Assessment of Alkali-Activated Materials Containing Steel Slag under Different Alkali Equivalents.

To improve solid waste resource utilization and environmental sustainability, an alkali-activated material (AAM) was prepared using steel slag (SS), fly ash, blast furnace slag and alkali activators in this work. The evolutions of SS content (10-50%) and alkali equivalent (4.0-8.0%) on workability, mechanical strength and environmental indicators of the AAM were investigated. Furthermore, scanning electron microscopy, X-ray diffraction and nuclear magnetic resonance techniques were adopted to characterize micromorphology, reaction products and pore structure, and the reaction mechanism was summarized. Results showed that the paste fluidity and setting time gradually increased with the increase in SS content. The highest compressive strength was obtained for the paste at 8.0% alkali equivalent due to the improved reaction rate and process, but it also increased the risk of cracking. However, SS was able to exert a microaggregate filling effect, where SS particles filling the pores increased the structural compactness and hindered crack development. Based on the optimal compressive strength, global warming, abiotic resource depletion, acidification and eutrophication potential of the paste are reduced by 76.7%, 53.0%, 51.6%, and 48.9%, respectively, compared with cement. This work is beneficial to further improve the utilization of solid waste resources and expand the application of environmentally friendly AAMs in the field of construction engineering.

Erratum: KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy: Erratum.

[This corrects the article DOI: 10.7150/thno.33282.].

Melatonin reduces IL-33 and TSLP expression in human nasal epithelial cells by scavenging ROS directly.

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic mucosal inflammation of the nasal cavity and sinuses. It is classified into CRS without nasal polyps and CRS with nasal polyps (CRSwNP). CRSwNP has high recurrence, especially CRSwNP with massive eosinophil infiltration which is mediated by type 2 inflammatory response. Melatonin is a hormone secreted by the pineal gland, it has powerful antioxidant and anti-inflammatory effects in addition to regulating biological rhythms. There are no studies on melatonin for the treatment of CRS, so we aimed to explore whether melatonin could be used for the treatment of CRS. MATERIALS AND METHODS: In this study, we used melatonin to treat a cell model of CRS. Subsequently, MTT assay was performed to examine the cell viability of human nasal epithelial cells (HNEpCs), a reactive oxygen species (ROS) kit to detect ROS production, a malondialdehyde (MDA) kit to detect the MDA content in the cell culture supernatant, and an apoptosis kit and Western blot analysis to detect apoptosis. The expressions of Nrf2, HO-1, IL-33, TSLP, and IL-25 were detected by Western blot analysis. RESULTS: Melatonin improved the viability of HNEpCs, reduced lipopolysaccharide-induced ROS, reduced the MDA content, and inhibited their apoptosis. More importantly, melatonin reduced the expression of IL-33 and TSLP, an important phenomenon for the treatment of CRSwNP. CONCLUSION: Melatonin protects HNEpCs from damage in inflammation and reduces IL-33 and TSLP expression of HNEpCs.

Comprehensive Perspectives for Erectile Dysfunction Pharmacotherapy: From Mechanism to Application.

In recent years, the incidence of erectile dysfunction (ED) has continued to rise worldwide. Since pharmacotherapy is still the most common and effective method for the treatment of ED at present, many methods and drugs have been designed or developed for the treatment of ED. Oral phosphodiesterase-5 inhibitors and androgen supplement therapy are currently the common therapeutics for ED; however, some patients have poor responses to these drugs because of the multiple pathogenic mechanisms of ED. Researchers are trying to find other treatment ways. On the one hand, many new strategies and concepts, such as targeted therapy, are also integrated into clinical or preclinical research; on the other hand, some combined therapies that have synergistic effects with a reduced dose of a single drug and less adverse effects are also developed. This review article summarized the efficacy of the latest first-line, second-line drugs and adjuvant therapies for the treatment of ED, as well as the application of comprehensive treatments, which will help doctors not only deeply understand the mechanism of ED but select the suitable therapeutics for those patients.

Combined Self-Assembled Hendeca-Arginine Nanocarriers for Effective Targeted Gene Delivery to Bladder Cancer.

Introduction: Bladder cancer (BCa) is among the most prevalent cancers worldwide. However, the effectiveness of intravesical therapy for BCa is limited due to the short dwell time and the presence of the permeation barrier. Methods: Nanocomplexes were self-assembled between DNA and hendeca-arginine peptide (R11). Stepwise intravesical instillation of R11 and the generated nanocomplexes significantly enhanced the targeting capacity and penetration efficiency in BCa therapy. The involved mechanism of cellular uptake and penetration of the nanocomplexes was determined. The therapeutic effect of the nanocomplexes was verified preclinically in murine orthotopic BCa models. Results: Nanocomplexes exhibited the best BCa targeting efficiency at a nitrogen-to-phosphate (NP) ratio of 5 but showed a lack of stability during cellular uptake. The method of stepwise intravesical instillation not only increased the stability and target specificity of the DNA component but also caused the delivered DNA to more effectively penetrate into the glycosaminoglycan layer and plasma membrane. The method promotes the accumulation of the delivered DNA in the clathrin-independent endocytosis pathway, directs the intracellular trafficking of the delivered DNA to nonlysosome-localized regions, and enables the intercellular transport of the delivered DNA via a direct transfer mechanism. In preclinical trials, our stepwise method was shown to remarkably enhance the targeting and penetration efficiency of DNA in murine orthotopic BCa models. Conclusion: With this method, a stepwise intravesical instillation of self-assembled nanocomplexes, which are generated from hendeca-arginine peptides, was achieved; thus, this method offers an effective strategy to deliver DNA to target and penetrate BCa cells during gene therapy and warrants further development for future intravesical gene therapy in the clinical context.

R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer.

Intravesical chemotherapy is generally used in the clinic for treating bladder cancer (BCa), but its efficacy is limited due to the permeation barrier and side effects caused by the off-targeting of normal urothelial cells. In this study, BCa cell-derived membrane nanovesicles were used as drug carriers, and their homologous tumor-targeting capacity was utilized. A BCa-targeting hendeca-arginine peptide was functionalized onto the nanovesicles to impart a mucus-penetrating ability and thus overcome the permeation barrier. The tumor-targeting and mucus-penetrating nanovesicles were stable in urine, were highly permeable to the glycosaminoglycan layer, and specifically targeted BCa. The vesicles were internalized through caveolin-mediated endocytosis, were transported to nonlysosome-localized intracellular regions, and efficiently infiltrated bladder tumor spheroids. In in vivo intravesical chemotherapy, the nanovesicles achieved chemo-resection in murine orthotopic BCa models. This BCa-targeting and mucus-penetrating drug delivery system may be promising for the intravesical chemotherapy of BCa.

A novel multidomain polyketide synthase is essential for zeamine production and the virulence of Dickeya zeae.

Dickeya zeae is the causal agent of the rice foot rot disease, but its mechanism of infection remains largely unknown. In this study, we identified and characterized a novel gene designated as zmsA. The gene encodes a large protein of 2,346 amino acids in length, which consists of multidomains arranged in the order of N-terminus, ß-ketoacyl synthase, acyl transferase, acyl carrier protein, ß-ketoacyl reductase, dehydratase. This multidomain structure and sequence alignment analysis suggest that ZmsA is a member of the polyketide synthase family. Mutation of zmsA abolished antimicrobial activity and attenuated the virulence of D. zeae. To determine the relationship between antimicrobial activity and virulence, active compounds were purified from D. zeae EC1 and were structurally characterized. This led to identification of two polyamino compounds, i.e., zeamine and zeamine II, that were phytotoxins and potent antibiotics. These results have established the essential role of ZmsA in zeamine biosynthesis and presented a new insight on the molecular mechanisms of D. zeae pathogenicity.

Predictive Biomarkers and Novel Targets in the Treatment of Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Partial or radical nephrectomy is the major surgical management for localized RCC, however, almost 30% of patients will develop recurrence and metastasis after surgery. Metastatic RCC (mRCC) is a disease with a very poor prognosis, and the 5-year survival of the mRCC is commonly less than 10%. Unfortunately, mRCC is highly resistant to chemo and radiotherapy. Therefore, mRCC treatment has become a big challenge for researchers as well as clinicians. RCC is characterized as clear genetic background, especially with von Hippel-Lindau (VHL) gene loss or mutation in more than 70% of the cases. Several molecular factors and signaling pathways have been discovered to possess impact on the progression of RCC, including VHL-HIF-VEGF angiogenesis signaling, PI3K/AKT/mTOR signaling, epithelial-to-mesenchymal transition-related pathways, and Wnt/ß-catenin pathway, which play crucial roles in the growth, invasiveness, metastasis and angiogenesis of RCC. Based on the recent studies of these signaling pathways, some medicines as well as immune check-point inhibitors have been developed, which have shown potential therapeutic effects for mRCC. Therefore, our current review aims to summarize the recent progress of the treatment for mRCC, with a special focus on the strategies to improve the responsiveness of medicines in patients with mRCC.