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Chronic kidney disease (CKD) was a major public health problem worldwide. Renal fibrosis, especially tubulointerstitial fibrosis, is final manifestation of CKD. Many studies have demonstrated that TGF-β/Smad signaling pathway plays a crucial role in renal fibrosis. Therefore, targeted inhibition of TGF-β/Smad signaling pathway can be used as a potential therapeutic measure for tubulointerstitial fibrosis. At present, a variety of targeting TGF-β1 and its downstream Smad proteins have attracted attention. Natural products used as potential therapeutic strategies for tubulointerstitial fibrosis have the characteristics of acting on multiple targets by multiple components and few side effects. With the continuous research and technique development, more and more molecular mechanisms of natural products have been revealed, and there are many natural products that inhibited tubulointerstitial fibrosis via TGF-β/Smad signaling pathway. This review summarized the role of TGF-β/Smad signaling pathway in tubulointerstitial fibrosis and natural products against tubulointerstitial fibrosis by targeting TGF-β/Smad signaling pathway. Additionally, many challenges and opportunities are presented for inhibiting renal fibrosis in the future.

The olfactory organ of vertebrates receives chemical cues present in the air or water and, at the same time, they are exposed to invading pathogens. Nasal-associated lymphoid tissue (NALT), which serves as a mucosal inductive site for humoral immune responses against antigen stimulation in mammals, is present also in teleosts. IgT in teleosts is responsible for similar functions to those carried out by IgA in mammals. Moreover, teleost NALT is known to contain B-cells and teleost nasal mucus contains immunoglobulins (Igs). Yet, whether nasal B cells and Igs respond to infection remains unknown. We hypothesized that water-borne parasites can invade the nasal cavity of fish and elicit local specific immune responses. To address this hypothesis, we developed a model of bath infection with the Ichthyophthirius multifiliis (Ich) parasite in rainbow trout, Oncorhynchus mykiss, an ancient bony fish, and investigated the nasal adaptive immune response against this parasite. Critically, we found that Ich parasites in water could reach the nasal cavity and successfully invade the nasal mucosa. Moreover, strong parasite-specific IgT responses were detected in the nasal mucus, and the accumulation of IgT+ B-cells was noted in the nasal epidermis after Ich infection. Strikingly, local IgT+ B-cell proliferation and parasite-specific IgT generation were found in the trout olfactory organ, providing new evidence that nasal-specific immune responses were induced locally by a parasitic challenge. Overall, our findings suggest that nasal mucosal adaptive immune responses are similar to those reported in other fish mucosal sites and that an antibody system with a dedicated mucosal Ig performs evolutionary conserved functions across vertebrate mucosal surfaces.

Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC. We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9–32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6–22·3]; hazard ratio [HR] 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1–5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD. Accurate monitoring of chronic kidney disease (CKD) progression is essential for efficient disease management. Here Chen et al. identify five serum metabolites in patients with stage 1–5 CKD whose levels associate with disease progression, and find that 5-methoxytryptophan and its regulatory enzyme TPH-1 exert anti-fibrotic effects in mouse models of kidney injury.

The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β -catenin is activated, associated with the development and progression of renal fibrosis. Wnt/ β -catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/ β -catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/ β -catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β -catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/ β -catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/ β -catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

Mesenchymal stem cells (MSCs) repair infarcted heart through paracrine mechanism. We sought to compare the effectiveness of MSCs and MSC-derived exosomes (MSC-Exo) in repairing infarcted hearts and to identify how MSC-Exo mediated cardiac repair is regulated. In a rat myocardial infarction model, we found that MSC-Exo inhibited cardiac fibrosis, inflammation, and improved cardiac function. The beneficial effects of MSC-Exo were significantly superior compared to that of MSCs. To explore the potential mechanisms underlying MSC-Exo’s effects, we performed several in vitro experiments and miRNA-sequence analysis. MSC-Exo stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis induced by H2O2, and inhibited TGF-β induced transformation of fibroblast cell into myofibroblast. Importantly, novel miRNA sequencing results indicated that MSC-Exo and MSCs have similar miRNA expression profile, which could be one of the reasons that MSC-Exo can replace MSCs for cardiac repair. In addition, the expression of several miRNAs from MSC-Exo was significantly different from that of MSCs, which may explain why MSC-Exo has better therapeutic effect than MSCs. In conclusion, this study demonstrates that MSC-Exo could be used alone to promote cardiac repair and are superior to MSCs in repairing injured myocardium.

A concise, two-dimensional discrete heat transfer model is presented, which considers the thermal resistance effects of cracks. The discrete heat transfer model discretizes the continuum into individual triangular elements, and the adjacent triangular elements transfer heat through corresponding joint elements. Then, the principle of selecting the heat exchange coefficient of the joint element is determined through a parameter sensitivity analysis. Moreover, the 2D discrete heat transfer model is combined with the finite discrete element method to build a thermomechanical coupled model for simulating brittle material thermal cracking. The thermal stress and thermal shock problems are studied by using the thermomechanical coupled model, and the numerical results are compared with either the analytical solution or experimental results to validate the 2D discrete heat transfer model and thermomechanical coupled model. The discrete heat transfer model and thermomechanical coupled model provide a powerful tool for solving heat transfer problems in discontinuous media as well as the thermal cracking problem in brittle materials.

Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals. Inflammasome multiprotein complexes are composed of three parts: a sensor protein, an adaptor, and pro-caspase-1. Activation of the inflammasome leads to the activation of caspase-1, which cleaves pro-inflammatory cytokines such as IL-1β and IL-18, leading to pyroptosis. Effectors of the inflammasome not only provide protection against infectious pathogens, but also mediate control over sterile insults. Aberrant inflammasome signaling has been implicated in the development of cardiovascular and metabolic diseases, cancer, and neurodegenerative disorders. Here, we review the role of the inflammasome as a double-edged sword in various diseases, and the outcomes can be either good or bad depending on the disease, as well as the genetic background. We highlight inflammasome memory and the two-shot activation process. We also propose the M- and N-type inflammation model, and discuss how the inflammasome pathway may be targeted for the development of novel therapy.