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Objective To elucidate the mechanism by which pancreatic kininogenase (PKase) impacts renal fibrosis in diabetic nephropathy through modulation of the Notch1/Hes1 and Pten/Akt pathways. Methods This study employed in vivo models and cellular assays to investigate PKase’s effects on cellular viability, apoptosis, and oxidative stress. Assay kits were used to assess these parameters, while protein expression levels were measured via Western Blot and RT-qPCR. Histological changes in kidney tissues were analyzed using HE and Masson’s staining. Fibrosis markers—including E-cadherin, vimentin, α-SMA, Collagen I, TGF-β, and fibronectin—were evaluated through immunofluorescence and immunohistochemistry. Results After eight weeks of PKase treatment, significant improvements in blood glucose levels and associated symptoms were observed in diabetic nephropathy rats. Both in vivo and in vitro results demonstrated that PKase treatment inhibited the expression of diabetic nephropathy markers, including vimentin, α-SMA, FN, Collagen I, and TGF-β, while increasing the expression of E-cadherin. Additionally, the expression of Notch1, Hes1, and phosphorylated Akt (p-Akt) was upregulated, and Pten expression was suppressed, all of which were reversed by PKase treatment. Furthermore, both analyses indicated that PKase alleviated Jagged1-induced apoptosis and oxidative stress, and mitigated tubulointerstitial fibrosis. Conclusion PKase appears to ameliorate diabetic nephropathy-induced renal fibrosis by activating the Pten/Akt pathway and inhibiting the Notch1/Hes1 pathway, suggesting its potential as a therapeutic agent in diabetic nephropathy. Clinical Trial Number Not applicable.

In many grassland ecosystems, nitrogen (N) and phosphorus (P) are added to improve plant productivity, and the aboveground plant biomass is mowed and stored as hay for the bullamacow. Nutrient addition and mowing affect the biodiversity and ecosystem functioning, and most of the previous studies have primarily focused on their effects on macro-organisms, neglecting the responses of soil microbial communities. In this study, we examined the changes in three community attributes (abundance, richness, and composition) of the entire bacterial kingdom and 16 dominant bacterial phyla/classes in response to mowing, N addition, P addition, and their combinations, by conducting a 5-year experiment in a steppe ecosystem in Inner Mongolia, China. Overall, N addition had a greater effect than mowing and P addition on most of these bacterial groups, as indicated by changes in the abundance, richness and composition in response to these treatments. N addition affected these soil bacterial groups primarily through reducing soil pH and increasing available N content. Meanwhile, the 16 bacterial phyla/classes responded differentially to these experimental treatments, with Acidobacteria, Acidimicrobidae, Deltaproteobacteria, and Gammaproteobacteria being the most sensitive. The changes in the abundance, richness, and composition of various bacterial groups could imply some potential shift in their ecosystem functions. Furthermore, the important role of decreased soil pH caused by N addition in affecting soil bacterial communities suggests the importance of restoring acidified soil to maintain soil bacterial diversity.

Tillage practices and residue management are highly important agricultural practices. However, very few studies have examined the influence of tillage practices and residue management on both bacterial and fungal communities and network patterns in consecutive years. We examined the effects of different tillage practices, including no tillage, rotary tillage, and deep tillage, on soil bacterial and fungal communities and co-occurrence networks following residue removal and residue retention in 2017 and 2018. This study showed that both bacterial and fungal communities were unaffected by tillage practices in 2017, but they were significantly impacted in 2018. Soil fungal operational taxonomic unit (OTU) richness was significantly enhanced by deep tillage compared with no tillage in 2018, while bacterial OTU richness was unaffected in either year. Tillage practices had differing effects on soil microbial co-occurrence networks, with rotary and deep tillage increasing the complexity of bacterial networks but simplifying fungal networks. However, residue retention only induced a shift in the fungal community and simplified soil bacterial and fungal networks in 2018. This study highlights the dissimilar responses of bacterial and fungal networks to tillage practices and emphasizes that tillage practice is more important than residue management in shaping soil microbial communities.

Cutaneous pigmentation was recently shown to be an event regulated by clock proteins. Cryptochrome (CRY) is a key protein composing the feedback loop of circadian clock, however, the function of CRY in melanocytes remains unclear. Here, we found that KL001, a synthetic small molecule modulator of CRY1, inhibited melanin synthesis, as well as reduced melanocyte dendrite elongation and melanosome transport. In addition, the dominant role of CRY1 in KL001-induced anti-melanogenesis was revealed by small interfering RNA transfection. Cellular tyrosinase activity and expression level of melanogenic proteins, including tyrosinase, TRP-1, TRP-2, and transport proteins like Rab27a, Cdc42 and Myosin Va induced by α-MSH were remarkably reversed after KL001 treatment. Mechanistically, CRY1 activation inhibited melanogenesis through CREB-dependent downregulation of MITF and CREB phosphorylation was mediated by classical cAMP/PKA pathway. In addition, the other CRY1 activator, KL044 also suppressed cAMP/PKA/CREB pathway and inhibited melanogenesis. Finally, anti-melanogenic efficacy of KL001 was confirmed by determination of melanin contents in UVB-tanning model of brown guinea pigs, which indicated that targeting CRY1 activity, via topical application of small molecule activator, can be utilized therapeutically to manage human pigmentary disorders.

Background Immunotherapy has been confirmed efficient in recurrent or metastatic nasopharyngeal carcinoma (NPC), but its role in the locoregionally advanced setting is undetermined. Previous evidence in non-endemic areas of NPC is also lacking. This study evaluated the efficacy and safety of induction chemotherapy plus camrelizumab followed by concurrent chemoradiotherapy (CCRT) for patients with locoregionally advanced NPC in non-endemic areas. Methods In this phase 2 trial, patients born and living in North China with untreated stage III to IVa NPC were enrolled. All patients received two 21-day cycles of camrelizumab (200 mg) plus docetaxel (75 mg/m 2 ) and cisplatin (75 mg/m 2 ), followed by intensity modulated radiotherapy and concurrent cisplatin (80 mg/m 2 for two 21-day cycles). After CCRT, patients received camrelizumab maintenance for 12 cycles. The primary endpoint was 3-year disease-free survival (DFS) rate. Results From February 2021 to September 2023, a total of 57 patients were included for analysis. The objective response rate was 92.8% after induction therapy and 100% after CCRT. With a median follow-up time of 21 months, the 3-year DFS rate was 84%. The 3-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 95.8%, 90.9%, and 89.5%, respectively. The most common grade 3 or 4 treatment-related adverse events were leukopenia and neutropenia during induction therapy, and weight loss and lymphopenia during CCRT. Conclusions Induction immunochemotherapy combined with CCRT shows promising antitumor activity with a manageable safety profile in patients with locoregionally advanced NPC from non-endemic areas, which deserves further validation. Trial registration ClinicalTrials.gov Identifier: NCT04782765.

Multiple co-occurring environmental changes are affecting soil nitrogen cycling processes, which are mainly mediated by microbes. While it is likely that various nitrogen-cycling functional groups will respond differently to such environmental changes, very little is known about their relative responsiveness. Here we conducted four long-term experiments in a steppe ecosystem by removing plant functional groups, mowing, adding nitrogen, adding phosphorus, watering, warming, and manipulating some of their combinations. We quantified the abundance of seven nitrogen-cycling genes, including those for fixation (nifH), mineralization (chiA), nitrification (amoA of ammonia-oxidizing bacteria (AOB) or archaea (AOA)), and denitrification (nirS, nirK and nosZ). First, for each gene, we compared its sensitivities to different environmental changes and found that the abundances of various genes were sensitive to distinct and different factors. Overall, the abundances of nearly all genes were sensitive to nitrogen enrichment. In addition, the abundances of the chiA and nosZ genes were sensitive to plant functional group removal, the AOB-amoA gene abundance to phosphorus enrichment when nitrogen was added simultaneously, and the nirS and nirK gene abundances responded to watering. Second, for each single- or multi-factorial environmental change, we compared the sensitivities of the abundances of different genes and found that different environmental changes primarily affected different gene abundances. Overall, AOB-amoA gene abundance was most responsive, followed by the two denitrifying genes nosZ and nirS, while the other genes were less sensitive. These results provide, for the first time, systematic insights into how the abundance of each type of nitrogen-cycling gene and the equilibrium state of all these nitrogen-cycling gene abundances would shift under each single- or multi-factorial global change.

American ginseng ( Panax quinquefolius L.) is a perennial medicinal plant that has a long usage history in China. However, root rot, which is mainly caused by Fusarium solani can severely reduce the yield and quality of American ginseng, but no disease-resistant variety of American ginseng exists, and the resistance against this disease is not yet well understood. Thus, it is very urgent to analyze the interaction mechanism regulating the interactions between American ginseng and F. solani to mine disease resistance genes. Using transcriptome data and quantitative polymerase chain reaction (qPCR), we screened the transcription factor PqbZIP1 in response to induction by chitin. Yeast self-activation and subcellular localization experiments proved that PqbZIP1 showed transcriptional activity and was localized in the plant nucleus. In addition, qPCR showed that the highest relative expression level was in the roots, wherein chitin and F. solani inhibited and activated the expression of PqbZIP1 , respectively, in American ginseng. Additionally, PqbZIP1 significantly inhibited the growth of the Pseudomonas syringae pv. tomato D36E strain in Nicotiana benthamiana , where expressing PqbZIP1 in N. benthamiana increased the jasmonic acid, salicylic acid, and abscisic acid content. Furthermore, PqbZIP1 expression was continually increased upon inoculation with F. solani . Hence, this study revealed that the PqbZIP1 transcription factor might mediate multiple hormonal signaling pathway to modulate root rot disease resistance in American ginseng, and provided important information to breed disease-resistant American ginseng.

Background The aim of this study was to investigate the role of long non-coding RNA (lncRNA) H19 in gastric cancer (GC) with Helicobacter pylori ( H. pylori ). Methods H19 expression in peripheral blood from H. pylori +/− GC patients and healthy donors (control) as well as in GC tissues and cells were detected by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay. Cell migration and invasion were evaluated by Transwell assay. The levels of pro-inflammatory cytokines were determined by ELISA. The protein levels of IκBα, p-IκBα and p65 were determined by western blotting. Results H19 expression was upregulated in H. pylori -infected GC tissues and cells. Furthermore, H. pylori promoted GC cell viability, migration, invasion and inflammatory response. Moreover, H19 overexpression promoted the proliferation, migration and invasion of H. pylori -infected GC cells via enhancing NF-κB-induced inflammation. Conclusions LncRNA H19 promotes H. pylori -induced GC cell growth via enhancing NF-κB-induced inflammation.

The therapeutic use of curcumin and chemically modified curcumin (CMC) for suppressing melanogenesis and tyrosinase activity have been recognized. J147 is a modified version of curcumin with superior bioavailability and stability. However, there is no report about the effects of J147 on pigmentation in vitro and in vivo . In our studies, we investigated the hypopigmentary effects of J147 treatment on melanocytes and explored the underlying mechanism. The present studies suggested that J147 suppressed both basal and α-MSH-induced melanogenesis, as well as decreased melanocyte dendricity extension and melanosome transport. J147 played these roles mainly by activating the extracellular signal-regulated protein kinase (ERK) pathway. Once activated, it resulted in MITF degradation and further down-regulated the expression of tyrosinase, TRP-1, TRP-2, Myosin Va, Rab27a and Cdc42, ultimately inhibited melanin synthesis and melanosome transport. Furthermore, the hypopigmentary effects of J147 were demonstrated in vivo in a zebrafish model and UVB-induced hyperpigmentation model in brown guinea pigs. Our findings also suggested that J147 exhibited no cytotoxicity in vitro and in vivo . Taken together, these data confirmed that J147 may prove quite useful as a safer natural skin-whitening agent.

Climate warming and shifting precipitation regimes are affecting biodiversity and ecosystem functioning. Most studies have focused on the influence of warming and altered precipitation on macro-organisms, whereas the responses of soil microbial communities have been neglected. We studied the changes in the abundance, richness, and composition of the entire bacterial kingdom and 16 dominant bacterial phyla/classes in response to increased precipitation, warming, and their combination, by conducting a 5-year experiment in a steppe ecosystem in Inner Mongolia, China. Watering had a greater effect than warming on almost all the bacterial groups as indicated by changes in all the three attributes (abundance, richness, and composition). The 16 phyla/classes responded differentially to the experimental treatments, with Acidobacteria and Gamma-proteobacteria being the most sensitive. Stepwise regression analyses further revealed that climate changes altered the abundance and richness of bacterial groups primarily through direct routes (e.g., increasing soil water content), and changed the community composition through both direct and indirect routes (e.g., reducing soil total nitrogen content and increasing soil pH). The diverse responses of various bacterial groups could imply some potential shift in their ecosystem functions under climate changes; meanwhile, the indirect routes that are important in altering bacterial composition suggest that specific strategies (e.g., adding NH4NO3 to maintain soil nitrogen content and pH) could be adopted to maintain soil microbial composition under climate changes.