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Diabetic nephropathy (DN) is characterized by sterile inflammation with continuous injury and loss of renal inherent parenchyma cells. Podocyte is an essential early injury target in DN. The injury and loss of podocytes are closely associated with proteinuria, the early symptom of renal injury in DN. However, the exact mechanism for podocyte injury and death in DN remains ambiguous. In this study we investigated whether pyroptosis, a newly discovered cell death pathway was involved in DN. Diabetic mice were generated by high-fat diet/STZ injections. We showed that the expression levels of caspase-11 and cleavage of gasdermin D (GSDMD-N) in podocytes were significantly elevated, accompanied by reduced expression of podocyte makers nephrin and podocin, loss and fusion in podocyte foot processes, increased inflammatory cytokines NF-κB, IL-1β, and IL-18, macrophage infiltration, glomerular matrix expansion and increased urinary albumin to creatinine ratio (UACR). All these changes in diabetic mice were blunted by knockout of caspase-11 or GSDMD. Cultured human and mouse podocytes were treated with high glucose (30 mM), which significantly increased the expression levels of caspase-11 or caspase-4 (the homolog of caspase-11 in human), GSDMD-N, NF-κB, IL-1β, and IL-18, and decreased the expression of nephrin and podocin. Either caspase-4 or GSDMD knockdown by siRNA significantly blunted these changes. In summary, our results demonstrate that caspase-11/4 and GSDMD-mediated pyroptosis is activated and involved in podocyte loss under hyperglycemia condition and the development of DN.

Acute renal injury (AKI) causes a long-term risk for progressing into chronic kidney disease (CKD) and interstitial fibrosis. Yes-associated protein (YAP), a key transcriptional cofactor in Hippo signaling pathway, shuttles between the cytoplasm and nucleus, which is required for the renal tubular epithelial cells repair in the acute phase of AKI. In this study we investigated the role of YAP during ischemia-reperfusion (IR)-induced AKI to CKD. Mice were subjected to left kidney IR followed by removal of the right kidney on the day before tissue harvests. Mouse shRNA expression adenovirus (Ad-shYAP or Ad-shKLF4) and mouse KLF4 expression adenovirus (Ad-KLF4) were delivered to mice by intrarenal injection on D7 after IR. We showed that the expression and nucleus distribution of YAP were persistently increased until the end of experiment (D21 after IR). The sustained activation of YAP in post-acute phase of AKI was accompanied by renal dysfunction and interstitial fibrosis. Knockdown of YAP significantly attenuated IR-induced renal dysfunction and decreased the expression of fibrogenic factors TGF-β and CTGF in the kidney. We showed that the expression of the transcription factor KLF4, lined on the upstream of YAP, was also persistently increased. Knockdown on KLF4 attenuated YAP increase and nuclear translocation as well as renal functional deterioration and interstitial fibrosis in IR mice, whereas KLF4 overexpression caused opposite effects. KLF4 increased the expression of ITCH, and ITCH facilitated YAP nuclear translocation via degrading LATS1. Furthermore, we demonstrated in primary cultured renal tubular cells that KLF4 bound to the promoter region of YAP and positively regulates YAP expression. In biopsy sample from CKD patients, we also observed increased expression and nuclear distribution of YAP. In conclusion, the activation of YAP in the post-acute phase of AKI is implicated in renal functional deterioration and fibrosis although it exhibits beneficial effect in acute phase. Reprogramming factor KLF4 is responsible for the persistent activation of YAP. Blocking the activation of KLF4-YAP pathway might be a way to prevent the transition of AKI into CKD. About 28.5% of the acute kidney injury (AKI) patients cannot recover completely. AKI has become an important risk factor for chronic kidney disease (CKD). It has been reported that the activation of YAP facilitates the recovery of AKI, however, this experiment demonstrated that the activation of YAP may last to the post-acute phase of AKI. The persistent activation of YAP is implicated with renal deterioration and fibrosis. Reprogramming factor KLF4 was responsible for the persistent activation of YAP. Shutting down the KLF4-related persistent activation of YAP after acute phase of AKI might be a way to prevent the transition of AKI into CKD.

Aim This study aimed to investigate the distribution patterns of plant diversity in Kenya, how climatic fluctuations and orogeny shaped them, and the formation of its β‐diversity. Location Kenya, East Africa. Taxon Angiosperms. Methods We quantified patterns of turnover and nestedness components of phylogenetic β‐diversity for angiosperm species among neighbouring sites using a well‐resolved phylogenetic tree and extensive distribution records from public databases and other published sources. We applied clustering methods to delineate biota based on pairwise similarities among multiple sites and used a random assembly null model to assess the effects of species abundance distribution on phylogenetic β‐diversity. Results The phylogenetic turnover of the Kenyan flora, intersecting with the biodiversity hotspots Eastern Afromontane, Coastal Forests of Eastern Africa, and Horn of Africa, shows a non‐monotonic pattern along a latitudinal gradient that is strongly structured into volcanic and coastal areas. The other areas are mainly dominated by phylogenetic nestedness, even in the eastern part of the equatorial region parallel to the volcanic area. Phylogenetic diversity and phylogenetic structure analyses explain the mechanism of the observed phylogenetic turnover and nestedness patterns. We identified five phytogeographical regions in Kenya: the Mandera, Turkana, Volcanic, Pan Coastal and West Highland Regions. Conclusions Variations in turnover gradient and coexistence are highly dependent on the regional biogeographical history resulting from climatic fluctuations and long‐lasting orogeny, which jointly shaped the biodiversity patterns of the Kenyan flora. The nestedness component dominated climatically unstable regions and is presumed to have been caused by heavy local species extinction and recolonization from the Volcanic Region. The high turnover component in climatically stable regions may have preserved old lineages and the prevalence of endemic species within narrow ranges.

Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1β (IL-1β) maturation. In Casp-11 −/− mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK-52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1β maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated from Casp-11 −/− mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R-induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.

Background The Sino-Himalayan flora harbors highly diverse high-elevation biotas, but our understanding of its evolutionary history in temporal and spatial dimensions is limited. In this study, we integrated a dated phylogenetic tree with comprehensive species distribution data to investigate changes over time and space in floristic elements, including the tropical, Tethys, northern temperate, and East Asian floristic elements, across the entire Sino-Himalaya and its three floristic regions: the Yunnan Plateau, Hengduan Mountains, and East Himalaya regions. Results Our results revealed that the Sino-Himalayan flora developed from lowland biomes and was predominantly characterized by tropical floristic elements before the collision between the Indian subcontinent and Eurasia during the Early Cenozoic. Subsequently, from the Late Eocene onwards, the uplifts of the Himalaya and Hengduan Mountains transformed the Sino-Himalayan region into a wet and cold plateau, on which harsh and diverse ecological conditions forced the rapid evolution of local angiosperms, giving birth to characteristic taxa adapted to the high altitudes and cold habitat. The percentage of temperate floristic elements increased and exceeded that of tropical floristic elements by the Late Miocene. Conclusions The Sino-Himalayan flora underwent four significant formation periods and experienced a considerable increase in endemic genera and species in the Miocene, which remain crucial to the present-day patterns of plant diversity. Our findings support the view that the Sino-Himalayan flora is relatively young but has ancient origins. The three major shifts in the divergence of genera and species during the four formation periods were primarily influenced by the uplifts of the Himalaya and Hengduan Mountains and the onset and intensification of the Asian monsoon system. Additionally, the temporal patterns of floristic elements differed among the three floristic regions of the Sino-Himalaya, indicating that the uplift of the Himalaya and surrounding areas was asynchronous. Compared to the Yunnan Plateau region, the East Himalaya and Hengduan Mountains experienced more recent and drastic uplifts, resulting in highly intricate topography with diverse habitats that promoted the rapid radiation of endemic genera and species in these regions.

Reference genes have been utilized in estimating gene expression levels using quantitative reverse transcriptase-quantitative polymerase chain reaction (qRT-PCR) analysis. Aphidius gifuensis Ashmaed is one of the most widely used biological control agents for aphids. The biological properties of this species have been studied in detail, and current investigations are focused on elucidating the regulatory mechanisms in its host However, the appropriate reference genes for target gene expression studies have not been identified. In this study, the expression profiles of 12 candidate reference genes were evaluated under different experimental conditions(development stage, sex, tissue type, diet) by using dedicated algorithms, including geNorm, Normfinder, BestKeeper, and ΔCt. In addition, RefFinder was used to rank the overall stability of the candidate genes. Finally, we recommend three optimal reference genes for the normalization of qRT-PCR data in the presence of specific variables, which include ACTB, RPL13, and PPI for different developmental stages; RPS18, ACTB, and RPL13 for sexes; RPL13, PRII3, and RPS18 in different tissue types; and RPL13, RPL27, and ACTB in diverse diets. The present study has identified optimal reference genes that could be used in estimating the expression levels of specific genes under these conditions following the Minimum Information for publication of Quantitative real-time PCR Experiments (MIQE) guidelines, which would facilitate in advancements in functional genomics research on A. gifuensis.

Caspase-11 is a key upstream modulator for activation of inflammatory response under pathological conditions. In this study, we investigated the roles of caspase-11 in the maturation of interleukin-1β (IL-1β) and development of renal interstitial fibrosis in vivo and in vitro. Mice were subjected to unilateral ureteral obstruction (UUO). The mice were treated with either caspase-11 inhibitor wedelolactone (Wed, 30 mg/kg/day, ig) for 7 days or caspase-11 siRNA (10 nmol/20 g body weight per day, iv) for 14 days. The mice were euthanized on day 14, their renal tissue and blood sample were collected. We found that the obstructed kidney had significantly higher caspase-11 levels and obvious tubular injury and interstitial fibrosis. Treatment with Wed or caspase-11 siRNA significantly mitigated renal fibrosis in UUO mice, evidenced by the improved histological changes. Furthermore, caspase-11 inhibition significantly blunted caspase-1 activation, IL-1β maturation, transforming growth factor-β (TGF-β), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 μmol/L), which stimulated caspase-11 activation and IL-1β maturation. Treatment with IL-1β (20 ng/ml) significantly increased the expression of TGF-β, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-β, fibronectin, and collagen I were suppressed by caspase-11 siRNA or Wed. Finally, we revealed using co-immunoprecipitation that caspase-11 was able to interact with caspase-1 in NRK-52E cells. These results suggest that caspase-11 is involved in UUO-induced renal fibrosis. Elevation of caspase-11 in the obstructed kidney promotes renal fibrosis by stimulating caspase-1 activation and IL-1β maturation.

The vacancy-ordered double perovskite Cs 2 PdBr 6 has the advantages of good optoelectronic properties, environmental friendliness, and high stability. It has been experimentally confirmed by researchers as an optoelectronic material with broad application prospects and research value, and is regarded as a potential substitute for lead halide perovskites. In this paper, based on the first-principles calculations in the framework of density functional theory, the crystal structure, elastic, electronic, and optical properties of Cs 2 PdBr 6 under hydrostatic pressure of 0–6 GPa have been investigated with a step size of 0.5 GPa. The calculated results obtained under the condition of 0 GPa hydrostatic pressure are in good agreement with the existing experimental values. When the hydrostatic pressure is applied, the crystal structure parameters of Cs 2 PdBr 6 appear nonlinear changes, but it can still maintain a stable cubic crystal structure. With the increase of pressure, the bulk modulus, shear modulus, and Young’s modulus of Cs 2 PdBr 6 increase gradually, and its ductility also improves gradually. Hydrostatic pressure can reduce the bandgap value of Cs 2 PdBr 6 , thereby enhancing the optoelectronic properties such as absorption and conductivity. In summary, hydrostatic pressure can change the bandgap value of Cs 2 PdBr 6 , improve its optoelectronic performance, and make it more suitable for use as the light-absorbing layer in solar cells.

SND p102 was first described as a transcriptional co-activator, and subsequently determined to be a co-regulator of Pim-1, STAT6 and STAT5. We previously reported that SND p102 expression was increased in high glucose-treated mesangial cells (MCs) and plays a role in the extracellular matrix (ECM) accumulation of MCs by regulating the activation of RAS. In this study, we further examined the roles of SND p102 in diabetic nephropathy (DN)-induced glomerulosclerosis. Rats were injected with STZ (50 mg/kg, ip) to induce diabetes. MCs or isolated glomeruli were cultured in normal glucose (NG, 5.5 mmol/L)- or high glucose (HG, 25 mmol/L)-containing DMEM. We found that SND p102 expression was significantly increased in the diabetic kidneys, as well as in HG-treated isolated glomeruli and MCs. In addition, HG treatment induced significant fibrotic changes in MCs evidenced by enhanced protein expression of TGF-β, fbronectin and collagen IV, and significantly increased the proliferation of MCs. We further revealed that overexpression of SND p102 significantly increased the protein expression of angiotensin II (Ang II) type 1 receptor (AT1R) in MCs by increasing its mRNA levels via directly targeting the AT1R 3′-UTR, which resulted in activation of the ERK/Smad3 signaling and subsequently promoted the up-regulation of fbronectin, collagen IV, and TGF-β in MCs, as well as the cell proliferation. These results demonstrate that SND p102 is a key regulator of AT1R-mediating ECM synthesis and cell proliferation in MCs. Thus, small molecule inhibitors of SND p102 may be a novel therapeutic strategy for DN.

(Miq.) Planch. is one of the most species-rich genera of the economically and agronomically important grape family Vitaceae. It includes ca. 95 species widely distributed in the tropics and subtropics of Asia and Australia. Species of exhibit great diversity in both vegetative and reproductive characters. Here we inferred a well-supported phylogeny of based on ten chloroplast DNA regions with an expanded taxon sampling of 72 species and two varieties. Our molecular results support six major clades within and the relationships among these clades were well-resolved. We also documented seed morphology of 44 species covering the six major clades of the genus. Ancestral states of eight characters (seed shape, seed surface rumination pattern, chalaza length/width ratio, chalaza position, ventral infold position, ventral infold divergence, ventral infold depth in cross section, and endosperm shape) were reconstructed in Mesquite and R with four models. Character optimizations suggest that all character states have evolved multiple times except that the irregular-shaped surface rumination has derived only once in . We evaluated the taxonomic importance of seed morphology and identified potential morphological evidence to support each major clade. Our comprehensive analyses of shed insights into the infrageneric classification of this morphologically diverse and ecologically important genus in tropical and subtropical Asia.