Background: Chronic kidney disease (CKD) is now globally recognized as a critical public health concern. Vascular calcification (VC) represents a significant risk factor for cardiovascular events in individuals with CKD. It is the accessible and precise diagnostic biomarkers for monitoring the progression of CKD and the concurrent VC are urgently needed. Methods: The adenine diet-induced CKD rat model was utilized to investigate chronic kidney injury, calcification in the kidney and thoracic aorta, and dysregulation of biochemical indices. Enzyme-linked immune sandwich assays were employed to analyze changes in calcification-related proteins. 16S rRNA sequencing was performed to delineate the microbiota characteristics in the gut and blood of CKD-afflicted rats. Additionally, transcriptome sequencing of kidney tissue was conducted to explore the relationship between CKD-associated microbiota features and alterations in kidney function. Results: The adenine diet-induced CKD inhibited body weight gain, and led to kidney injury, and pronounced calcification in kidney and thoracic aorta. The microbiota both in the gut and blood of these affected rats exhibited significantly lower alpha diversity and distinctive beta diversity than those in their healthy counterparts. CKD resulted in dysregulation of several biochemical indices (including elevated levels of creatinine, low-density lipoprotein-cholesterol, sodium, phosphorous, total cholesterol, and urea and decreased levels of albumin, calcium, lactate dehydrogenase, and total bilirubin). Moreover, it upregulated calcification-related factors (bone sialoprotein [BSP], Klotho, fibroblast growth factor [FGF]-23, and sclerostin [SOST]) and lipopolysaccharide (LPS). Notably, the increased Acinetobacter in the blood was positively associated with calcifications in the kidney and thoracic aorta, in addition to the positive correlation with gut microbiota. The enrichment of Acinetobacter was concurrent with increases in calcification factors (BSP, FGF-23, and SOST), LPS, and phosphorous. Furthermore, transcriptome sequencing revealed that the enrichment of Acinetobacter was positively correlated with the majority of upregulated genes and negatively correlated with downregulated genes involved in the mineral absorption pathway. Conclusion: Our findings, for the first time, underscore that dysbiosis of symbiotic microbiota, both in the gut and blood, is involved in the progression of CKD. Particularly, the enrichment of Acinetobacter in blood emerges as a potential risk factor for CKD and its accompanying VC.
The plant extract "total glucosides of peony" (TGP) constitutes a mixture of glycosides that is isolated from the roots of the well-known traditional Chinese herb Paeonia lactiflora Pall. Paeoniflorin (Pae) is the most abundant component and the main biologically active ingredient of TGP. Pharmacologically, Pae exhibits powerful anti-inflammatory and immune regulatory effects in some animal models of autoimmune diseases including Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). Recently, we modified Pae with an addition of benzene sulfonate to achieve better bioavailability and higher anti-inflammatory immune regulatory effects. This review summarizes the pharmacological activities of Pae and the novel anti-inflammatory and immunomodulatory agent Paeoniflorin-6'-O-benzenesulfonate (CP-25) in various chronic inflammatory and autoimmune disorders. The regulatory effects of Pae and CP-25 make them promising agents for other related diseases, which require extensive investigation in the future.
Abstract The high‐temperature stress gene GrpE plays an important role in coping with high‐temperature stress. The mutation of key sites of this gene can improve the high‐temperature resistance of organisms. In the present study, using complementary DNAs from the silkworm fat body as the template, the open reading frame sequence of the GrpE gene ( BmGrpE ) was amplified and was found to be 644 bp in length and encode a protein with a predicted molecular weight of 24.1 kDa. The presence of a binding site for the heat shock transcription factor (Hsf1) at −1440 bp upstream of its coding region indicates that BmGrpE may respond to high‐temperature stress. BmGrpE was constitutively expressed throughout developmental stages, with the highest level observed in the 5th instar larvae stage. Moreover, in 5th instar larvae (the 3th day), BmGrpE was expressed in all tissues examined, with the highest levels in the fat body, silk gland, and midgut. Interestingly, under high‐temperature stress, TiO 2 nanoparticle treatment increased the messenger RNA levels of BmGrpE in the fat body and silk gland. After treatment with dsRNA of BmGrpE , the cell viability of BmN cells was significantly decreased under 34°C and H 2 O 2 stress ( p < .05). Mutation of BmGrpE (H163L) enhanced the resistance of BmN cells under high‐temperature stress. These results provide new clues for the study of molecular mechanisms of insect resistance to high temperatures.
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Abstract The global warming has affected the growth, development and reproduction of insects. However, the molecular mechanism of high temperature stress-mediated metamorphosis regulation of lepidopteran insect has not been elucidated. In this study, the relationship between the insect developmental process and endogenous hormone level was investigated under high temperature (36 ° C) stress in Bombyx mori ( B. mori ). The results showed that the duration of 5 th instar larvae were shortened by 28 ± 2 h, and the content of 20E was up-regulated significantly after 72 h of high temperature treatment, while the transcription levels of 20E response genes E93, Br-C, USP, E75 were up-regulated 1.35, 1.25, 1.28, and 1.27-fold, respectively. The high temperature treatment promoted the phosphorylation level of Akt and the downstream BmCncC/keap1 pathway was activated, the transcription levels of 20E synthesis-related genes cyp302a1, cyp306a1, cyp314a1 and cyp315a1 were up-regulated by 1.12, 1.51, 2.17 and 1.23-fold, respectively. After treatment with double stranded RNA of BmCncC (dsBmCncC) in BmN cells, the transcription levels of cyp302a1 and cyp306a1 were significantly decreased, whereas up-regulated by 2.15 and 1.31-fold, respectively, after treatment with CncC activator Curcumin. These results suggested that BmCncC/keap1-mediated P450 genes ( cyp302a1, cyp306a1 ) expression resulted in the changes of endogenous hormone level, which played an important role in the regulation of metamorphosis under high temperature stress. Studies provide novel clues for understanding the CncC/keap1 pathway-mediated metamorphosis regulation mechanism in insects. Author Summary Mammalian nuclear transcription factor Nrf2 (NF-E2-related factor 2) plays an important role in the stress response of cells. CncC is a homolog of mammalian Nrf2 in insect, regulating the genes expression of insect antioxidant enzymes and cytochrome P450 detoxification enzyme. Evidence suggests that the CncC/Keap1 pathway also plays an important role in regulating insect development. Here, we investigated the regulatory mechanism between the CncC/Keap1 pathway and metabolism of silkworm hormones in Lepidoptera. We found that high temperature induction accelerated the development of silkworm, the ecdysone content and related metabolic genes in hemolymph were significantly up-regulated, the CncC/Keap1 pathway was activated, and the expression of BmCncC was significantly increased, indicating that the Cncc/Keap1 pathway plays an important role in this process. The expression of cyp302a1 and cyp306a1 was significantly decreased by RNA interference with BmCncC , which indicated that CncC in silkworm had a regulatory relationship with downstream 20E synthetic gene. In summary, the results indicate that the CncC/Keap1 pathway plays an important role in regulating hormone metabolism in silkworm, providing a basis for further study of the relationship between CncC/Keap1 pathway and development in insects.
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