The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang ...(L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3–5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.
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•L. casei Zhang improves renal function and pathology in mouse models of AKI and CKD•L. casei Zhang ameliorates gut microbial dysbiosis in both AKI and CKD•L. casei Zhang reduces renal inflammation and damage via SCFAs and nicotinamide•L. casei Zhang slows the decline of kidney function in individuals with stage 3–5 CKD
Zhu et al. demonstrate that the probiotic L. casei Zhang slows kidney disease progression in mouse models and individuals with chronic kidney disease (CKD) through increasing the levels of short-chain fatty acids and via nicotinamide metabolism, which together modulate the inflammatory response of local macrophages and tubular epithelia cells. These findings suggest a potential therapeutic approach for acute kidney injury and CKD.
Chronic lead (Pb) exposure causes cognitive deficits. This study aimed to explore the neuroprotective effect and mechanism of β-asarone, an active component from Chinese Herbs Acorus tatarinowii ...Schott, to alleviate impairments of spatial memory and synaptogenesis in Pb-exposed rats. Both Sprague-Dawley developmental rat pups and adult rats were used in the study. Developmental rat pups were exposed to Pb throughout the lactation period and β-asarone (10, 40mg kg-1, respectively) was given intraperitoneally from postnatal day 14 to 21. Also, the adult rats were exposed to Pb from embryo stage to 11 weeks old and β-asarone (2.5, 10, 40mg kg-1, respectively) was given from 9 to 11 weeks old. The level of β-asarone in brain tissue was measured by High Performance Liquid Chromatography. The Morris water maze test and Golgi-Cox staining method were used to assess spatial memory ability and synaptogenesis. The protein expression of NR2B subunit of NMDA receptor, Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and Wnt family member 7A (Wnt7a) in hippocampus, as well as mRNA expression of Arc/Arg3.1 and Wnt7a, was also explored. We found that β-asarone could pass through the blood brain barrier quickly. And β-asarone effectively attenuated Pb-induced reduction of spine density in hippocampal CA1 and dentate gyrus areas in a dose-dependent manner both in developmental and adult rats, meanwhile the Pb-induced impairments of learning and memory were partially rescued. In addition, β-asarone effectively up-regulated the protein expression of NR2B, Arc and Wnt7a, as well as the mRNA levels of Arc/Arg3.1 and Wnt7a, which had been suppressed by Pb exposure. The results suggest the neuroprotective properties of β-asarone against Pb-induced memory impairments, and the effect is possibly through the regulation of synaptogenesis, which is mediated via Arc/Arg3.1 and Wnt pathway.
Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining ...proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.Graphic abstract
Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by the intake of pyrrolizidine alkaloids (PAs). To date, PAs-induced HSOS has not been extensively studied. In view of the difference in ...etiology of HSOS between the West and China, clinical profiles, imaging findings, treatment, and outcomes of HSOS associated with hematopoietic stem cell transplantation or oxaliplatin might be hardly extrapolated to PAs-induced HSOS. Reactive metabolites derived from PAs form pyrrole-protein adducts that result in toxic destruction of hepatic sinusoidal endothelial cells. PAs-induced HSOS typically manifests as painful hepatomegaly, ascites, and jaundice. Laboratory tests revealed abnormal liver function tests were observed in most of the patients with PAs-induced HSOS. In addition, contrast computed tomography and magnetic resonance imaging scan show that patients with PAs-induced HSOS have distinct imaging features, which reveal that radiological imaging provides an effective noninvasive method for the diagnosis of PAs-induced HSOS. Liver biopsy and histological examination showed that PAs-induced HSOS displayed distinct features in acute and chronic stages. Therapeutic strategies for PAs-induced HSOS include rigorous fluid management, anticoagulant therapy, glucocorticoids, transjugular intrahepatic portosystemic shunt, liver transplantation,
. The aim of this review is to describe the pathogenesis, clinical profiles, diagnostic criteria, treatment, and outcomes of PAs-induced HSOS.
Abstract
Inherited retinal degenerations (IRDs) are a group of untreatable and commonly blinding diseases characterized by progressive photoreceptor loss. IRD pathology has been linked to an ...excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na
+
- and Ca
2+
-influx, subsequent activation of voltage-gated Ca
2+
-channels (VGCC), and further Ca
2+
influx. However, a connection between excessive Ca
2+
influx and photoreceptor loss has yet to be proven.
Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the
rd1
mouse model for IRD and wild-type (
wt
) mice. Differentially expressed genes indicated links to several Ca
2+
-signalling related pathways. To explore these,
rd1
and
wt
organotypic retinal explant cultures were treated with the intracellular Ca
2+
-chelator BAPTA-AM or inhibitors of different Ca
2+
-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca
2+
-release-activated channel (CRAC), and Na
+
/Ca
2+
exchanger (NCX). Moreover, we employed the novel compound NA-184 to selectively inhibit the Ca
2+
-dependent protease calpain-2. Effects on the retinal activity of poly(ADP-ribose) polymerase (PARP), sirtuin-type histone-deacetylase, calpains, as well as on activation of calpain-1, and − 2 were monitored, cell death was assessed
via
the TUNEL assay.
While
rd1
photoreceptor cell death was reduced by BAPTA-AM, Ca
2+
-channel blockers had divergent effects: While inhibition of T-type VGCC and NCX promoted survival, blocking CNGCs and CRACs did not. The treatment-related activity patterns of calpains and PARPs corresponded to the extent of cell death. Remarkably, sirtuin activity and calpain-1 activation were linked to photoreceptor protection, while calpain-2 activity was related to degeneration. In support of this finding, the calpain-2 inhibitor NA-184 protected
rd1
photoreceptors.
These results suggest that Ca
2+
overload in
rd1
photoreceptors may be triggered by T-type VGCCs and NCX. High Ca
2+
-levels likely suppress protective activity of calpain-1 and promote retinal degeneration via activation of calpain-2. Overall, our study details the complexity of Ca
2+
-signalling in photoreceptors and emphasizes the importance of targeting degenerative processes specifically to achieve a therapeutic benefit for IRDs.
Conflict and Identity Qian, Yang
Asian perspectives (Honolulu),
01/2019, Volume:
58, Issue:
2
Journal Article
Peer reviewed
This article examines the rituals involved in wall construction in the Neolithic and Early Bronze Age of China. Since the building of a settlement wall required the involvement of most of the ...residents and the settlement gate was used as a public place, such rituals were probably conducted in public without any restrictions on the participants. During the Longshan period, when early states first formed in China, these ritual activities became increasingly elaborate and more humans were sacrificed. The people who were sacrificed were probably captives caught during warfare. Sacrificing enemies in public rituals can reinforce ethnic identity, which is conducive to the ideological formation of an early state.
Abstract
Essential cellular functions require efficient production of many large proteins but synthesis of large proteins encounters many obstacles in cells. Translational control is mostly known to ...be regulated at the initiation step. Whether translation elongation process can feedback to regulate initiation efficiency is unclear. Codon usage bias, a universal feature of all genomes, plays an important role in determining gene expression levels. Here, we discovered that there is a conserved but codon usage-dependent genome-wide negative correlation between protein abundance and CDS length. The codon usage effects on protein expression and ribosome flux on mRNAs are influenced by CDS length; optimal codon usage preferentially promotes production of large proteins. Translation of mRNAs with long CDS and non-optimal codon usage preferentially induces phosphorylation of initiation factor eIF2α, which inhibits translation initiation efficiency. Deletion of the eIF2α kinase CPC-3 (GCN2 homolog) in Neurospora preferentially up-regulates large proteins encoded by non-optimal codons. Surprisingly, CPC-3 also inhibits translation elongation rate in a codon usage and CDS length-dependent manner, resulting in slow elongation rates for long CDS mRNAs. Together, these results revealed a codon usage and CDS length-dependent feedback mechanism from translation elongation to regulate both translation initiation and elongation kinetics.
Graphical Abstract
Graphical Abstract
The mechanism of translation elongation feeding back to regulate translation initiation and elongation speed in a codon usage and CDS length-dependent manner. Rare codons cause ribosome pausing during elongation, resulting in CPC-3 activation and phosphorylation of eIF2a in a codon usage-and CDS length-dependent manner. Phosphorylated eIF2a inhibits translation initiation. In addition, CPC-3 also regulates translation elongation speed in a codon usage and CDS length-dependent manner.
Supported liquid membranes (SLM) are studied in various fields like analytical, inorganic and organic chemistry, chemical engineering, biotechnology and biomedical engineering. This technique offers ...the advantages of active transport, possible usage of expensive carriers, high selectivity, easy scale-up, low energy requirements, low capital and operating costs, etc. This paper gives a brief overview of mechanism and kinetic studies of SLM based separations. The problems with stability and possible applications of SLM are also reviewed.
Herein, a novel strategy was explored to enhance the photocatalytic activity of graphitic carbon nitride (g-C3N4, GCN) by modulating its molecular structure, which involved modifying supramolecular ...precursor by molecular engineering, followed by pyrolysis. Specifically, 1-amino-2-propanol (monoisopropanolamine, MIPA), a substance that carries both –NH2 and –OH, was introduced into the system of hydrothermally treating dicyandiamide (DCDA). The precursors obtained at the MIPA volume concentration of more than 0.5% display hexagonal prisms, and then transform into the ethyl grafted GCN with a tubular-like morphology, abundant pores and enlarged specific surface area. Besides the intrinsic band absorption, the obtained GCN exhibit an enhanced visible light absorption in the region between 450 and 560 nm, owing to the existence of a midgap state related to the ethyl grafting. A much reduction in charge recombination is observed for the ethyl-grafted GCN, originated from its spatial separation between LUMO and HOMO. Consequently, the hydrogen evolution rate of the GCN sample, obtained at the optimal concentration of MIPA, is 13.84 mmol/h/g (AQE = 18.25% at 420 nm), about 30.1 times higher than that of the bulk C3N4 (BCN) under visible light (λ > 420) irradiation. This work sheds light on modulating GCN by molecular engineering of supramolecular precursors.
Employing 1-amino-2-propanol, a substance that carries both –NH2 and –OH, to modify the structure and morphology of supramolecular precursor, thus producing tubular-like g-C3N4 with greatly enhanced photocatalytic hydrogen evolution. Display omitted
•1-amino-2-propanol (MIPA) was employed to modulate supramolecular precursor.•MIPA could be implanted into the structure of supramolecular precursor.•The resultant GCN exhibited enhanced visible light absorption.•An obvious reduction in charge recombination was also observed.•The photocatalytic hydrogen evolution was dramatically increased.
SHMT2 was overexpressed in many tumors, however, the role of SHMT2 in bladder cancer (BLCA) remains unclear. We first analyzed the expression pattern of SHMT2 in BLCA using the TNMplot, Oncomine, the ...Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases. Next, the association between SHMT2 expression and overall survival (OS)/disease-free survival (DFS) in BLCA patients were analyzed using TCGA and PrognoScan database. The correlation between SHMT2 expression and clinicopathology was determined using TCGA database. Furthermore, the genes co-expressed with SHMT2 and their underlying molecular function in BLCA were explored based on the Oncomine database, Metascape and gene set enrichment analysis (GSEA). Finally, the effects of SHMT2 on cell proliferation, cell cycle, and apoptosis were assessed using
in vitro
experiments. As a results, SHMT2 was significantly overexpressed in BLCA tissues and cells compared to normal bladder tissues and cells. A high SHMT2 expression predicts a poor OS of BLCA patients. In addition, SHMT2 expression was higher in patients with a high tumor grade and in those who were older than 60 years. However, the expression of SHMT2 was not correlated with gender, tumor stage, lymph node stage, and distant metastasis stage. Finally, overexpression of SHMT2 promoted BLCA cell proliferation and suppressed apoptosis, the silencing of SHMT2 significantly inhibited BLCA cell proliferation by impairing the cell cycle, and promoting apoptosis. SHMT2 mediates BLCA cells growth by regulating STAT3 signaling. In summary, SHMT2 regulates the proliferation, cell cycle and apoptosis of BLCA cells, and may act as a candidate therapeutic target for BLCA.
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