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Receptor Interacting Protein Kinase 1 (RIPK1) and RIPK3 are key adaptors that play critical roles in inflammatory and cell death signaling. Work in recent years have shown that their activities are tightly regulated by ubiquitination, phosphorylation and proteolysis. In addition to these post-translational modifications, the expression and activities of these kinases can further be tuned by environmental changes in pH and oxygen content. Proper control of these regulatory processes is crucial for the RIP kinases to execute their functions in immune responses and tissue homeostasis. In this review, we discuss recent advance in our understanding of the molecular mechanisms that regulate the activities of the RIP kinases. We will also discuss how the different regulatory mechanisms contribute to the functions of RIPK1 and RIPK3 in different pathophysiological settings. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) contamination in wheat fields has become a major environmental issue in many regions of the world. Mercapto-palygorskite (MPAL) is a high-performance amendment that can effectively immobilize Cd in alkaline wheat soil. However, MAPL as an in-situ Cd immobilization strategy for alkaline wheat soil remains to be evaluated on a field-scale and the underlying mechanisms requires further evaluation. Here, MPAL were used as soil amendment to evaluate their immobilization efficiency on Cd-contaminated alkaline soil in the field experiments. The field experiments showed that MPAL application significantly reduced wheat grain Cd concentration from 0.183 mg/kg to 0.056 mg/kg, with Cd concentration in wheat grain treated with MPAL all falling below the limit value of 0.1 mg/kg as defined in China's food safety standard (GB 2762–2022). The maximal immobilization efficiency of MPAL on soil Cd figured out by diethylenetriaminepentaacetic acid (DTPA) extraction was 61.5%. The mechanisms involved in Cd immobilization by MPAL were mainly related to the enhanced sorption of Cd onto Fe oxides, and the removal of amorphous or free Fe oxides from soil had a substantial impact on Cd immobilization efficiency by MPAL. Furthermore, the antagonistic effect between Mn and Cd uptake may also contribute to the reduction of wheat Cd accumulation after MPAL application. The current research can provide theoretical and technical support for the large-scale application of MPAL in Cd-contaminated wheat fields. [Display omitted] • MPAL demonstrated great immobilization efficiency on Cd-contaminated alkaline soil under field conditions. • Wheat grain Cd with MPAL treatment met the national standard. • MPAL significantly increased soil-available Mn and Mn concentration in wheat plants • MPAL enhanced the sorption of soil Cd onto Fe oxides. [ABSTRACT FROM AUTHOR]

Abstract: Cases of pet poisoning and infant renal calculus have attracted much attention to the toxicity of melamine and its derivatives, such as cyanuric acid. Although individually melamine and cyanuric acid have low toxicity, their simultaneous presence can cause severe damage. Little is known about their adverse effects on the reproductive system. In this study, mice were orally administrated 1, 5 or 25mg/kg/d of both melamine and cyanuric acid for 13weeks. Lethargy, rough hair, and reduction of food and water intake and of body and testis weight were found after exposure to the combination, and pathological changes were found in the morphology of the testes, such as disruption of the seminiferous tubule structure, decrease of the spermatogenic cell series and coagulation necrosis. Total antioxidant capacity and superoxide dismutase activities and glutathione concentration was lower and malondialdehyde concentration was higher than in control mice. The activities of malate dehydrogenase, lactate dehydrogenase and Na+/K+-ATPase were also lower in combination treated mice than in control mice. These results indicate that the combined exposure to both melamine and cyanuric acid damaged testes in mice by either a direct or indirect effect, which may be related to renal failure and secondary anorexia. Oxidative stress and lower energy production levels both contributed to the testicular damage. [Copyright &y& Elsevier]

Abstract: A nonautonomous n-species Lotka–Volterra system with neutral delays is investigated. A set of verifiable sufficient conditions is derived for the existence of at least one strictly positive periodic solution of this Lotka–Volterra system by applying an existence theorem and some analysis techniques, where the assumptions of the existence theorem are different from that of Gaines and Mawhin''s continuation theorem [R.E. Gaines, J.L. Mawhin, Coincidence Degree and Nonlinear Differential Equations, Springer-Verlag, Berlin, 1977] and that of abstract continuation theory for k-set contraction [W. Petryshyn, Z. Yu, Existence theorem for periodic solutions of higher order nonlinear periodic boundary value problems, Nonlinear Anal. 6 (1982) 943–969]. Moreover, a problem proposed by Freedman and Wu [H.I. Freedman, J. Wu, Periodic solution of single species models with periodic delay, SIAM J. Math. Anal. 23 (1992) 689–701] is answered. [Copyright &y& Elsevier]

In this paper we study the existence of positive periodic solutions for a class of neutral type competitive system with delay. Applying the continuation theorem of coincidence degree theory, a general criteria on the existence of positive periodic solutions are established. Some the related results are generalized and improved. It is shown that the arguments delays have no effect on the existence positive periodic solution of system. [Copyright &y& Elsevier]

Difenoconazole (DIF) is frequently used for the management of fungal infections in fruit and vegetables and excessive residues in the aquatic environment can have adverse effects on fish such as growth inhibition. A treatment based on the dietary additive quercetin (QUE) is a promising approach to positively regulate the state of fish growth. This study focused on whether and how QUE alleviated DIF-induced growth inhibition in fish. In this study, carp were exposed to DIF (0.3906 mg/L) for consecutive 30 d, which showed growth inhibition. Disruption of the intestinal barrier led to elevated levels of intestinal lipopolysaccharide (LPS) and an inflammatory response. Through the intestinal-brain axis, LPS entered the brain where it disrupted the blood-brain barrier, triggered neuroinflammation, caused brain cell apoptosis, and damaged nerves in addition to other things. The dietary supplementation of QUE (400 mg/kg) reduced the levels of LPS in the intestinal and brain, while reducing inflammation and increasing the expression of appetite factors, thereby reducing growth inhibition in carp. This work provided evidence for QUE from the intestinal-brain axis perspective as a potential candidate for alleviating growth inhibition in fish. [Display omitted] • QUE alleviated growth inhibition of carp induced by DIF via the intestine-brain axis. • QUE alleviated brain and intestinal damage induced by DIF in carp. • QUE decreased the increase of LPS induced by DIF the brain and intestine of carp. • QUE alleviated brain and intestinal inflammation induced by DIF in carp. [ABSTRACT FROM AUTHOR]

[Display omitted] • Five pairs of novel merosesquiterpenoid enantiomers were isolated and identified. • Dauresorcinol A (1) possesses an unprecedented methyl-shifted merosesquiterpenoid carbon skeleton. • Dauresorcinol B (2) bears a novel caged merosesquiterpenoid carbon skeleton. • (+)/(−)- 1 and 3 − 5 showed more potent α -glucosidase inhibitory activity than acarbose. • The structure−activity relationships of isolates were discussed. Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A−E (1 − 5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh 2 (OCOCF 3) 4 -induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1 − 5 are proposed involving key oxa-electrocyclization and Wagner−Meerwein rearrangement reactions. (+)/(−)- 1 and 3 − 5 showed potent α -glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α -glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α -glycosidase inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Z-GP-Pcb has been designed and synthesized with an overall yield of 32.7%. • Z-GP-Pcb targets to FAPα. • Z-GP-Pcb shows less spermatoxicity than Pcb. • Z-GP-Pcb demonstrates less myelosuppression than Pcb. Abstract Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or β position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb. [ABSTRACT FROM AUTHOR]

As a special type of glaucoma, Posner-Schlossman syndrome (PSS) is characterized by elevated intraocular pressure (IOP) and anterior uveitis. Cytomegalovirus (CMV) anterior chamber infection has now been considered the leading cause of PSS. We used murine CMV (MCMV) intracameral injection to establish a rat model manifested in IOP elevation and mild anterior uveitis, much like PSS; viral localization and gene expression at various time points and inflammatory cell infiltration derived from innate and adaptive immunity were investigated, as well as pathogenetic changes of the trabecular meshwork (TM). The IOP and uveitic manifestations peaked at 24 h post-infection (p.i.) and returned to normal after 96 h; the iridocorneal angle remained open consistently. At 24 h p.i., leucocytes gathered at the chamber angle. Maximum transcription of MCMV immediate early 1 (IE1) was reached at 24 h in the cornea and 48 h in the iris and ciliary body. MCMV localized in aqueous humor outflow facilities and the iris from 24 h to 28 d p.i. and was detected by in situ hybridization, though it did not transcribe after 7 d p.i. TM and iris pigment epithelial cells harboring viral inclusion bodies and autophagosomes were present at 28 d p.i. These findings shed light on how and where innate and adaptive immunity reacted after MCMV was found and transcribed in a highly ordered cascade, as well as pathogenetic changes in TM as a result of virus and uveitis behaviors. • Clinical manifestations similar to PSS are present in the rat model infected with intracameral MCMV. • MCMV localizes in trabecular meshwork, iris and ciliary body and no productive infection was observed after acute infection. • MCMV transcribes in a highly ordered cascade of IE1, E1 and gB in cornea and aqueous humor outflow facilitiesafter entry. • Long-lasting CD8+ T cell responses infiltrate iridocorneal angle and form keratic precipitates after acute phase. • Trabecular cells are impaired morphologically during acute infection and recover cellularity on trabecular beams afterwards. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new series of 5F -like ARIs with molecular diversity has been designed and synthesized. 4b was the best ARI. • The inhibition to ALR2 is closely correlated with the length and rigidity of the spacer. • 5F -like ARIs adopt dual-occupied binding mode to ALR2. • Docking studies and molecular simulation well explore the structure–activity relationship. • Pharmacophore model has been set up for 5F -type ARI. The primary objective of this study was to investigate the structure–activity relationship of a new series of 5F -like Aldose Reductase Inhibitors (ARIs) using in silico docking method. In this perspective, 6 novel ARIs have been designed and synthesized. Evaluation of the inhibition of these compounds to ALR2 was carried on with epalrestat and 5F as the references. It was found that the spacer of 5F -like ARIs has a great influence on their inhibitory activity. Rigid spacer with length equal to 3 ∼ 4 carbon alkyl chain brings about better inhibitory activity. Among them, compound 4b was verified as the most active ARIs, where its IC 50 value was 16.8 ± 1.3 nM. Furthermore, in silico docking studies using AutoDock 4.2 as well as molecular simulation using GROMACS 2022.1 showed that 5F -like ARIs adopt a dual-occupation mode. The interaction energy (−25 to −74 kcal/mol), as well as MM-GBSA binding free energy (−37 to −65 kcal/mol) was positively correlated with their ALR2 inhibition constant (2000 to 16.8 nM). Docking interaction explained well the structure–activity relationship. A pharmacophore model has been set up for 5F -like ARIs thereafter. This model indicates that as an effective ARI, the entity should have four characteristics: an aromatic center, two hydrogen bond donors, and one hydrogen bond acceptor. By the way, all the 5F -like ARIs reported here are good to mild antioxidant with EC 50 value between 13.6 ± 1.2 and 71.1 ± 3.2 μM. All our data direct the further development of more optimal ARIs for the treatment of diabetic complication in the future. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been suggested to play critical roles in skeletal muscle in response to exercise. Previous study has shown that miR-761 was involved in a novel model regulating the mitochondrial network. However, its role in mitochondrial biogenesis remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-761 on mitochondrial biogenesis in skeletal muscle. Real-time quantitative PCR analysis demonstrated that aberrantly expressed miR-761 is involved in exercise activity and miR-761 is decreased by exercise training compared with the sedentary control mice. miR-761 suppresses mitochondrial biogenesis of C 2 C 12 myocytes by targeting the 3′-UTR of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 (PGC-1α). Overexpression of miR-761 was capable of inhibiting the protein expression levels of PGC-1α. Moreover, miR-761 overexpression suppressed the p38 MAPK signaling pathway and down-regulated the expression of phosphorylated MAPK-activated protein kinase-2 (P-MK2), a downstream kinase of p38 MAPK. The phosphorylation of activating transcription factors 2 (ATF2) that plays a functional role in linking the activation of the p38 MAPK pathway to enhanced transcription of the PGC-1α was also inhibited by the overexpression of miR-761. These findings revealed a novel regulation mechanism for miR-761 in skeletal myocytes, and contributed to a better understanding of the modulation of skeletal muscle in response to exercise. [ABSTRACT FROM AUTHOR]

Abstract: Using mtDNA sequencing and allozyme electrophoresis data, we tested the “vicariance followed by dispersal” hypothesis of the Bufo gargarizans species group and re-evaluated the species status in the general lineages species concept. A phylogenetic analysis suggested that dispersal, instead of vicariance, dominated the history of the species group. There was a general trend of west to east dispersal, while some lineages from the east subsequently returned to the west. The secondary admixture of those previously allopatric lineages produced substantial levels of sympatric genetic diversity, often as high as 7.0% pairwise difference within populations. The phylogenetic hypothesis does not support the current two species designation. Neither B. andrewsi nor B. gargarizans represents an independent evolutionary lineage, and monophyletic groups did not correspond to geographically discrete groups. Allozyme data also failed to reveal any fixed allelic difference among the populations. Therefore, we recommend regarding the complex as a single species, Bufo gargarizans, without subspecies division. [Copyright &y& Elsevier]

ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10. Proposed mechanism of CP55 in inhibiting the multidrug resistance mediated by ABCC10 in cancer cells. [Display omitted] • Multidrug resistance (MDR) in cancer is one of the major obstacles in chemotherapy. • ABCC10 mediates resistance to wide spectrum of chemotherapeutic agents, but only limited number of studies are available. • Overexpression of ABCC10 has been linked to various types of cancers including colorectal, gastric and lung cancer. • CP55 is a potent ABCC10 inhibitor which enhances the anticancer drug sensitivity in ABCC10-overexpression MDR cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Conjugation of GABA make 5b more active anti-depressant. • 5b was a better modulator on programmed cell apoptosis than DHA. • 5b was able to modulate Akt, while DHA could not. • 5b maintained activity to induce neurite outgrowth and cell differentiation. Three hybrids of dihydro-artemisinin (DHA) with β-aminopropionic acid, γ-aminobutyric acid, and histamine have been designed and synthesized. The conjugate of DHA with GABA labelled as 5b was confirmed the most active candidate against both Cort- and SNP-induced PC12 cell impairments with EC 50 value of 8.04 ± 0.35, and 9.38 ± 0.56 μM, respectively. 5b was clearly highlighted as a good modulator on protein expression of Akt, Bcl-2, and Bax, indicating its functions against programmed cell apoptosis. 5b significantly reversed the Cort-induced excessive calcium influx and release from internal organelles. It was demonstrated the ability to express increased levels of β-tubulin III and to up-regulate phosphorylation level of cAMP response element-binding protein (CREB), leading to cell differentiation. It can penetrate blood − brain barrier (BBB) with propriate stability. Altogether, these data strongly support that 5b is a potential anti-depressant. [ABSTRACT FROM AUTHOR]

• Phosphorylation of RssB happens on the interface thus weakens the interaction σS. • IraD interacts with the RssB at higher affinity regardless of phosphorylation. • A new two-tier mechanism for controlled proteolysis of σS is proposed. RssB is fully activated during logarithmic growth, promoting σS degradation. Phosphorylation on D58 partially switches the degradation off as the phosphorylation reduces RssB affinity for σS. The binding of anti-adaptor protein IraD to RssB prevents any RssB- σS interaction and shuts off σS degradation completely. Regulation of bacterial stress responding σS is a sophisticated process and mediated by multiple interacting partners. Controlled proteolysis of σS is regulated by RssB which maintains minimal level of σS during exponential growth but then elevates σS level while facing stresses. Bacteria developed different strategies to regulate activity of RssB, including phosphorylation of itself and production of anti-adaptors. However, the function of phosphorylation is controversial and the mechanism of anti-adaptors preventing RssB-σS interaction remains elusive. Here, we demonstrated the impact of phosphorylation on the activity of RssB and built the RssB-σS complex model. Importantly, we showed that the phosphorylation site - D58 is at the interface of RssB-σS complex. Hence, mutation or phosphorylation of D58 would weaken the interaction of RssB with σS. We found that the anti-adaptor protein IraD has higher affinity than σS to RssB and its binding interface on RssB overlaps with that for σS. And IraD-RssB complex is preferred over RssB-σS in solution, regardless of the phosphorylation state of RssB. Our study suggests that RssB possesses a two-tier mechanism for regulating σS. First, phosphorylation of RssB provides a moderate and reversible tempering of its activity, followed by a specific and robust inhibition via the anti-adaptor interaction. [ABSTRACT FROM AUTHOR]

NDM-1-producing Enterobacteriaceae are multidrug-resistant bacteria, also called superbacteria, that have become important global human health threats in recent years. However, data about NDM-1-producing bacteria in animals are rare. In this study, an NDM-1-producing Escherichia coli isolate (designated E120413) was obtained from pigs in Henan province, China in 2012. The susceptibility of E. coli E120413 to antimicrobial agents was determined using Kirby-Bauer disk diffusion and micro-dilution methods. Susceptibility tests indicated that E. coli E120413 was resistant to almost all common antibiotics with high MIC values obtained for most antibiotics tested. E. coli E120413 was detected in the heart, liver, spleen, lung, kidney, brain, stomach, duodenum, mesenteric lymph nodes, and fecal samples of piglets in both cohabitation and experimental groups and the bacteria persisted for more than 2 weeks. However, no obvious clinical symptoms or serious pathological lesions were observed. This is the first investigation of NDM-1-producing E. coli isolate from pigs in China. Although no significant pathological lesions were observed, NDM-1-producing E. coli was found to be highly transmissible and to cause persistent infection in pigs. • First investigation of NDM-1-producing E. coli isolate from pigs in China. • NDM-1-producing E. coli persisted for more than 2 weeks in piglets. • No significant pathological lesions were observed in piglets infected with NDM-1-producing E. coli. [ABSTRACT FROM AUTHOR]