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Gap junction channels in cumulus–oocyte complexes (COCs) enable the transmission and communication of small molecular signals between adjacent cells, such as cAMP. However, the regulation of gap junction function (GJF) by cAMP and the underlying mechanisms involved are not fully clarified. This study investigated the effect of cAMP on connexin 43 (CX43) expression and GJF in ovine COCs using immunofluorescence , quantitative real-time PCR (qRT-PCR), western blotting, and GJF detection. The CX 43 was only found in the cumulus cells (CCs) side of ovine COC. The intra-oocyte cAMP sh owed a significant increase at 30 min, while the intra-CC cAMP exhibited two peaks at 10 min and 1 h during in vitro maturation (IVM). Phosphorylated CX43 protein exhibited an immediate increase at 10 min, and CX43 protein displayed two peaks at 10 min and 1 h during IVM. The duration of pre- IVM exposure to forskolin and IBMX significantly enhanced phosphorylated and total CX43, as well as Gja1 and Creb genes, for 10 min; these effects were counteracted by Rp-cAMP. Both pre-IVM with forskolin and IBMX for 1 h and the GJF and CX43/p-CX43 ratio were elevated. The closure of gap junction channels caused by phosphorylated CX43 to prevent cAMP outflow from oocytes in early IVM of COC. Cyclic AMP upregulated phosphorylated and total CX43 via genomic and non-genomic pathways, but its functional regulation was dependent on the balance of the two proteins. This study provides a new insight into the regulatory mechanism between cAMP and GJF, which would improve IVM in animal and clinical research.

Abstract Extensive investigations in outer space have revealed not only how life adapts to the space environment, but also that interesting biophysical phenomena occur. These phenomena affect human health and other life forms (animals, plants, bacteria, and fungi), and to ensure the safety of future human space exploration need to be further investigated. This calls for joint research efforts between biologists and physicists, as these phenomena present cross-disciplinary barriers. Various national organizations provide useful forums for bridging this gap. Additional discussion avenues and database resources are helpful for facilitating the interdisciplinary investigations of these phenomena. In this paper, we present the newly established Space Life Investigation Database (SpaceLID, https://bidd.group/spacelid/ ) which provides information about biophysical phenomena occurring in space. Examples obtained using the database are given while discussing the underlying causes of these phenomena and their implications for the physiology and health of life in space.

Zizyphus jujuba Mill is a typical food-medicine homology in China, and the adage of “three jujubes a day, longevity” highlights its potential antiaging properties. However, its antiaging effect and mechanism have been poorly explored. In this study, Caenorhabditis elegans was utilized to investigate the antiaging effects and underlying mechanisms of the active components of jujube water extract (ZJME). We discovered that ZJME is rich in polysaccharides (264.15 mg/g), polyphenols (9.29 mg/g), cAMP and other components with antioxidant effects. ZJME significantly prolonged the average and maximum lifespan (31 % and 14 %) of nematodes under oxidative stress conditions. ZJME reduced the release of ROS and RNS by 44 % and 22 %, and increased the activity of the antioxidant enzymes SOD by 18 % (P

Gap junctional connection (GJC) in the cumulus–oocyte complex (COC) provides necessary support for message communication and nutrient transmission required for mammalian oocyte maturation. Cyclic adenosine monophosphate (cAMP) is not only a prerequisite for regulating oocyte meiosis, but also the key intercellular factor for affecting GJC function in COCs. However, there are no reports on whether cAMP regulates connexin 37 (Cx37) expression, one of the main connexin proteins, in sheep COCs. In this study, the expression of Cx37 protein and gene in immature sheep COC was detected using immunohistochemistry and PCR. Subsequently, the effect of cAMP on Cx37 expression in sheep COCs cultured in a gonadotropin-free culture system for 10 min or 60 min was evaluated using competitive ELISA, real-time fluorescent quantitative PCR (RT-qPCR), and Western blot. The results showed that the Cx37 protein was present in sheep oocytes and cumulus cells; the same results were found with respect to GJA4 gene expression. In the gonadotropin-free culture system, compared to the control, significantly higher levels of cAMP as well as Cx37 gene and protein expression were found in sheep COCs following treatment in vitro with Forskolin and IBMX (100 μM and 500 μM)) for 10 min (p < 0.05). Compared to the controls (at 10 or 60 min), cAMP levels in sheep COCs were significantly elevated as a result of Forskolin and IBMX treatment (p < 0.05). Following culturing in vitro for 10 min or 60 min, Forskolin and IBMX treatment can significantly promote Cx37 expression in sheep COCs (p < 0.05), a phenomenon which can be counteracted when the culture media is supplemented with RP-cAMP, a cAMP-specific competitive inhibitor operating through suppression of the protein kinase A (PKA). In summary, this study reports the preliminary regulatory mechanism of cAMP involved in Cx37 expression for the first time, and provides a novel explanation for the interaction between cAMP and GJC communication during sheep COC culturing in vitro.

Jujube is a plant native to China that could be used in medicine and food. Its dried fruit is a superior herb commonly used in traditional Chinese medicine formulations for its calming effect and for nourishing the blood and strengthening the spleen and stomach. Jujube contains numerous active components including polysaccharides, phenols, and triterpene acids, which show a diverse array of pharmacological activities such as neuroprotection and the prevention and treatment of cardiovascular diseases. In this paper, the research status of jujube over the past two decades has been statistically evaluated. Meanwhile, by tracking the latest research advances, the pharmacological efficacy and molecular mechanisms of jujube are exhaustively expounded to provide specific and systematic references for further research on the pharmacological effects of jujube and its application in the food and pharmaceutical industries.

Summary: Development of highly efficient and practical chiral ligands and catalysts is an eternal theme in asymmetric synthesis. Here, we report the design, synthesis, and evaluation of a new kind of adjustable axially chiral biphenyl ligands and catalysts, in which six model reactions including asymmetric additions of diethylzinc or alkynes to aldehydes in the presence of axially chiral [1,1′-biphenyl]-2,2′-diol ligands, palladium-catalyzed asymmetric cycloadditions in the presence of phosphoramidite ligands, and chiral phosphoric acid-catalyzed asymmetric synthesis of 1,1′-spirobiindane-7,7′-diol derivative and [4 + 3] cyclization were attempted. The results showed that variation of 2,2′-substituent groups could provide different types of ligands and catalysts, and adjustment of substituent groups at the 3,3′, 5,5′, 6,6′-positions could make ligands and catalysts more efficient in the asymmetric catalytic synthesis. Therefore, our present research should provide a new and useful strategy for development of diverse axially chiral ligands and catalysts.

Plant proteins are a good source of active peptides, which can exert physiological effects on the body. Predicting the possible activity of plant proteins and obtaining active peptides with oral potential are challenging. In this study, the potential activity of peptides from Zizyphus jujuba proteins after in silico simulated gastrointestinal digestion was predicted using the BIOPEP-UWM™ database. The ACE-inhibitory activity needs to be further investigated. The actual peptides in mouse intestines after the oral administration of Zizyphus jujuba protein were collected and analyzed, 113 Zizyphus jujuba peptides were identified, and 3D-QSAR models of the ACE-inhibitory activity were created and validated using a training set (34 peptides) and a test set (12 peptides). Three peptides, RLPHV, TVKPGL and KALVAP, were screened using the 3D-QSAR model and were found to bind to the active sites of the ACE enzyme, and their IC50 values were determined. Their values were 6.01, 3.81, and 17.06 μM, respectively. The in vitro digestion stabilities of the RLPHV, TVKPGL, and KALVAP peptides were 82%, 90%, and 78%. This article provides an integrated method for studying bioactive peptides derived from plant proteins.

Multicomponent reactions (MCRs) have undoubtedly emerged as the most indispensable tool for organic chemists worldwide, finding extensive utility in the synthesis of intricate natural products, heterocyclic molecules with significant bioactivity, and pharmaceutical agents. The multicomponent one-pot 1,3-dipolar cycloaddition reactions, which were initially conceptualized by Rolf Huisgen in 1960, find extensive application in contemporary heterocyclic chemistry. In terms of green synthesis, the multicomponent 1,3-dipolar cycloaddition is highly favored owing to its numerous advantages, including high step- and atom-economies, remarkable product diversity, as well as excellent efficiency and diastereoselectivity. Among the numerous pieces of research, the most fascinating reaction involves the utilization of azomethine ylides generated from isatins and amino acids that can be captured by various dipolarophiles. This approach offers a highly efficient and convenient method for constructing spiro-pyrrolidine oxindole scaffolds, which are crucial building blocks in biologically active molecules. Consequently, this review delves deeper into the dipolarophiles utilized in the 1,3-dipolar cycloaddition of isatins and amino acids over the past six years.

Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by inflammatory responses and oxidative stress. Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-γ, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition.

The phosphorylation of nucleosides and their polymerization are crucial issues concerning the origin of life. The question of how these plausible chemical processes took place in the prebiotic Earth is still perplexing, despite several studies that have attempted to explain these prebiotic processes. The purpose of this article is to review these chemical reactions with respect to chemical evolution in the primeval Earth. Meanwhile, from our perspective, the chiral properties and selection of biomolecules should be considered in the prebiotic chemical origin of life, which may contribute to further research in this field to some extent.

Biological experiments performed in space crafts like space stations, space shuttles, and recoverable satellites has enabled extensive spaceflight life investigations (SLIs). In particular, SLIs have revealed distinguished space effects on microbial growth, survival, metabolite production, biofilm formation, virulence development and drug resistant mutations. These provide unique perspectives to ground-based microbiology and new opportunities for industrial pharmaceutical and metabolite productions. SLIs are with specialized experimental setups, analysis methods and research outcomes, which can be accessed by established databases National Aeronautics and Space Administration (NASA) Life Science Data Archive, Erasmus Experiment Archive, and NASA GeneLab. The increasing research across diverse fields may be better facilitated by databases of convenient search facilities and categorized presentation of comprehensive contents. We therefore developed the Space Life Investigation Database (SpaceLID) http://bidd.group/spacelid/, which collected SLIs from published academic papers. Currently, this database provides detailed menu search facilities and categorized contents about the studied phenomena, materials, experimental procedures, analysis methods, and research outcomes of 448 SLIs of 90 species (microbial, plant, animal, human), 81 foods and 106 pharmaceuticals, including 232 SLIs not covered by the established databases. The potential applications of SpaceLID are illustrated by the examples of published experimental design and bioinformatic analysis of spaceflight microbial phenomena.

A novel angiotensin-converting enzyme (ACE) inhibitory peptide ser-ala-ser-val-ile-pro-val-ser-ala-val-arg-ala (SASVIPVSAVRA) was purified and identified from yak bone by Electrospray Ionization-Time of Flight-Mass Spectrometry (ESI-TOF-MS). Results in vitro showed that the peptide exhibited strong ACE inhibition activities with an IC50 of 54.22 μM. Molecular docking results showed the binding between the peptide SASVIPVSAVRA and ACE mainly driven by van der Waals forces, hydrogen bonds and metal receptor. Interestingly, the ACE inhibition activities of the peptide increased about 19% after digestion, but none of its metabolites showed stronger activity than it. The in vivo experiment showed that the antihypertensive effect of peptide SASVIPVSAVRA at dose of 30 mg/kg is nearly equal to Captopril at dose of 10 mg/kg to spontaneously hypertensive rats (SHRs). The antihypertensive effect mechanism of SASVIPVSAVRA should be further studied through plasma metabolomics and bioanalysis. Structure analysis of amino acids and peptides produced during digestion may help better understand the antihypertensive effect of peptides.

Ruthenium (Ru)-based organometallic drugs have gained attention as chemotherapeutic and bioimaging agents due to their fewer side effects and excellent physical optical properties. Tuning the electronic structures of Ru complexes has been proven to increase the cytotoxicity of cancer cells and the luminescent efficiency of the analytical probes. However, the relationship between electronic structures and bioactivities is still unclear due to the potential enhancement of both electron donor and acceptor properties. Thus, we investigated the relationship between the electronic structures of Ru(II) complexes and cytotoxicity by optimizing the electron-withdrawing (complex 1), electron-neutral (complex 2), and electron-donating (complex 3) ligands through DFT calculations, bioactivities tests, and docking studies. Our results indicated that it was not sufficient to consider only either the effect of electron-withdrawing or electron-donating effects on biological activities instead of the total electronic effects. Furthermore, these complexes with electron-donating substituents (complex 3) featured unique “off-on” luminescent emission phenomena caused by the various “HOMO-LUMO” distributions when they interacted with DNA, while complex with electron-withdrawing substituent showed an “always-on” signature. These findings offer valuable insight into the development of bifunctional chemotherapeutic agents along with bioimaging ability.

Life’s origins have always been a scientific puzzle. Understanding the production of biomolecules is crucial for understanding the evolution of life on Earth. Numerous studies on trimetaphosphate have been conducted in the field of prebiotic chemistry. However, its role in prebiotic chemistry has been documented infrequently in the review literature. The goal of this thesis is to review the role of trimetaphosphate in the early Earth’s biomolecule synthesis and phosphorylation. Additionally, various trimetaphosphate-mediated reaction pathways are discussed, as well as the role of trimetaphosphate in prebiotic chemistry. Finally, in our opinion, interactions between biomolecules should be considered in prebiotic synthesis scenarios since this may result in some advances in subsequent research on this subject. The research establishes an essential and opportune foundation for an in-depth examination of the “mystery of life".

Background: Liver cancer (LCa) is one of the most common malignancies. Western medicine is the main treatment strategy of LCa, but it has not achieved the ideal therapeutic effect. Traditional Chinese Medicines (TCMs) have a wide range of biological effects, lots of evidence suggests that they may kill tumors by regulating the tumor microenvironment and enhancing the immune system. Object: The purpose of this research is to explore the medication rules of TCMs in treating LCa and excavate the potential TCMs for LCa. Methods: We combined genes associated with the MAPK, PI3K/Akt, and mTOR signaling pathways, as well as differentially expressed genes of LCa from the TCGA database, to determine 12 prospective core targets by building a prognostic model. We added 18 previously published LCa core targets to create a list of key targets. GO and KEGG analyses were used to validate the rationality of the key targets. The reliability of the corresponding relationships between targets and compounds was verified by molecular docking. The targets-compounds-herbs network was constructed and topologically analyzed to obtain potential herbs for LCa. The nature, flavor and meridian tropism of the herbs were analyzed to explore the rule of TCMs in the treatment of LCa. Results: We obtained 30 potential targets including BRCA1, STMN1, MECOM, ITGB5 and SKP2. A total of 115 candidate compounds including resveratrol, quercetin, epigallocatechin gallate, estradiol and curcumin, and 1182 candidate herbs, including Jinyinhua, Gouguye, Tufuling, Huzhang, Jishiteng, Nvzhenzi, Sangbaipi and Qianhu were obtained. The vast majority of LCa's core targets, compounds and herbs we obtained have been verified by previous studies. Among the potential herbs, the categories of clearing heat and detoxifying, activating blood and dissolving stasis, and strengthening the spleen and benefiting the qi accounted for a high percentage. The herbs against LCa are mainly bitter, pungent, sweet in flavor, warm, cold, and mild in nature, and are mainly distributed in the liver, stomach, and lung meridians. Conclusions: Some of the potential herbs we obtained like Jinyinhua, Gouguye, Tufuling, Huzhang and Qianhu have been proved to be effective for LCa, while some of them like Jishiteng, Nvzhenzi and Sangbaipi have been shown to have a protective effect on the liver. The potential herbs have not been widely and deeply used and need to be further explored. The combination of network pharmacology and data mining provides novel approaches to the screening and exploitation of TCM.

Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global health issue. The clinical presentation of COVID-19 is highly variable, ranging from asymptomatic and mild disease to severe. However, the mechanisms for the high mortality induced by SARS-CoV-2 infection are still not well understood. Recent studies have indicated that the cytokine storm might play an essential role in the disease progression in patients with COVID-19, which is characterized by the uncontrolled release of cytokines and chemokines leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. Cell death, especially, inflammatory cell death, might be the initiation of a cytokine storm caused by SARS-CoV-2 infection. This review summarizes the forms of cell death caused by SARS-CoV-2 in vivo or in vitro and elaborates on the dedication of apoptosis, necroptosis, NETosis, pyroptosis of syncytia, and even SARS-CoV-2 E proteins forming channel induced cell death, providing insights into targets on the cell death pathway for the treatment of COVID-19.

Amino acid (AA) analysis is important in biochemistry, food science, and clinical medicine. However, due to intrinsic limitations, AAs usually require derivatization to improve their separation and determination. Here, we present a liquid chromatography-mass spectrometry (LC-MS) method for the derivatization of AAs using the simple agent urea. The reactions proceed quantitatively under a wide range of conditions without any pretreatment steps. Urea-derivatized products (carbamoyl amino acids) of 20 AAs exhibit better separation on reversed-phase columns and increased response in a UV detector compared to underivatized ones. We applied this approach to AA analysis in complex samples using a cell culture media as a model, and it showed potential for the determination of oligopeptides. This fast, simple, and inexpensive method should be useful for AA analysis in complex samples.

A microwave-promoted multicomponent reaction of isatins, α-amino acids and 1,4-dihydro-1,4-epoxynaphthalene is achieved under environmentally friendly conditions, delivering oxygen-bridged spirooxindoles within 15 min in good to excellent yields. The attractive features of the 1,3-dipolar cycloaddition are the compatibility of various primary amino acids and the high efficiency of the short reaction time. Moreover, the scale-up reaction and synthetic transformations of spiropyrrolidine oxindole further demonstrate its synthetic utility. This work provides powerful means to expand the structural diversity of spirooxindole as a promising scaffold for novel drug discovery.

Aging is an irreversible physiological process in the human body, and the aging characteristics of the body that accompany this process also lead to many other chronic diseases, such as neurodegenerative diseases represented by Alzheimer’s disease and Parkinson’s disease, cardiovascular diseases, hypertension, obesity, cancer, and so on. The marine environment is highly biodiverse, the natural active products of these organisms constitute a vast treasure trove of marine drugs or drug candidates that play an essential role in disease prevention and treatment, and the active peptide products among them have received special attention because of their unique chemical properties. Therefore, the development of marine peptide compounds as anti-aging drugs is emerging as an important research area. This review highlights the currently available data on marine bioactive peptides with anti-aging potential from 2000 to 2022 by analyzing the prevalent aging mechanisms, critical aging metabolic pathways and well-established multi-omics aging characteristics, as well as grouping different bioactive and biological species lines of peptides from marine organisms and discussing their research modalities and functional characteristics. Active marine peptides is a promising topic to explore and to develop their potential as anti-aging drugs or drug candidates. We expect this review to be instructive for future marine drug development and to reveal new directions for future biopharmaceuticals.

The biological system uses L-amino acids (L-AAs) to construct peptides. The selection of AA chirality in the prebiotic Earth still remains a mystery. Here we report the intrinsic mechanism of AA chiral selection in the formation of prebiotic proline-containing cyclic dipeptide (DKPs). The DKPs were synthesized by equal amounts of L-AA and D-AA with L-Pro that exhibited a clear preference for D-AA as opposed to L-AA. And surprisingly, the L-AA was preferred over D-AA in the mirror-image system with D-Pro. These results indicate that prebiotic DKPs synthesis has a certain selectivity for AA chirality preceded the biological enzymatic catalysis.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

The versatile roles of D-amino acids (D-AAs) in foods, diseases, and organisms, etc., have been widely reported. They have been regarded, not only as biomarkers of diseases but also as regulators of the physiological function of organisms. Over the past few decades, increasing data has revealed that D-AAs have great potential in treating disease. D-AAs also showed overwhelming success in disengaging biofilm, which might provide promise to inhibit microbial infection. Moreover, it can effectively restrain the growth of cancer cells. Herein, we reviewed recent reports on the potential of D-AAs as therapeutic agents for treating neurological disease or tissue/organ injury, ameliorating reproduction function, preventing biofilm infection, and inhibiting cancer cell growth. Additionally, we also reviewed the potential application of D-AAs in drug modification, such as improving biostability and efficiency, which has a better effect on therapy or diagnosis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease with increasing prevalence rates over years and is associated with hepatic lipid accumulation, liver injury, oxidative stress, hepatic inflammation, and liver fibrosis and lack of approved pharmacological therapy. Alanyl-glutamine (Ala-Gln) is a recognized gut-trophic nutrient that has multiple pharmacological effects in the prevention of inflammation- and oxidative-stress-associated diseases. Nevertheless, whether Ala-Gln has a protective effect on NASH still lacks evidence. The aim of this study is to explore the influence of Ala-Gln on NASH and its underlying mechanisms. Here, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet to establish the model of NASH, and Ala-Gln at doses of 500 and 1500 mg/kg were intraperitoneally administered to mice along with a MCD diet. The results showed that Ala-Gln treatment significantly attenuated MCD-induced hepatic pathological changes, lowered NAFLD activity score, and reduced plasma alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels. Ala-Gln dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). In addition, Ala-Gln exerted an anti-oxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, Ala-Gln exhibited an anti-inflammatory effect via decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators. Notably, Ala-Gln suppressed the development of liver fibrosis in MCD-diet-fed mice, which may be due to the inhibition of hepatic stellate cells activation. In conclusion, these findings revealed that Ala-Gln prevents the progression of NASH through the modulation of oxidative stress and inflammation and provided the proof that Ala-Gln might be an effective pharmacological agent to treat NASH.

A Brønsted acid-catalyzed domino ring-opening cyclization transformation of donor-acceptor (D-A) cyclopropanes and 2-naphthols has been developed. This formal [3+2] cyclization reaction provided novel and efficient access to the naphthalene-fused cyclopentanes in the absence of any transition-metal catalysts or additives. This robust procedure was completed smoothly on a gram-scale to afford the corresponding product with comparable efficiency. Furthermore, the synthetic application of the prepared product has been demonstrated by its transformation into a variety of synthetically useful molecules.

Cyclic dipeptides (DKPs) are peptide precursors and chiral catalysts in the prebiotic process. This study reports proline-containing DKPs that were spontaneously obtained from linear dipeptides under an aqueous solution. Significantly, the yields of DKPs were affected by the sequence of linear dipeptides and whether the reaction contains trimetaphosphate. These findings provide the possibility that DKPs might play a key role in the origin of life.

Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages.

Rapid quantitative analysis of single chiral amino acid (aa) was achieved using circular dichroism (CD) with data analysis by standard calibration curve. The absolute concentrations of D- and L-aas in enantiomeric mixtures were determined by CD and achiral liquid chromatography (LC) method. It is worth noting that CD and LC were used independently, not online LC/CD in this study. The errors of the experimental results were less than 10%. The method is also applicable to the quantification of non-aa chiral molecules, such as chiral nucleoside and chiral quinine. With this study, we provide a new method for the chiral quantitative analysis of enantiomeric aas mixtures.

Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.

Metal-iodosylarene complexes have been recently viewed as a second oxidant alongside of the well-known high-valent metal-oxo species. Extensive efforts have been exerted to unveil the structure-function relationship of various metal-iodosylarene complexes. In the present manuscript, density functional theoretical calculations were employed to investigate such relationship of a specific manganese-iodosylbenzene complex [MnIII(TBDAP)(PhIO)(OH)]2+ (1). Our results fit the experimental observations and revealed new mechanistic findings. 1 acts as a stepwise 1e+1e oxidant in sulfoxidation reactions. Surprisingly, C-H bond activation of 9,10-dihydroanthracene (DHA) by 1 proceeds via a novel ionic hydride transfer/proton transfer (HT/PT) mechanism. As a comparison to 1, the electrophilicity of an iodosylbenzene monomer PhIO was investigated. PhIO performs concerted 2e-oxidations both in sulfoxidation and C-H activation. Hydroxylation of DHA by PhIO was found to proceed via a novel ionic and concerted proton-transfer/hydroxyl-rebound mechanism involving 2e-oxidation to form a transient carbonium species.

The mechanisms shaping the amino acids recruitment pattern into the proteins in the early life history presently remains a huge mystery. In this study, we conducted genome-wide analyses of amino acids usage and genetic codons structure in 7270 species across three domains of life. The carried-out analyses evidenced ubiquitous usage bias of amino acids that were likely independent from codon usage bias. Taking advantage of codon usage bias, we performed pseudotime analysis to re-determine the chronological order of the species emergence, which inspired a new species relationship by tracing the imprint of codon usage evolution. Furthermore, the multidimensional data integration showed that the amino acids A, D, E, G, L, P, R, S, T and V might be the first recruited into the last universal common ancestry (LUCA) proteins. The data analysis also indicated that the remaining amino acids most probably were gradually incorporated into proteogenesis process in the course of two long-timescale parallel evolutionary routes: I→F→Y→C→M→W and K→N→Q→H. This study provides new insight into the origin of life, particularly in terms of the basic protein composition of early life. Our work provides crucial information that will help in a further understanding of protein structure and function in relation to their evolutionary history.

Epigenetic therapy using histone deacetylase (HDAC) inhibitors has become an attractive project in new drug development. However, DNA methylation and histone acetylation are important epigenetic ways to regulate the occurrence and development of leukemia. Given previous studies, N-(2-aminophenyl)benzamide acridine (8a), as a histone deacetylase 1 (HDAC1) inhibitor, induces apoptosis and shows significant anti-proliferative activity against histiocytic lymphoma U937 cells. HDAC1 plays a role in the nucleus, which we confirmed by finding that 8a entered the nucleus. Subsequently, we verified that 8a mainly passes through the endogenous (mitochondrial) pathway to induce cell apoptosis. From the protein interaction data, we found that 8a also affected the expression of DNA methyltransferase 1 (DNMT1). Therefore, an experiment was performed to assess the binding of 8a to DNMT1 at the molecular and cellular levels. We found that the binding strength of 8a to DNMT1 enhanced in a dose-dependent manner. Additionally, 8a inhibits the expression of DNMT1 mRNA and its protein. These findings suggested that the anti-proliferative and pro-apoptotic activities of 8a against leukemia cells were achieved by targeting HDAC1 and DNMT1.

Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient depletion, and acidosis. The physiological function of eEF2K and its role in the development and progression of cancer are here reviewed in detail. In addition, a summary of progress for in vitro eEF2K inhibitors from anti-cancer drug discovery research in recent years, along with their structure–activity relationships (SARs) and synthetic routes or natural sources, is also described. Special attention is given to those inhibitors that have been already validated in vivo, with the overall aim to provide reference context for the further development of new first-in-class anti-cancer drugs that target eEF2K.

Ultraviolet (UV) irradiation is considered an energy source for the prebiotic chemical synthesis of life’s building blocks. However, it also results in photodegradation of biology-related organic compounds on early Earth. Thus, it is important to find a process to protect these compounds from decomposition by UV irradiation. Herein, pH effects on both the adsorption of peptides on montmorillonite (MMT) and the abilities of peptides to resist UV irradiation due to this adsorption were systematically studied. We found that montmorillonite (MMT) can adsorb peptides effectively under acidic conditions, while MMT-adsorbed peptides can be released under basic conditions. Peptide adsorption is positively correlated with the length of the peptide chains. MMT’s adsorption of peptides and MMT-adsorbed peptide desorption are both rapid-equilibrium, and it takes less than 30 min to reach the equilibrium in both cases. Furthermore, compared to free peptides, MMT-adsorbed peptides under acidic conditions are well protected from UV degradation even after prolonged irradiation. These results indicate amino acid/peptides are able to concentrate from aqueous solution by MMT adsorption under low-pH conditions (concentration step). The MMT-adsorbed peptides survive under UV irradiation among other unprotected species (storage step). Then, the MMT-adsorbed peptides can be released to the aqueous solution if the environment becomes more basic (releasing step), and these free peptides are ready for polymerization to polypeptides. Hence, a plausible prebiotic concentration–storage–release cycle of amino acids/peptides for further polypeptide synthesis is established.

Black liquor produced from pulping with a high value of chemical oxygen demand (COD) and biological oxygen demand (BOD) is highly harmful if discharged into the environment directly. One possible way to decrease the damage to the soil and water is to reuse the organic substances contained in it to cultivate yeasts for producing single-cell proteins (SCP) while reducing the COD. With this in mind, this study is devoted to treatment technology and the comprehensive utilization of black liquor. Various parameters were evaluated, and the COD of black liquor, initial pH, and nitrogen sources had significant influences on biomass and crude protein production. The research resulted in the maximum values of COD removal rate and crude protein production with 78.78 ±3.21% and 1.18 ±0.02 g/L achieved, respectively, under the optimized condition of black liquor concentration (60%), the recruitment of urea (0.5 g/L), initial pH (6.0), temperature (34 °C), shaking speed (180 rpm), and incubation time (36 h). Furthermore, this study provided a potential viable treatment of black liquor and revealed a feasible way to make full use of black liquor for the economical production of SCP.

Pin1-type parvulins are phosphorylation-dependent peptidyl-prolyl cis-trans isomerases. Their functions have been widely reported to be involved in a variety of cellular responses or processes, such as cell division, transcription, and apoptosis, as well as in human diseases including Alzheimer's disease and cancers. TbPin1 was identified as a novel class of Pin1-type parvulins from Trypanosoma brucei, containing a unique PPIase domain, which can catalyze the isomerization of phosphorylated Ser/Thr-Pro peptide bond.We determined the solution structure of TbPin1 and performed (15)N relaxation measurements to analyze its backbone dynamics using multi-dimensional heteronuclear NMR spectroscopy. The average RMSD values of the 20 lowest energy structures are 0.50±0.05 Å for backbone heavy atoms and 0.85±0.08 Å for all heavy atoms. TbPin1 adopts the typical catalytic tertiary structure of Pin1-type parvulins, which comprises a globular fold with a four-stranded anti-parallel β-sheet core surrounded by three α-helices and one 3(10)-helix. The global structure of TbPin1 is relatively rigid except the active site. The 2D EXSY spectra illustrate that TbPin1 possesses a phosphorylation-dependent PPIase activity. The binding sites of TbPin1 for a phosphorylated peptide substrate {SSYFSG[p]TPLEDDSD} were determined by the chemical shift perturbation approach. Residues Ser15, Arg18, Asn19, Val21, Ser22, Val32, Gly66, Ser67, Met83, Asp105 and Gly107 are involved in substantial contact with the substrate.The solution structure of TbPin1 and the binding sites of the phosphorylated peptide substrate on TbPin1 were determined. The work is helpful for further understanding the molecular basis of the substrate specificity for Pin1-type parvulin family and enzyme catalysis.

The title compound, C7H6N4O4, plays an important role in the synthesis of biologically active compounds. The planar hydrazone group is oriented at a dihedral angle of 8.27 (3)° with respect to the benzene ring. In the crystal structure, intermolecular N—H...O and N—H...N hydrogen bonds link the molecules.