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Lipid nanoparticle (LNP) is commonly used to deliver mRNA vaccines. Currently, LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time. Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines. Firstly, 325 data samples of mRNA vaccine LNP formulations with IgG titer were collected. The machine learning algorithm, lightGBM, was used to build a prediction model with good performance (R2 > 0.87). More importantly, the critical substructures of ionizable lipids in LNPs were identified by the algorithm, which well agreed with published results. The animal experimental results showed that LNP using DLin-MC3-DMA (MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102, which was consistent with the model prediction. Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment. The result showed that the lipid molecules aggregated to form LNPs, and mRNA molecules twined around the LNPs. In summary, the machine learning predictive model for LNP-based mRNA vaccines was first developed, validated by experiments, and further integrated with molecular modeling. The prediction model can be used for virtual screening of LNP formulations in the future.

Memory is composed of various phases including cellular consolidation, systems consolidation, reconsolidation, and extinction. In the last few years it has been shown that simple association memories can be encoded by a subset of the neuronal population called engram cells. Activity of these cells is necessary and sufficient for the recall of association memory. However, it is unclear which molecular mechanisms allow cellular engrams to encode the diverse phases of memory. Further research is needed to examine the possibility that it is the synapses between engram cells (the synaptic engram) that constitute the memory. In this review we summarize recent findings on cellular engrams with a focus on different phases of memory, and discuss the distinct molecular mechanism required for cellular and synaptic engrams.

Sleep requires that we disconnect from the environment, losing the ability to promptly respond to stimuli. There must be at least one essential function that justifies why we take this risk every day, and that function must depend on the brain being offline. We have proposed that this function is to renormalize synaptic weights after learning has led to a net increase in synaptic strength in many brain circuits. Without this renormalization, synaptic activity would become energetically too expensive and saturation would prevent new learning. There is converging evidence from molecular, electrophysiological, and ultrastructural experiments showing a net increase in synaptic strength after the major wake phase, and a net decline after sleep. The evidence also suggests that sleep-dependent renormalization is a smart process of synaptic down-selection, comprehensive and yet specific, which could explain the many beneficial effects of sleep on cognition. Recently, a key molecular mechanism that allows broad synaptic weakening during sleep was identified. Other mechanisms still being investigated should eventually explain how sleep can weaken most synapses but afford protection to some, including those directly activated by learning. That synaptic down-selection takes place during sleep is by now established; why it should take place during sleep has a plausible explanation; how it happens is still work in progress.

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs. Four subclasses of circRNAs have been identified in animal cells, and they have unique features in their biogenesis, degradation, and transport. CircRNAs have diverse molecular functions in sponging miRNAs, regulating transcription, modulating RNA-binding proteins, and even encoding proteins. Some circRNAs are important regulators of various physiological processes to maintain homeostasis. Dysregulation of circRNAs is associated with human disorders, and individual circRNAs are crucial factors that contribute to major diseases including non-immunological diseases such as cancers, neurological disorders, cardiovascular disease, and metabolic disease. Debates on circRNAs have also been raised in recent years, and further studies would help to resolve these disputes and potentially lead to biomedical applications of circRNAs.

Mesenchymal stem cells (MSCs), multipotent stromal cells, have attracted extensive attention in the field of regenerative medicine and cell therapy due to the capacity of self-renewal, multilineage differentiation, and immune regulation. MSCs have different cellular effects in different diseases, and even have markedly different curative effects with different tissue sources, indicating the plasticity of MSCs. The phenotypes, secreted factors, and proliferative, migratory, differentiating, and immunomodulatory effects of MSCs depend on certain mediators present in their microenvironment. Understanding microenvironmental factors and their internal mechanisms in MSC responses may help in subsequent prediction and improvement of clinical benefits. This review highlighted the recent advances in MSC plasticity in the physiological and pathological microenvironment and multiple microenvironmental factors regulating MSC plasticity. It also highlighted some progress in the underlying molecular mechanisms of MSC remodeling in the microenvironment. It might provide references for the improvement in vitro culture of MSCs, clinical application, and in vivo induction.

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being “transcriptional noise,” they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.

Treatment of myasthenia gravis (MG), a chronic autoimmune neuromuscular disorder, remains challenging due to side effects associated with modern medications used to treat the disease. JianPi YiQi BuSui Method (JPYQBSM) is a traditional Chinese medicine (TCM) which has been shown to provide pivotal MG-alleviating therapeutic benefits. However, JPYQBSM active chemical components and molecular mechanisms and therapeutic targets have not yet been comprehensively investigated, prompting this study. The pharmacodynamic basis and action mechanism of JPYQBSM in the treatment of myasthenia gravis were predicted by computer network pharmacological technology and molecular docking technology of chemical composition. JPYQBSM alleviated MG through multi-chemical component, multitarget and multi-pathway synergistic therapeutic effects. This study provides new insights into specific mechanisms underlying JPYQBSM therapeutic effects for alleviating MG.

International audience; Invasive growth along white matter (WM) tracts is one of the most prominent clinicopathological features of glioma and is also an important reason for surgical treatment failure in glioma patients. A full understanding of relevant clinical features and mechanisms is of great significance for finding new therapeutic targets and developing new treatment regimens and strategies. Herein, we review the imaging and histological characteristics of glioma patients with WM tracts invasion and summarize the possible molecular mechanism. On this basis, we further discuss the correlation between glioma molecular typing, radiotherapy and tumor treating fields (TTFields) and the invasion of glioma along WM tracts.

Breast cancer (BC) is a serious threat to female health. tRNA-derived fragments (tRFs) are popular biomarkers for the diagnosis and treatment of cancer. The purpose of this study was to identify tRFs related to BC and to explore the function and regulatory mechanism of crucial tRFs in BC cells. Small RNA database was used to detect the tRF profiles from BC patients and controls. Differentially expressed tRFs were determined by quantitative reverse transcription PCR (RT-qPCR), and a crucial tRF was evaluated through silence and overexpression experiments, and the target gene was investigated by luciferase reporter gene assay, Western blot and rescue experiment. We screened tRF-19-W4PU732S, which was processed from the mature tRNA-Ser-AGA, and significantly highlyexpressed in BC tissues and cells. Inhibition of tRF-19-W4PU732S weakened MDA-MB-231 cell proliferation, migration and invasion, while enhanced apoptosis. On the contrary, overexpression of tRF-19-W4PU732S promoted MCF-7 cell proliferation, migration and invasion, whereasreduced apoptosis. Furthermore, tRF-19-W4PU732S induced BC cell epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSC) phenotypes, such as up-regulation of OCT-4A, SOX2 and Vimentin and down-regulation of E-cadherin. Ribosomal protein-L27A (RPL27A) was a downstream target of tRF-19-W4PU732S, which was lowly expressed in BC cells. The knockdown of RPL27A expression partially restored the promoting effects of tRF-19-W4PU732S on BC cell viability, invasion, migration, EMT and CSC phenotypes, and the suppression of apoptosis. In conclusion, our results manifested that tRF-19-W4PU732S promotes the malignant activity of BC cells by inhibiting RPL27A, which provides a new scientific basis for the treatment of BC. Abbreviations BC: breast cancer; tRNAs: transfer RNAs; tiRNAs: tRNA-derived stressinduced RNAs; tRFs: tRNA-derived fragments; CCK-8: Cell Counting Kit-8; PI: propidium iodide; EMT: epithelial-to-mesenchymal transition; CSC: cancer stem-like cells; RPL27A: ribosomal protein-L27A; RT-qPCR: quantitative reverse transcription PCR.

Barnacles are notorious marine fouling creatures; their planktonic cyprid larvae attach to material substrates and metamorphose. Histamine has shown great importance in regulating cyprid settlement and metamorphosis. This study aimed to investigate the mechanisms of histamine-induced larval settlement. Cyprids were exposed to histamine or loratadine, an anti-histamine compound. The percent larval settlements of the histamine- and anti-histamine-treated cyprids were significantly higher and lower, respectively, than the control group. Transcriptomic analyses showed that histamine-treated cyprids had 18498 differentially expressed genes (DEGs, 14531 up-regulated, 3967 down-regulated) and the anti-histamine group had 18055 DEGs (17237 up-regulated, 818 down-regulated) in comparison to untreated controls. In both treatment groups, significant enrichment of DEGs involved in the mitogen-activated protein kinase signaling pathway was observed. Based on the results of larval settlement bioassays, we set 4 filter conditions to perform DEG analyses, and 19 DEGs were selected as functional genes related to cyprid settlement. The functional categories of these genes included structural proteins, spider silk proteins, energy metabolism proteins, cement proteins, glycosyl proteins, and multifunctional proteins. The energy metabolism protein AdipoR was significantly up-regulated in the histamine-treated cyprids but significantly down-regulated in the anti-histamine group. The activity of adenosine monophosphate-activated protein kinase, a downstream signaling protein of AdipoR, increased in the histamine-treated group and decreased in the anti-histamine-treated group. Our results provide new insights into the molecular mechanisms underlying the histamine-induced settlement of barnacle cyprids and identify AdipoR as an important gene that can affect the settlement of cyprids, likely through regulating cyprid energy metabolism.

It has been estimated that approximately 20% of employed adults worldwide are required to undertake shift work, which has led to severe public health decline and depression. Sini powder (SNP) has been shown to be a promising medicine. However, the effectiveness and mechanism of reducing the risk of depression for shift workers are still unclear. Thus, network pharmacological analysis and gene expression profiling were introduced to reveal the mechanism of SNP in the prevention of depression. First, five databases were used to collect the chemical compounds of SNP, and absorption, distribution, metabolism, and excretion (ADME) properties were selected to identified high-quality compounds. Second, the targets of compounds were obtained by BATMAN-TCM. And the differentially expressed genes associated with depression among shift workers were obtained using gene expression profiling (GSE98793, GSE122541). Subsequently, key targets were screened out with a protein–protein interaction (PPI) network by String. Furthermore, functional enrichment was carried out by Metascape. Molecular docking was introduced to verify the interaction between core targets and compounds. SNP reduced the risk of depression by regulating ESR2, GPER1, TNF and APOE through the estrogen pathway and NOD-like receptor signaling pathway. This study provides a scientific basis for further investigating the mechanism by which SNP prevents depression and reduces the risk of depression for shift workers.

To explore the mechanism of miR-29b in gestational diabetes mellitus (GDM) and its effect on the function of trophoblast cell (TBC), the placenta tissues of 55 normal term pregnancies and 55 GDM patients were selected and rolled into control group and observation group. In the early stage, microRNA (miRNA) chips were utilized to screen the differentially expressed miRNAs in the placenta of observation group and control group. According to the microarray results of miRNAs, three differentially expressed miRNAs, namely let-7b, miR-1202, and miR-29b were selected. Then, the differences in the miR-29b level in the four groups were analyzed, namely the microRNA-29b (miR-29b minic), mini-control (minic control), microRNA-29b inhibitor (miR-29b inhibitor), and inhibitor control (inhibitor control). The results showed that miR-29b level in the placenta of observation group was substantially inferior to that of controls, with remarkable differences (P < 0.05). miR-29b level in miR-29b minic and minic control had significant changes (P < 0.01). The TBC activity of minic control was greatly superior to that of minic control, and there was considerable difference between the two (P < 0.05). The difference between miR-29b inhibitor and inhibitor control in TBC was not obvious, without considerable differences (P > 0.05). The invasion ability of miR-29b inhibitor TBC was notably superior to inhibitor control, and there were substantial differences (P < 0.05). To sum up, miR-29b had a significant inhibitory effect on the proliferation and cell activity of TBC, and can promote the apoptosis and death of TBC. Moreover, its inhibitory effect on cell migration and invasion was also suggested.

The objective of this study was to investigate the molecular mechanism of the histopathological characteristics of liver cirrhosis (LC) complicated with acute kidney injury (AKI) and the signaling pathway of silent information regulator 1 (SIRT1)-peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) during the pathogenesis of LC. 20 healthy male rats with AKI complicated by laparoscopic cholecystectomy were selected and divided randomly into control group (C group), lipopolysaccharide (LPS) group, bile duct ligation (BDL) group, and model group (lipopolysaccharide+BDL) (D group). The indexes of all the rats were determined, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), sarcoplasmic enzyme (Scr), and blood urea nitrogen (BUN); the SIRT1 and PGC-1α expressions in renal tissues of rats from each group was detected. Results showed that the AST and ALT levels in BDL group and D group were higher markedly than those before surgery (P < 0.05). The serum levels of Scr and BUN in D group 4 hours after LPS injection increased hugely compared with before injection (P < 0.05). Compared with BDL group, the protein levels of SIRT1 and PGC-1α in renal tissue of group D were decreased sharply (P < 0.05), and the SIRT1 protein expression was positively correlated with PGC-1α (r = 0.836 and P < 0.01). When LC were complicated with AKI, SIRT1 activity was reduced and PGC-1α expression was inhibited. Moreover, SIRT1-PGC-1α signaling pathway played a protective role in pathogenesis of LC complicated with AKI.

Photosystem II (PSII), as a multiple-subunit chloroplast membrane-associated pigment-protein complex on the thylakoid membrane, is a primary target of light-induced photodamage. However, the overal...

Context Elian Granules have been applied in the treatment of precancerous lesions of gastric cancer (PLGC) and achieved good results. However, its exact mechanism remains unclear. Objectives To explore the mechanism of Elian granules in treating PLGC through the mitogen-activated protein kinase (MAPK) signalling pathway based on network pharmacology. Materials and methods Through network pharmacological methods, the targets of the active component of Elian granules against PLGC were obtained. Subsequently, Specific Pathogen Free (SPF) male Sprague Dawley (SD) rats were randomly divided into normal, model, and Elian granule groups. The N-methyl-N′-nitro-N-nitrosoguanidine comprehensive method was used to establish the PLGC rat model. The model and Elian granule groups were given normal saline and Elian granule aqueous solution (3.24 g/kg/d) intragastric administration, respectively, for 24 weeks. The pathological changes in gastric tissues were observed by hematoxylin-eosin staining. The protein expression of p-JNK and p-p38 was verified by western blotting. Results 394 and 4,395 targets were identified in Elian granules and PLGC, respectively. The 190 common targets were mainly enriched in MAPK signalling pathways. The gastric mucosal epithelium was still intact, the glands were arranged regularly, and no goblet cells or apparent inflammatory cell infiltration were observed in the Elian granule group. The expression of p-JNK and p-p38 protein of the Elian granule group (0.83 ± 0.08; 1.18 ± 0.40) was significantly higher than the model group (0.27 ± 0.14; 0.63 ± 0.14) (p

Background and objective: Exposure to mycotoxins may delay and/or negatively influence the development of neurological, gastrointestinal and inflammatory mechanisms in individuals with Autism Spectrum Disorder (ASD). Therefore, there is a need to address the possible links between mycotoxins and the risk and prevalence of ASD to increase the understanding of the molecular mechanism underlying these links. In this context, the aim of this study was to investigate the molecular mechanism underpinning mycotoxin exposure and autism. Methods: The study was based on a systematic approach which focused on the possible associations between mycotoxins and ASD in addition to the role of the mycotoxins on the risk and prevalence of ASD. The systematic review included all molecular mechanism studies examining mycotoxin exposure and autism, and was not limited to a specific period of time. A search was performed on the PubMed, Web of Science, Scopus, and Google Scholar databases. Results: The investigation of the literature revealed that a total number of 11 studies with a specific focus on the molecular mechanism of mycotoxin exposure and autism were published between 2008 and 2019. Out of these studies, 7 were research articles and 4 were review articles. In almost all the articles, possible links between mycotoxins and ASD were revealed. Conclusion: The examination of the given studies provided data related to the links between mycotoxins and ASD. However, evidence related to these links needs to be investigated in larger samples, while the effects of separate mycotoxins and their metabolisms should also be examined.

Abstract: Garcinia pedunculata Roxb.(GP) belongs to the family of Clusiaceae and is an evergreen tree that grows in semi-wild conditions and is widely distributed throughout the Northeastern part of India. Traditionally, this plant is believed to be of immense medicinal importance and is used for the treatment of various ailments. In Assam, the acidic fruit of GP is effectively used in folklore medicine to treat gastrointestinal disorders and is an integral part of ethnic Assamese cuisine. The ripe fruit, seldom consumed fresh or raw, is cut into thin slices, sun-dried for preservation as it is believed that the medicinal property of the fruit increases as it ages. With much traditional claims and beliefs regarding the medicinal properties of this plant, many therapeutic potentials of GP have been explored through research till now, including its antioxidant, antibacterial, antifungal, anthelmintic, hypolipidemic, antidiabetic, hepatoprotective, neuroprotective, and nephroprotective properties. Moreover, the presence of polyphenols, flavonoids along with bioactive components like hydroxycitric acid, garcinol, and cambogin have also been reported from this plant, thereby increasing its research avenues. Even with the available knowledge, there is a huge lacking in the understanding of its underlying molecular mechanism responsible for the therapeutic properties, pharmacological mode of action, and its effect in different pathological conditions, along with detailed information about its chemical composition. This review mainly aims to summarise the potentially beneficial properties of GP that have already been reported, along with identifying the new avenues that still need to be addressed, thereby increasing the future prospect for in-depth research on this plant, along with its distribution and conservation status.

This study aims to assess the action of miR-34a on MSCs homing onto OSCC. Sixty cases of tissue sample in OSCC was analyzed retrospectively and thirty of normal oral tissue was included as a control group. miR-34a expression in OSCC was detected by qRT-PCR. The relation of expression with OSCC was analyzed. The independent risk factor in the life time of OSCC was studied. pc-DNA-miR-34a and si-miR-34a was transfected into MSCs to analyze its action on MSCs homing onto OSCC by CCK-8 and clone formation assays as well as on cell apoptosis by flow cytometry. The level of miR-34a in patients with OSCC was significantly elevated and was associated with overall survival and prognosis. The FIGO staging and miR-34a expression was the independent risk factor of DFS and OS of patients with OSCC. The cell activity and homing capacity of MSCs was reduced significantly after knock-down of miR-34a expression along with increased apoptotic cell rate. In addition, the miR-34a could prompt the MSC homing onto OSCC. In conclusion, miR-34a level was up-regulated significantly in OSCC and associated with the prognosis, indicating that it might be a novel target for the treatment of OSCC.

Abstract: TMEM16A mediates the calcium-activated transmembrane flow of chloride ions and a variety of physiological functions. The binding of cytoplasmic calcium ions of TMEM16A and the consequent conformational changes of it are the key issues to explore the structure-function relationship. In recent years, researchers have explored this issue through electrophysiological experiments, structure resolving, molecular dynamic simulation, and other methods. The structures of TMEM16 family members determined by cryo-Electron microscopy (cryo-EM) and X-ray crystallization provide the primary basis for the investigation of the molecular mechanism of TMEM16A. However, the binding and activation mechanism of calcium ions in TMEM16A are still unclear and controversial. This review discusses four Ca2+ sensing sites of TMEM16A and analyzes activation properties of TMEM16A by them, which will help understand the structure-function relationship of TMEM16A and throw light on the molecular design targeting the TMEM16A channel.

Introduction Recently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury. Objectives This paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs. Methods A literature search was carried out regarding our topic with the keywords of “atherosclerosis” or “Nrf2/HO-1” or “vascular endothelial cells” or “oxidative stress” or “Herbal medicine” or “natural products” or “natural extracts” or “natural compounds” or “traditional Chinese medicines” based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed. Results These agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies. Conclusion Our present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Background: Experimental evidence has shown that lncRNA MALAT1 is related to proliferation ability, invasion and migration ability, autophagy ability, and chemoresistance in gastric cancer. Moreover, MALAT1 is related to metastasis and patient prognosis in gastric cancer. This review aims to reveal the biological functions and specific mechanisms of MALAT1 in gastric cancer. Methods: After a comprehensive and systematic search in PubMed, various molecular mechanisms of MALAT1 in mediating gastric carcinogenesis are collated and summarized. Results: MALAT1-mediated gastric cancer is involved in a variety of molecular mechanisms. For example, MALAT1 can enhance the proliferation ability of gastric cancer cells by inhibiting the expressions of miR-122, miR-1297, miR-22-3p, miR-202, etc. MALAT1 enhances the metastasis and invasion of gastric cancer by participating in the EMT process, PI3-Akt and other pathways. MALAT1 enhances the proliferation and invasion of gastric cancer by inhibiting the function of the tumor suppressor gene PCDH10. MALAT1 can increase the autophagy ability of gastric cancer cells by inhibiting miR-183 and increasing the level of autophagy markers. MALAT1 enhances chemical resistance by inhibiting UPF1 and miR-30e levels. Conclusions: MALAT1 is tightly linked to gastric carcinogenesis through various molecular mechanisms. Moreover, MALAT1 is also closely associated with chemoresistance and poor prognosis in gastric cancer patients, suggesting the possibility of its use as a clinical therapeutic target and a promising independent risk factor for predicting patient prognosis.

Adenoviruses (Ads), common self-limiting pathogens in humans and animals, usually cause conjunctivitis, mild upper respiratory tract infection or gastroenteritis in humans and hepatotoxicity syndrome in chickens and dogs, posing great threats to public health and livestock husbandry. Artificially modified Ads, which wipe out virulence-determining genes, are the most frequently used viral vectors in gene therapy, and some Ad vector (AdV)-related medicines and vaccines have been licensed and applied. Inherent liver tropism enables AdVs to specifically deliver drugs/genes to the liver; however, AdVs are closely associated with acute hepatotoxicity in immunocompromised individuals, and the side effects of AdVs, which stimulate a strong inflammatory reaction in the liver and cause acute hepatotoxicity, have largely limited clinical application. Therefore, this review systematically elucidates the intimate relationship between AdVs and hepatotoxicity in terms of virus and host and precisely illustrates the accumulated understanding in this field over the past decades. This review demonstrates the liver tropism of AdVs and molecular mechanism of AdV-induced hepatotoxicity and looks at the studies on AdV-mediated animal hepatotoxicity, which will undoubtedly deepen the understanding of AdV-caused liver injury and be of benefit in the further safe development of AdVs.

The outer membrane (OM) of Gram-negative bacteria exhibits unique lipid asymmetry that makes it an effective permeability barrier against toxic molecules, including antibiotics. Central to the maintenance of OM lipid asymmetry is the OmpC-Mla (maintenance of lipid asymmetry) system, which mediates the retrograde transport of phospholipids from the outer leaflet of the OM to the inner membrane. The molecular mechanism(s) of this lipid trafficking process is not fully understood; however, recent advances in structural elucidations and biochemical reconstitutions have provided detailed new insights. Here, we present an integrated understanding of how the OmpC-Mla system transports mislocalized phospholipids across the bacterial cell envelope.

One of the goals of precision medicine is to uncover selective vulnerabilities in various cancers. A notable success has been the development of PARP inhibitors for the treatment of breast and ovarian cancers with mutations in BRCA genes. Only two years ago, it was discovered that cancers with microsatellite instability (MSI) were selectively dependent on the RecQ DNA helicase WRN. Subsequently, the molecular mechanism underlying WRN dependency in MSI cancers was uncovered. Here, we review how these developments have led to a promising new drug target in MSI cancers.

Acute myocardial infarction (AMI) has been a preclinical and clinical concern due to high hospitalization rate and mortality. This study was aimed at evaluating the effectiveness and safety of Shexiang Baoxin Pill (SBP) for AMI and exploring the possible mechanism of oxidative stress. Six databases were searched on March 26, 2021. Twenty-four studies were included and accessed by the RoB 2.0 or SYRCLE tool. Compared with routine treatment (RT), SBP showed the effectiveness in the clinical efficacy ( RR = 1.15 , 95% CI [1.06, 1.25]), left ventricular ejection fraction (LVEF) ( SMD = 0.73 , 95% CI [0.62, 0.95]), glutathione (GSH) ( SMD = 2.07 , 95% CI [1.51, 2.64]), superoxide dismutase (SOD) ( SMD = 0.92 , 95% CI [0.58, 1.26]), malondialdehyde (MDA) ( SMD = − 4.23 , 95% CI [-5.80, -2.66]), creatine kinase-myocardial band (CK-MB) ( SMD = − 4.98 , 95% CI [-5.64, -4.33]), cardiac troponin I (cTnI) ( SMD = − 2.17 , 95% CI [-2.57, -1.76]), high-sensitivity C-reactive protein (Hs-CRP) ( SMD = − 1.34 , 95% CI [-1.56, -1.12]), interleukin-6 (IL-6) ( SMD = − 0.99 , 95% CI [-1.26, -0.71]), triglycerides (TG) ( SMD = − 0.52 , 95% CI [-0.83, -0.22]), flow-mediated dilation (FMD) ( SMD = 1.39 , 95% CI [1.06, 1.72]), von Willebrand Factor (vWF) ( SMD = − 1.77 , 95% CI [-2.39, -1.15]), nitric oxide (NO) ( SMD = 0.89 , 95% CI [0.65, 1.13]), and recurrent rate ( RR = 0.30 , 95% CI [0.15, 0.59]). But SBP adjunctive to RT plus PCI had no improvements in almost pooled outcomes except for the Hs-CRP ( SMD = − 1.19 , 95% CI [-1.44, -0.94]) and TG ( SMD = − 0.25 , 95% CI [-0.48, -0.02]). Laboratory findings showed that SBP enhanced the endothelial nitric oxide synthase (eNOS) activity and regulated laboratory indexes especially for homocysteine. In conclusion, SBP has adjunctive effects on AMI via the mechanism of antioxidative stress. The current evidence supports the use of SBP for mild and moderate AMI patients.

The fundamental concepts of the aging process are exposed: Its dimension as a health problem, aspects related to its repercussion from the social point of view, and Its influence on aspects that can affect the normal development of contemporary society. The roles of genetics, cellular and biochemical processes that concur in the development of aging is analyzed, making special reference to the role of Adenosine Mono Phosphate Kinase [AMPK]. activation in the regulation of the aging process and the participation of mechanisms for its activation. It is concluded that Policosanol is a medicament of natural origin that could be proposed as candidate to be used for a healthy aging, based on the results of various investigations in experimental models and data obtained from different clinical trials.

Objective. Nephrotic syndrome (NS) is a common glomerular disease caused by a variety of causes and is the second most common kidney disease. Guizhi is the key drug of Wulingsan in the treatment of NS. However, the action mechanism remains unclear. In this study, network pharmacology and molecular docking were used to explore the underlying molecular mechanism of Guizhi in treating NS. Methods. The active components and targets of Guizhi were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Hitpick, SEA, and Swiss Target Prediction database. The targets related to NS were obtained from the DisGeNET, GeneCards, and OMIM database, and the intersected targets were obtained by Venny2.1.0. Then, active component-target network was constructed using Cytoscape software. And the protein-protein interaction (PPI) network was drawn through the String database and Cytoscape software. Next, Gene Ontology (GO) and pathway enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by DAVID database. And overall network was constructed through Cytoscape. Finally, molecular docking was conducted using Autodock Vina. Results. According to the screening criteria, a total of 8 active compounds and 317 potential targets of Guizhi were chosen. Through the online database, 2125 NS-related targets were identified, and 93 overlapping targets were obtained. In active component-target network, beta-sitosterol, sitosterol, cinnamaldehyde, and peroxyergosterol were the important active components. In PPI network, VEGFA, MAPK3, SRC, PTGS2, and MAPK8 were the core targets. GO and KEGG analyses showed that the main pathways of Guizhi in treating NS involved VEGF, Toll-like receptor, and MAPK signaling pathway. In molecular docking, the active compounds of Guizhi had good affinity with the core targets. Conclusions. In this study, we preliminarily predicted the main active components, targets, and signaling pathways of Guizhi to treat NS, which could provide new ideas for further research on the protective mechanism and clinical application of Guizhi against NS.

Preclinical evidence suggests effectiveness of the combined inhibition of bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) proteins in the treatment of Waldenstr��m macroglobulinemia (WM). However, toxicity, dosing scheduling, and drug���drug interactions are common challenges in combined therapy. In this article, we scrutinise the potential synergistic effect of a dual acting anti-cancer therapy using a single drug TW22 that concomitantly inhibits BET/HDAC proteins, which may open a new line of therapeutic protocol in the treatment of Waldenstr��m macroglobulinemia (WM). The preferential binding mechanisms of the dual inhibition of BET/HDAC enzymes have been a subject of debate in literature. In this report, molecular dynamic simulations coupled with other advanced biocomputational tools were applied to investigate the preferential binding modes and the conformational implications of dual inhibition of both BET/HDAC enzymes. Intriguingly, findings show that multitarget TW22 have superior binding affinity by16.2% and 39.8% than BET/HDAC parent inhibitor molecules JQ1 and Panobinostat, respectively. This disparity has also resulted in higher protein stability and prominent correlated motions were observed with the least fluctuations and multiple van der Waals interactions. The findings of this study will aid in the design of improved anti-cancer agents, thus allowing for increased patient adherence.

A diastereoselective synthesis of biologically interesting spirobarbiturates has been achieved via [3+2] cycloaddition of alloxan-derived azomethine ylides to 3-R-1,2-diphenylcyclopropenes. With this approach, a range of spirobarbiturate-3-azabicyclo[3.1.0]hexanes and spirobarbiturate-cyclopropa[a]pyrrolizines were obtained in moderate to good yields with excellent diastereoselectivities. DFT calculations (M11 density functional theory) were carried out to shed light on the molecular mechanism of 1,3-dipolar cycloaddition of alloxan-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some obtained compounds against human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.

BACKGROUND Basic 7S globulins, a group of proteins commonly found in legumes, undergo the intriguing phenomenon of release from the seeds into hot water. γ-Conglutin is a representative of this group of proteins found in lupin seeds. The physiological significance and the molecular mechanism of the selective release of γ-conglutin from lupin seeds remain unknown. Therefore, the presented study aimed to determine changes in the functionality of this protein in response to the high temperature occurring during lupin seed incubation. RESULTS It was confirmed that the main protein fraction released from the seeds during high-temperature incubation was γ-conglutin. The incubation condition favours the occurrence of this protein in a monomeric form, and the temperature used corresponds to its midpoint unfolding temperature. Subsequent analysis carried out on the γ-conglutin monomer revealed changes in its functionality after heat shock. The thermally treated protein shows a considerable increase in its interaction strength with flavonoids. Moreover, the inhibitory activity against glycoside hydrolases was enhanced when γ-conglutin monomer was exposed to specific temperatures. CONCLUSION The results of the present study provide a potential explanation of the physiological relevance of γ-conglutin and shed new light on a possible mechanism of its activation upon specific heat treatment. This knowledge will help characterise homologous proteins, which are commonly found in other legumes and undergo a similar heat-induced secretion phenomenon. © 2021 Society of Chemical Industry.

Hyperlipidemia is a lipid metabolism disorder occurring due to consumption of a high-fat diet (HFD), which contributes to atherosclerosis and cardiovascular disease development. HFD causes metabolic problems in Rodentia animals like human metabolic abnormalities, making it a popular model for studying the signaling systems involved. Hyperlipidemia is a condition in which the body's cholesterol levels elevate. In recent years, several studies have investigated the relationship between HFD feeding and hyperlipidemia and signaling pathways involved in cholesterol homeostasis. However, this signaling mechanism in lipid metabolism has not been fully explained, so additional analysis is needed. The present study aimed to investigate the mechanism that occurs from hyperlipidemia due to HFD feeding. The method used is a literature review approach following the PRISMA scheme for selecting the primary literature, including identification, screening, eligibility test, and inclusion. Eleven articles included primary literature with credibility (H-index) of 20, 33, 71, 92, 93, 162, 180, 192, and 332 (six articles from Q1 journals and five from Q2 journals). Long-term administration of HFD directly affects lipid metabolism, including an increase in the concentration of total cholesterol, triglycerides, LDL, and a decrease in HDL concentration, followed by an increase in body weight. In addition, HFD also disrupts adipose tissue and insulin resistance. The conclusion of this study is that HFD can cause hyperlipidemia either directly or indirectly by inducing insulin resistance, which contributes to lipid metabolism disorders.

P-Coumaric acid (p-CA) is a hydroxycinnamic acid, an organic compound that is a hydroxyl derivative of cinnamic acid. P-CA is the most abundant isomer in nature and can be found in a wide variety of edible plants such as fungi, peanuts, navy beans, tomatoes, carrots, basil, and garlic. Recently, the therapeutic properties of p-CA have received a great deal of attention from scientific society. Here, we described the medicinal effects of p-CA on various pathological conditions. This review was performed via evaluating PubMed reported studies from January 2010 to January 2020. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, in vitro studies, and controlled trials (CTs) on p-CA were acceptable. However plant extract studies without indication of main active substances were excluded due to the considerable diversities and heterogeneities. According to recent evidence regarding the beneficial effects of p-CA, numerous diseases such as nephropathies, cardiovascular diseases, neuroinflammatory diseases, liver diseases, cancers, and some metabolic disorders could potentially be controlled by this natural herb. Interestingly, autophagy is a novel molecular mechanism involved in the crosstalk between classic effects of p-CA and introduces alternative therapeutic pathways for this compound. Much work remains in clarifying the main therapeutic properties among the various p-CA effects; these will be the subject of forthcoming work, resulting in presenting further mechanism of action.

BACKGROUND Orthodontic treatment is the main treatment approach for malocclusion. Orthodontic pain is an inevitable undesirable adverse reaction during orthodontic treatment. It is reported orthodontic pain has become one of the most common reason that patients withdraw from orthodontic treatment. Therefore, understanding the underlying mechanism and finding treatment of orthodontic pain are in urgent need. AIMS This article aims to sort out the mechanisms and treatments of orthodontic pain, hoping to provide some ideas for future orthodontic pain relief. MATERIALS Tooth movement will cause local inflammation. Certain inflammatory factors and cytokines stimulating the trigeminal nerve and further generating pain perception, as well as drugs and molecular targeted therapy blocking nerve conduction pathways, will be reviewed in this article. METHOD We review and summaries current studies related to molecular mechanisms and treatment approaches in orthodontic pain control. RESULTS Orthodontics pain related influencing factors and molecular mechanisms has been introduced. Commonly used clinical methods in orthodontic pain control has been evaluated. DISCUSSION With the clarification of more molecular mechanisms, the direction of orthodontic pain treatment will shift to targeted drugs.

The favorable physicochemical properties are essential for the application of protein-based nanovehicles in the field of biomaterials. Herein, we found that the thermal stability of Marsupenaeus japonicus ferritin (MjFer) (Tm = 109.1 ± 0.4 °C) is markedly higher than human H-chain ferritin (HuHF) (Tm = 87.7 ± 0.3 °C), although they share a high structural similarity. Multiple results indicated that the promoted thermal stability of MjFer is mainly derived from the salt bridges located at the C3 interface. Consequently, MjFer exhibits strong protective effects on encapsulated curcumin upon exposure at high temperatures. In contrast, most of the curcumin loaded HuHF composites precipitated rapidly under the same conditions. These findings elucidated the molecular mechanism of the hyperthermostability of MjFer and illustrated that MjFer could act as a robust insulation nanocarrier for bioactive compounds against various thermal treatments.

As a crucial molecular mechanism, post-translational modifications (PTMs) play critical roles in a wide range of biological processes in plants. Recent advances in mass spectrometry-based proteomic technologies have greatly accelerated the profiling and quantification of plant PTM events. Although several databases have been constructed to store plant PTM data, a resource including more plant species and more PTM types with quantitative dynamics still remains to be developed. In this paper, we present an integrative database of quantitative PTMs in plants named qPTMplants (http://qptmplants.omicsbio.info), which hosts 1 242 365 experimentally identified PTM events for 429 821 nonredundant sites on 123 551 proteins under 583 conditions for 23 PTM types in 43 plant species from 293 published studies, with 620 509 quantification events for 136 700 PTM sites on 55 361 proteins under 354 conditions. Moreover, the experimental details, such as conditions, samples, instruments and methods, were manually curated, while a variety of annotations, including the sequence and structural characteristics, were integrated into qPTMplants. Then, various search and browse functions were implemented to access the qPTMplants data in a user-friendly manner. Overall, we anticipate that the qPTMplants database will be a valuable resource for further research on PTMs in plants.

Background: Long term intake of high amount of fluoride leads to fluorosis causing metabolic, functional and structural damages affecting many tissues and organs including dental and skeletal manifestations. The liver is the most susceptible organ to fluoride toxicity because of its active and major role in digestion and detoxification. Aim: The present study aims to elucidate the effects of sodium fluoride on hepatic function biomarkers, lipid peroxidation and gene expression of Cu/Zn SOD in albino rats. Materials and Methods: Wistar albino rats were randomly assigned to three groups. The control rats were given 1 ml deionized water orally for 40 days. Groups II and III were administered 300 and 600 mg NaF/kg b.w. /day for the same period. Animals were sacrificed under anaesthesia, liver tissue was excised and used for biochemical and molecular analysis. The level of fluoride and lipid peroxidation (MDA) as well as reduced glutathione (GSH) content was determined. The activities of cytosolic copper/zinc superoxide dismutase (Cu/Zn SOD), aminotransferases (ALT and AST), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in the hepatic tissue were determined. The analysis of gene expression of Cu/Zn SOD in the liver was determined using Real-time PCR. Results: The results revealed significantly (P

Background: Both prescription and over-the-counter (OTC) drugs recently emerged among novel psychoactive substances (NPS) being reported as ingested for recreational purposes. Among them, benzydamine (BZY), normally prescribed as an OTC anti-inflammatory drug, is reportedly being diverted and recreationally used. Objective: The aim of this study was to investigate how the misuse of BZY has been reported, illustrating its psychotropic molecular mechanism, and studying its psychopathological effects. Methods: We firstly conducted a systematic review of the literature concerning the abuse of BZY and its effects. For data gathering purposes, both PRISMA and PROSPERO guidelines were followed. All research methods were approved by PROSPERO (identification code CRD42020187266). Second, we analysed BZY-related data from the European Monitoring Agency (EMA) Adverse Drug Reactions (ADRs) database recorded during 2005-2020 regarding its abuse. Results: Eleven articles, published during 1997-2019, were included in our systematic review, including five case reports, four surveys, and two retrospective case series analyses. While nine articles dealt with the recreational use of BZY, two described an oral overdose of the drug. When specified, dosages of BZY consumed ranged from 500 to 1500mg. The EMA dataset contained three cases of BZY abuse. Conclusion: Results from the systematic review showed BZY might be diverted for typical hallucinogenic properties occurring at high dosages. Healthcare professionals should be warned about a possible misuse/abuse of a commonly prescribed anti-inflammatory drug and be vigilant when prescribing it. Physicians working in emergency units should know that psychotic symptoms may be related to BZY abuse.

Structure-specific endonucleases (SSEs) cleave the DNA substrate in a precise position based on the specific DNA 3D structure. Human flap endonuclease 1 (hFEN1) is a 5′ SSE that prevents DNA instability by processing Okazaki fragment 5′-flaps with remarkable efficiency and selectivity using two-metal-ion catalysis. Recent structural and mutagenesis data of hFEN1 suggest that phosphate steering favors specificity and catalysis. Here, we investigate the phosphate steering mechanism at the atomistic level using microsecond-long molecular dynamics and well-tempered metadynamics simulations of wild-type and mutant systems of hFEN1. We show how positively charged second and third-shell residues operate the phosphate steering mechanism to promote catalysis through (i) substrate recruitment; (ii) precise cleavage localization; and (iii) substrate release, thus actively preventing the off-target incision of the substrate. Importantly, structural comparisons of hFEN1 and other nuclease enzymes suggest that phosphate steering may also serve the structure-based selection of the specific DNA substrate by other 5′ structure-specific nucleases.

Atmospheric gases trapped in polar ice have been used to reconstruct polar and global climate changes, providing better time resolution when less diffused. Experiments have shown that gas diffusion...

In this study, we aim to identify the clinical significance of basonuclin 1 ( BNC1) expression in ovarian carcinoma (OV) and to explore its latent mechanisms. Via integrating in-house tissue microarrays, gene chips, and RNA-sequencing data, we explored the expression and clinical value of BNC1 in OV. Immunohistochemical staining was utilized to confirm the protein expression status of BNC1. A combined SMD of –2.339 (95% CI: –3.649 to –1.028, P < 0.001) identified that BNC1 was downregulated based on 1346 samples, and the sROC (AUC = 0.93) showed a favorable discriminatory ability of BNC1 in OV patients. We used univariate and multivariate Cox regulation to evaluate the prognostic role of BNC1 for OV patients, and a combined hazard ratio of 0.717 (95% CI: 0.445–0.989, P < 0.001) revealed that BNC1 was a protective factor for OV. Furthermore, the fraction of infiltrating naive B cells, memory B cells, and other immune cells showed statistical differences between the high- and low- BNC1 expression groups through cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. Enrichment analysis showed that BNC1 may have a relationship with immune-related items in OV. By predicting the potential regulatory transcription factors (TFs) of BNC1, friend leukemia virus integration 1 ( FLI1) may be a potential upstream TF of BNC1. Corporately, a decreasing trend of BNC1 may serve as a tumor suppressor and prognostic biomarker in OV patients. Moreover, BNC1 may take part in immune-related pathways and influence the fraction of tumor-infiltrating immune cells.

High temperature (HT) stress has become one of the most detrimental stresses in crop production among constantly changing environmental factors. Exploiting approaches to enhance crop thermotolerance would have great significance in assuaging adverse effects of HT stress on crop growth and development. As jasmonates (JAs) and brassinosteroids (BRs) are novel phytohormones and play important roles in responses to biotic and abiotic stresses and in a wide range of plant developmental processes, this paper reviewed the roles and mechanisms of JAs and BRs in mitigating HT stress, with focus on rice (Oryza sativa L.) subjected to HT stress during anthesis. It is demonstrated that JAs alleviate spikelet-opening impairment and BRs ameliorate pistil fertilization ability under HT stress during anthesis of rice, although there are controversial observations. Activating the defense system, enhancing osmotic regulation, protecting photosynthesis, and interacting with other phytohormones, especially with ethylene and abscisic acid, are main physiological mechanisms by which JAs or BRs attenuate HT stress to plants. Elevating levels of JAs or BRs in plants could be considered as an important approach to enhance crop thermotolerance through breeding new varieties. Using JAs or BRs as chemical regulators and adopting proper water and nitrogen management practices could reduce the harm of HT stress to rice. Further research is needed to elucidate the roles of JAs and BRs in different plant tissues in responses to HT stress under different genetic backgrounds and environments, reveal the molecular mechanism underlying JAs and BRs mediating HT stress, understand the cross-talk between phytohormones in modulating HT stress, and establish integrated crop management to minimize the hazard of HT stress in rice production.

Yam (Dioscorea opposita) is a kind of vegetables with important nutritional, medicinal and economic value. To reveal the relationship between starch synthesis and gene expression in yam tubers at gene transcription level, transcriptome profiling was conducted by RNA-Seq in Bikeqi yam (Dioscorea opposita Thunb.) tubers at five key developmental stages (105, 120, 135, 150, and 165 days after sowing, DAS). Based on transcriptome sequencing data, a total of 45,867 unigenes were obtained. The results showed that 135 days after sowing are the key period of starch accumulation. During yam tuber development, 1,941 candidate differentially expressed genes (DEGs) were successfully classified into three GO categories, respectively, and there were 292, 267 and 478 unigenes in cellular component, molecular function and biological process. There were 767, 90 and 73 DEGs enriched in metabolic, plant hormone signal transduction and Plant-pathogen interaction pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG), individually. Especially 72 DEGs were enriched in starch and sucrose metabolism pathway. In this pathway, the metabolic process was mainly positive regulated by genes encoding sucrose synthase, glucose-1-phosphate adenylyltransferase, alpha-trehalase, and so on. There was negative regulated by genes encoding beta-glucosidase. 10 DEGs involved in starch synthesis were selected to prove the accuracy of the RNA-Seq data by qPCR, 85% (34/40) of the results were consistent. The results lay a theoretical foundation be used for further understanding the starch synthesis mechanism of yam tubers development and accelerating breeding progress.

The abnormal expression of transgelin-2 (TAGLN2) is related to tumor occurrence and progression. However, the underlying molecular mechanism of TAGLN2 in human colorectal cancer (CRC) is still poorly understood. Compared with adjacent tissues, TAGLN2 is overexpressed in CRC tissues. Its expression level is negatively correlated with the overall survival rate of patients with CRC. In addition, knockdown of TAGLN2 inhibited the proliferation and invasion of CRC cells. We also showed that TAGLN2 could interact with CD44 to regulate the Notch-1 signaling pathway. Our findings indicate there is increased TAGLN2 expression in CRC and that it may serve as a promising potential therapeutic target for CRC.

Summary Yield in rice is determined mainly by panicle architecture. Using map‐based cloning, we identified an R2R3 MYB transcription factor REGULATOR OF GRAIN NUMBER1 (RGN1) affecting grain number and panicle architecture. Mutation of RGN1 caused an absence of lateral grains on secondary branches. We demonstrated that RGN1 controls lateral grain formation by regulation of LONELY GUY (LOG) expression, thus controlling grain number and shaping panicle architecture. A novel favourable allele, RGN1 C, derived from the Or‐I group in wild rice affected panicle architecture by means longer panicles. Identification of RGN1 provides a theoretical basis for understanding the molecular mechanism of lateral grain formation in rice; RGN1 will be an important gene resource for molecular breeding for higher yield.

Long non–coding RNA AC020978 (lncRNA AC020978) is an oncogenic regulator of non–small cell lung cancer (NSCLC). However, the function of AC020978 in regulating NSCLC metastasis and the potential molecular mechanism remains largely unknown. In this study, we evaluated the expression levels of AC020978 in a series of NSCLC tissues using FISH assays and found that higher AC020978 expression levels were closely associated with metastasis and unfavorable prognosis. Functional studies showed that AC020978 promoted NSCLC migration and invasion both in vitro and in vivo. Further investigation demonstrated that AC020978 interacted with malate dehydrogenase 2 (MDH2) and maintained MDH2 stability. Knockdown of MDH2 weakened the facilitating effect on cell metastasis and 2‐hydroxyglutarate (2‐HG) metabolism in AC020978‐overexpressed NSCLC cells. RNA sequencing, bioinformatic analysis, and western blotting revealed that AC020978 was associated with the AKT signaling pathway. Taken together, our findings revealed that AC020978 might serve as a prognostic biomarker and activate the AKT pathway by stabilizing MDH2, leading to metastasis and progression of NSCLC., We identified the metastasis‐related function of lncRNA AC020978 in NSCLC, which directly interacts with MDH2 and promotes migration and invasion of lung cancer through the AC020978/MDH2/AKT axis.

Trichomes are specialized glandular or non-glandular structures that provide physical or chemical protection against insect and pathogen attack. Trichomes in Arabidopsis have been extensively studied as typical non-glandular structures. By contrast, the molecular mechanism underlying glandular trichome formation and elongation remains largely unknown. We previously demonstrated that Hair is essential for the formation of type I and type VI trichomes. Here, we found that overexpression of Hair increased the density and length of tomato trichomes. Biochemical assays revealed that Hair physically interacts with its close homolog SlZFP8-like (SlZFP8L), and SlZFP8L also directly interacts with Woolly. SlZFP8L-overexpressing plants showed increased trichome density and length. We further found that the expression of SlZFP6, which encodes a C2H2 zinc finger protein, is positively regulated by Hair. Using chromatin immunoprecipitation, yeast one-hybrid, and dual-luciferase assays we identified that SlZFP6 is a direct target of Hair. Similar to Hair and SlZFP8L, the overexpression of SlZFP6 also increased the density and length of tomato trichomes. Taken together, our results suggest that Hair interacts with SlZFP8-like to regulate the initiation and elongation of trichomes by modulating SlZFP6 expression in tomato.

The dysregulation of Notch signaling is found in many cancers and is closely related to cancer progression. As an important Notch receptor, abnormal Notch4 expression affects several tumor-cell behaviors, including stemness, the epithelial–mesenchymal transition, radio/chemoresistance and angiogenesis. In order to inhibit the oncogenic effects of Notch4 activation, several methods for targeting Notch4 signaling have been proposed. In this review, we summarize the known molecular mechanisms through which Notch4 affects cancer progression. Finally, we discuss potential Notch4-targeting therapeutic strategies as a reference for future research.

Xiao Cheng, Zhihui Song, Xin Wang, Shanshan Xu, Liming Dong, Jie Bai, Guangyao Li, Chao Zhang Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Chao ZhangDepartment of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel/Fax +86-10-58267167Email laural.zhang@yahoo.comPurpose: Protocatechualdehyde (PCA) is a phenolic compound found in the roots of Salvia miltiorrhiza with anti-proliferative and antioxidant activities. At present, there are few studies on protocatechualdehyde against diabetic cataract (DC), and there is also lack of systematic research on the mechanism of protocatechualdehyde. Therefore, this study tried to comprehensively clarify the targets and complex mechanisms of PCA against DC from the perspective of network pharmacology.Materials and Methods: Through collecting relevant targets from the databases, GO and KEGG enrichment analysis were performed on the potential targets. Moreover, core genes were identified by topological analysis of protein–protein interaction (PPI) network and gene–phenotype correlation analysis.Results: The results indicated that protocatechualdehyde may be closely related to targets such as AKT1, MAPK3 and HDAC3, as well as signal pathways such as MAPK signaling pathway, PI3K-Akt signaling pathway and AGE-RAGE signaling pathway in diabetic complications.Conclusion: Together, the present study systematically clarified the possible mechanisms of protocatechualdehyde in the treatment of diabetic cataract and provided new ideas for the drug research of this disease.Keywords: protocatechualdehyde, diabetic cataract, network pharmacology, topological analysis, gene–phenotype correlation analysis

Pathological cardiac hypertrophy begins as an adaptive response to increased workload; however, sustained hemodynamic stress will lead it to maladaptation and eventually cardiac failure. Mitochondria, being the powerhouse of the cells, can regulate cardiac hypertrophy in both adaptive and maladaptive phases; they are dynamic organelles that can adjust their number, size, and shape through a process called mitochondrial dynamics. Recently, several studies indicate that promoting mitochondrial fusion along with preventing mitochondrial fission could improve cardiac function during cardiac hypertrophy and avert its progression toward heart failure. However, some studies also indicate that either hyperfusion or hypo-fission could induce apoptosis and cardiac dysfunction. In this review, we summarize the recent knowledge regarding the effects of mitochondrial dynamics on the development and progression of cardiac hypertrophy with particular emphasis on the regulatory role of mitochondrial dynamics proteins through the genetic, epigenetic, and post-translational mechanisms, followed by discussing the novel therapeutic strategies targeting mitochondrial dynamic pathways., Graphical abstract, This review summarizes the current knowledge regarding the role of mitochondrial dynamics (MD) in cardiac hypertrophy with particular emphasis on the regulatory role of mitochondrial dynamic proteins through the genetic, epigenetic, and post-translational mechanisms, followed by discussing the novel therapeutic strategies targeting MD pathways.