Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Bcl-2 over-expression and activation of protein kinase C suppress the Trail-induced apoptosis in Jurkat T cells

Trail, a tumor necrosis factor-related apoptosis-inducing ligand, is a novel potent endogenous activator of the cell death pathway through the activation of cell surface death receptors Trail-R1 and Trail-R2. Its role, like FasL in activation-induced cell death (AICD), has been demonstrated in immune system. However the mechanism of Trail induced apoptosis remains unclear. In this report, the recombinant Trail protein was expressed and purified. The apoptosis-inducing activity and the regulation mechanism of recombinant Trail on Jurkat T cells were explored in vitro. Trypan blue exclusion assay demonstrated that the recombinant Trail protein actively killed Jurkat T cells in a dose-dependent manner. Trail-induced apoptosis in Jurkat T cells were remarkably reduced by Bcl-2 over expression in Bcl-2 gene transfected cells. Treatment with PMA (phorbol 12-myristate 13-acetate), a PKC activator, suppressed Trail-induced apoptosis in Jurkat T cells. The inhibition of apoptosis by PMA was abolished by pretreatment with Bis, a PKC inhibitor. Taken together, it was suggested that Bcl-2 over-expression and PMA activated PKC actively down-regulated the Trail-mediated apoptosis in Jurkat T cell.

Yinchenhao decoction attenuates obstructive jaundice-induced liver injury and hepatocyte apoptosis by suppressing protein kinase RNA-like endoplasmic reticulum kinase-induced pathway

BACKGROUND Chronic biliary obstruction results in ischemia and hypoxia of hepatocytes,and leads to apoptosis.Apoptosis is very important in regulating the homeostasis of the hepatobiliary system.Endoplasmic reticulum(ER)stress is one of the signaling pathways that induce apoptosis.Moreover,the protein kinase RNA-like endoplasmic reticulum kinase(PERK)-induced apoptotic pathway is the main way;but its role in liver injury remains unclear.Yinchenhao decoction(YCHD)is a traditional Chinese medicine formula that alleviates liver injury and apoptosis,yet its mechanism is unknown.We undertook this study to investigate the effects of YCHD on the expression of ER stress proteins and hepatocyte apoptosis in rats with obstructive jaundice(OJ).AIM To investigate whether YCHD can attenuate OJ-induced liver injury and hepatocyte apoptosis by inhibiting the PERK-CCAAT/enhancer-binding protein homologous protein(CHOP)-growth arrest and DNA damage-inducible protein 34(GADD34)pathway and B cell lymphoma/leukemia-2 related X protein(Bax)/B cell lymphoma/leukemia-2(Bcl-2)ratio.METHODS For in vivo experiments,30 rats were divided into three groups:control group,OJ model group,and YCHD-treated group.Blood was collected to detect the indicators of liver function,and liver tissues were used for histological analysis.For in vitro experiments,30 rats were divided into three groups:G1,G2,and G3.The rats in group G1 had their bile duct exposed without ligation,the rats in group G2 underwent total bile duct ligation,and the rats in group G3 were given a gavage of YCHD.According to the serum pharmacology,serum was extracted and centrifuged from the rat blood to cultivate the BRL-3A cells.Terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling(TUNEL)assay was used to detect BRL-3A hepatocyte apoptosis.Alanine aminotransferase(ALT)and aspartate transaminase(AST)levels in the medium were detected.Western blot and quantitative real-time polymerase chain reaction(qRT-PCR)analyses were used to detect protein and gene expression levels of PERK,CHOP,GADD34,Bax,and Bcl-2 in the liver tissues and BRL-3A cells.RESULTS Biochemical assays and haematoxylin and eosin staining suggested severe liver function injury and liver tissue structure damage in the OJ model group.The TUNEL assay showed that massive BRL-3A rat hepatocyte apoptosis was induced by OJ.Elevated ALT and AST levels in the medium also demonstrated that hepatocytes could be destroyed by OJ.Western blot or qRT-PCR analyses showed that the protein and mRNA expression levels of PERK,CHOP,and GADD34 were significantly increased both in the rat liver tissue and BRL-3A rat hepatocytes by OJ.The Bax and Bcl-2 levels were increased,and the Bax/Bcl-2 ratio was also increased.When YCHD was used,the PERK,CHOP,GADD34,and Bax levels quickly decreased,while the Bcl-2 levels increased,and the Bax/Bcl-2 ratio decreased.CONCLUSION OJ-induced liver injury and hepatocyte apoptosis are associated with the activation of the PERK-CHOP-GADD34 pathway and increased Bax/Bcl-2 ratio.YCHD can attenuate these changes.

Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins

The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.

Protein tyrosine phosphatase non-receptor Ⅱ:A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma

BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

A potential hyphal fusion protein complex with an important role in development and virulence interacts with autophagy-related proteins in Fusarium pseudograminearum

Hyphal fusion(anastomosis)is a common process serving many important functions at various developmental stages in the life cycle of ascomycetous fungi.However,the biological roles and molecular mechanisms in plant pathogenic fungi were widely unknown.In this study,a hyphal fusion protein FpHam-2 was screened from a T-DNA insertion mutant library of Fusarium pseudograminearum,and FpHam-2 interacts with another 2 hyphal fusion protein homologues FpHam-3 and FpHam-4.Each of these 3 genes deletion mutant revealed in similar defective phenotypes compared with the WT and complemented strains,including reduction in growth rate,defects in hyphal fusion and conidiation,more sensitive for cell membrane,cell wall and oxidative stress responses,and decreased in virulence.The yeast two-hybrid assay was used to identify that FpHam-2 interacts with 3 autophagy-related proteins,including FpAtg3,FpAtg28 and FpAtg33.Furthermore,FpHam-2-deletion mutant showed decreased accumulation of autophagic bodies in hypha.In conclusion,FpHam-2,FpHam-3 and FpHam-4 have an essential role for hyphal fusion and regulating the growth,conidiation and virulence in F.pseudograminearum.

Low-density lipoprotein receptor-related protein 2(LRP2)is required for lipid export in the midgut of the migratory locust,Locusta migratoria

Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis.However,little is known about the role of LRP2 in lipid homeostasis in insects.In the present study,we investigated the function of LRP2 in the migratory locust Locusta migratoria(LmLRP2).The mRNA of LmLRP2 is widely distributed in various tissues,including integument,wing pads,foregut,midgut,hindgut,Malpighian tubules and fat body,and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage.Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut.Using RNAi to silence LmLRP2 caused molting defects in nymphs(more than 60%),and the neutral lipid was found to accumulate in the midgut and surface of the integument,but not in the fat body,of dsLmLRP2-treated nymphs.The results of a lipidomics analysis showed that the main components of lipids(diglyceride and triglyceride)were significantly increased in the midgut,but decreased in the fat body and hemolymph.Furthermore,the content of total triglyceride was significantly increased in the midgut,but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs.Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells,and is required for lipid export from the midgut to the hemolymphand fat body in locusts.

Decreased Amino Acid Transporter LAT2 Is the Main Determinant of Impaired Protein Utilization During Aging

As the global demographic shifts toward an aging population,understanding the efficiency of protein uti-lization in older adults becomes crucial.Our study explores the intricate relationship between protein intake and aging,with a focus on precision nutrition for older people.Through a meta-analysis,we con-firm a decline in protein-utilization capacity in older individuals and examine the different contributions of plant and animal protein.In experiments involving mice of different ages,older mice exhibited decreases in the biological utilization of four proteins(casein,beef protein,soy protein,and gluten),par-ticularly casein.In subsequent research,casein was studied as a key protein.A decline in gastric digestion function was observed through peptidomics and the examination of pepsin levels using casein.Nevertheless,this decline did not significantly affect the overall protein digestion during the aging pro-cess.The combined application of targeted amino acid metabolomics identified abnormal absorption of amino acids as the underlying cause of decreased protein utilization during aging,particularly emphasiz-ing a reduction in branched-chain amino acids(BCAAs)in older mice.Delving deeper into the proteomics of the intestinal protein digestion and absorption pathway,a reduction of over 60%in large neutral amino acid transporter 2(LAT2)protein expression was observed in both older humans and aged mice.The reduction in LAT2 protein was found to be a key factor influencing the diminished BCAA availability.Overall,our study establishes the significance of amino acid absorption through LAT2 in protein utiliza-tion during aging and offers a new theoretical foundation for improving protein utilization in the older adults.

Exploration of cyclooxygenase-2 inhibitory peptides from walnut dreg proteins based on in silico and in vitro analysis

Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis.In total,1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry(nano LC-MS/MS)and 4 novel COX-2 inhibitory peptides(AGFP,FPGA,LFPD,and VGFP)were identified.Enzyme kinetic data indicated that AGFP,FPGA,and LFPD displayed mixed-type COX-2 inhibition,whereas VGFP was a non-competitive inhibitor.This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site.These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.

Subtraction of liposome signals in cryo-EM structural determination of protein-liposome complexes

Reconstituting membrane proteins in liposomes and determining their structure is a common method for determining membrane protein structures using single-particle cryo-electron microscopy(cryo-EM).However,the strong signal of liposomes under cryo-EM imaging conditions often interferes with the structural determination of the embedded membrane proteins.Here,we propose a liposome signal subtraction method based on single-particle two-dimensional(2D)classification average images,aimed at enhancing the reconstruction resolution of membrane proteins.We analyzed the signal distribution characteristics of liposomes and proteins within the 2D classification average images of protein–liposome complexes in the frequency domain.Based on this analysis,we designed a method to subtract the liposome signals from the original particle images.After the subtraction,the accuracy of single-particle three-dimensional(3D)alignment was improved,enhancing the resolution of the final 3D reconstruction.We demonstrated this method using a PIEZO1-proteoliposome dataset by improving the resolution of the PIEZO1 protein.

Jiaohong pills attenuate neuroinflammation and amyloid-βprotein-induced cognitive deficits by modulating the mitogen-activated protein kinase/nuclear factor kappa-B pathway

Background:Jiaohong pills(JHP)consist of Pericarpium Zanthoxyli(PZ)and Radix Rehmanniae,two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment.However,the precise mechanisms underlying the beneficial effects remain elusive.Here,research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease.Methods:BV-2 cell inflammation was induced by lipopolysaccharide.AD mice were administered amyloid-β(Aβ).Behavioral experiments were used to evaluate learning and memory ability.The levels of nitric oxide(NO),tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and interleukin-10(IL-10)were detected using enzymelinked immunosorbent assay(ELISA).The protein expressions of inducible nitric oxide synthase(iNOS)and the phosphorylation level of mitogen-activated protein kinase(MAPK)and nuclear factor kappa-B(NF-κB)were detected using Western blot.Nissl staining was used to detect neuronal degeneration.Results:The results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO,IL-1β,TNF-α,and iNOS;increased the expression level of IL-10;and significantly decreased the phosphorylation levels of MAPK and NF-κB.These inhibitory effects were further confirmed in the AD mouse model.Meanwhile,JHP improved learning and memory function in AD mice,reduced neuronal damage,and enriched the Nissl bodies in the hippocampus.Moreover,IL-1βand TNF-αin the cortex were significantly downregulated after JHP administration,whereas IL-10showed increased expression.Conclusions:It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF-κB signaling pathway.

GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines

BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.

Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.

Bone morphogenetic protein-7 induced bone marrow stromal cells differentiate into neuron-like cells

Bone morphogenetic protein-7 is widely accepted as an inducer for bone marrow stem cells differentiating into osteoblasts and chondrocytes. Whether bone marrow stromal cells differentiate into neuron-like cells remains unclear. The current study examined the presence of positive cells for intermediate filament protein and microtubule associated protein-2 in the cytoplasm of bone marrow stromal cells induced by bone morphogenetic protein-7 under an inverted microscope, while no expression of glial fibrillary acidic protein was found. Reverse transcription PCR electrophoresis also revealed a positive target band for intermediate filament protein and microtubule-associated protein 2 mRNA. These results confirmed that bone morphogenetic protein-7 induces rat bone marrow stromal cells differentiating into neuron-like cells.

Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis

BACKGROUND Recently,type 2 diabetic osteoporosis(T2DOP)has become a research hotspot for the complications of diabetes,but the specific mechanism of its occurrence and development remains unknown.Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP.Polycytosine RNA-binding protein 1(PCBP1),an iron ion chaperone,is considered a protector of ferroptosis.AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes.METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose(HG)and/or ferroptosis inhibitors at different concentrations and times.Transmission electron microscopy was used to examine the morpho-logical changes in the mitochondria of osteoblasts under HG,and western blotting was used to detect the expression levels of PCBP1,ferritin,and the ferroptosis-related protein glutathione peroxidase 4(GPX4).A lentivirus silenced and overex-pressed PCBP1.Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin(OPG)and osteocalcin(OCN),whereas flow cytometry was used to detect changes in reactive oxygen species(ROS)levels in each group.RESULTS Under HG,the viability of osteoblasts was considerably decreased,the number of mitochondria undergoing atrophy was considerably increased,PCBP1 and ferritin expression levels were increased,and GPX4 expression was decreased.Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1,increased the expression levels of ferritin,GPX4,OPG,and OCN,compared with the HG group.Flow cytometry results showed a reduction in ROS,and an opposite result was obtained after silencing PCBP1.CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment.Moreover,PCBP1 may be a potential therapeutic target for T2DOP.

Glucokinase regulatory protein rs780094 polymorphism is associated with type 2 diabetes mellitus, dyslipidemia, non-alcoholic fatty liver disease, and nephropathy

In this editorial,we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes(Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria).Type 2 diabetes mellitus(T2DM)is a chronic disorder characterized by dysregulated glucose homeostasis.The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications,including cardiovascular disease,re-tinopathy,neuropathy,and nephropathy.T2DM arises from a complex interplay between genetic,epigenetic,and environmental factors.Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM.Specifically,variations within the glucokinase regulatory protein(GCKR)gene have been linked to heightened susceptibility to T2DM and its associated complications.The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development.Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype.These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.

Targeting neuronal PAS domain protein 2 and KN motif/ankyrin repeat domains 1:Advances in type 2 diabetes therapy

This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.

Response of the Ginseng C_(2)H_(2)-Type Zinc Finger Protein Family PgZFPs Gene to Methyl Jasmonate Regulation

The main active components of ginseng are ginsenosides,which play significant roles in treating cardiovascular diseases,cancer,and providing antioxidant effects.Ginsenosides are primarily synthesized through the mevalo-nate pathway and the methylerythritol phosphate pathway.Many key enzyme genes involved in this biosynthetic process have been cloned and validated,yet the regulatory functions of transcription factors remain unclear.The C_(2)H_(2)-type zincfinger protein family,one of the largest families of transcription factors,is crucial in plant growth and development,response to biotic and abiotic stresses,and regulation of secondary metabolism.This study,based on the ginseng transcriptome database from Jilin,conducted a correlation analysis between the expression levels of PgZFPs genes in the Jilin ginseng C_(2)H_(2)-type zincfinger protein family and ginsenoside content,a gen-ome-wide association study of PgZFPs,and co-expression analysis of PgZFPs with validated key enzyme genes.Ultimately,five candidate genes involved in ginsenoside biosynthesis were identified.The involvement of PgZFP27 and PgZFP-59-02 genes from the PgZFPs family in the biosynthesis of ginsenosides was validated through in vitro methyl jasmonate(MeJA)induction experiments.This result provides new genetic resources for the biosynthesis of ginsenosides.

Agronomic Trait and Protein Component of F_2 Hybrid Originated from Intergeneric Somatic Hybridization Between Triticum aestivum and Agropyron elongatum

Protoplasts derived from common wheat (Triticum aestivum L,. cv. Jinan 177) were fused with UV-treated protoplasts of Agropyron elongatum. (Host) Nevski by PEG method, and fertile asymmetric somatic hybrid plants resembling wheat morphology were obtained. The F-2 hybrid plants could be divided into 3 types according to their morphology. Type I hybrids had high and loosely standing stalks with big spikes and grains. Type ii hybrids were dwarf and compact in shape with high tillering ability and smaller spikes. Type III hybrids were similar to type I as a whole but had more compact and erect spikes. All the F-2 hybrid lines were superior to wheat in seed protein content, although some difference existed between themselves. Protein analysis of immature embryos and flag leaves from hybrids by two-dimensional electrophoresis showed that they possessed characteristic proteins of both parents and some new proteins. There existed also some different kinds of proteins in different lines.

Molecular Docking Studies of Botanical Beverage Mix Berries (LIFEGREENTM) against Breast Cancer Cells from Targeted Protein 1QQG, 7B5Q & 7B5O & Uterine Fibroid from Targeted Protein 2AYR, 6T41 & 3GRF

Fibroids, also called leiomyomas or myomas, are communal tumors of the muscle or uterine wall that affect about 20% of females who are of reproductive age. They can look as if singly or in clusters, and they often cease to grow after menopause. Fibroids can be classified as intramural, sub serosal, pedunculated, or submucosal based on where they are positioned in the uterus. Although fibroids are benign, they can grow quickly and cause a range of symptoms, such as pelvic pressure, heavy menstrual flow, and infertility. As a result, fibroids are a main reason behind hysterectomy surgeries. The majority of cases of breast cancer are ductal and lobular cancers, making it the second utmost common cancer in women international. Gene mutations like those in BRCA1 or BRCA2 knowingly raise the risk of breast and other cancers, typically with an earlier cancer onset. Cancer risk is influenced by a complex interplay of genetic abnormalities, environmental factors, and lifestyle selections. Further research into these relations is domineering. Although they are common in uterine leiomyomas, especially multiple leiomyomas, MED12 mutations do not significantly correlate with tumor size. These mutations have also been noticed in smooth muscle tumors and leiomyosarcomas, two other types of uterine cancer. The identification of MED12 mutations as the sole genetic abnormality originates in leiomyomas raises the opportunity of a role in the genesis of cancer. 10% - 15% of women who are of reproductive age have endometriosis, which grants serious difficulties because of its chronic nature and range of clinical symptoms. Even after effective surgeries, issues reoccur often, adding to the enormous financial burden. The effects of MED12 mutations have been experiential in recent studies examining the molecular causes of endometriosis-associated infertility, which have shown anomalies in cellular connections and signaling cascades. Computational techniques were used in this study to investigate LifeGreenTM’s potential to prevent uterine fibroids and breast cancer. The efficacy of LifeGreenTM as a preventive measure or a treatment for common gynecological matters was examined and modeled. We investigated the mechanisms underlying LifeGreenTM’s benefits in the treatment of uterine fibroids and breast cancer using computational techniques. Our research contributes to our understanding of its potential therapeutic benefits for women’s health.