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Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features.Communicated by Ramaswamy H. Sarma. Show less

Genetic variants in melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) genes are strongly associated with childhood obesity. This study aims to identify and functionally characterize MC3R and MC4R variants in an Asian cohort of children with severe early-onset obesity. Whole-exome sequencing was performed to screen for MC3R and MC4R coding variants in 488 Asian children with severe early-onset obesity (body mass index for age ≥97th percentile). Functionality of the identified variants were determined via measurement of intracellular cyclic adenosine monophosphate (cAMP) concentrations and luciferase activity. Four MC3R and 2 MC4R heterozygous nonsynonymous rare variants were detected. There were 3 novel variants: MC3R c.151G > C (p.Val51Leu), MC4R c.127C > A (p.Gln43Lys), and MC4R c.272T > G (p.Met91Arg), and 3 previously reported variants: MC3R c.127G > A (p.Glu43Lys), MC3R c.97G > A (p.Ala33Thr), and MC3R c.437T > A (p.Ile146Asn). Both MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants demonstrated defective downstream cAMP signaling activity. The MC4R c.127C > A (p.Gln43Lys) variant showed reduced cAMP signaling activity at low substrate concentration but the signaling activity was restored at high substrate concentration. The MC3R c.151G > C (p.Val51Leu) variant did not show a significant reduction in cAMP signaling activity compared to wild-type (WT) MC3R. Coexpression studies of the WT and variant MC3R/MC4R showed that the heterozygous variants did not exhibit dominant negative effect. Our functional assays demonstrated that MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants might predispose individuals to early-onset obesity, and further studies are needed to establish the causative effect of these variants in the pathogenesis of obesity. Show less

Sepsis-induced acute lung injury (ALI) is a life-threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell pyroptosis in sepsis-induced ALI, thus providing new insights into the pathogenesis and prevention and treatment measures of sepsis-induced ALI. In vivo animal models and in vitro cell models were established by cecal ligation and puncture (CLP) method and lipopolysaccharide-induced macrophages RAW264.7. ANGPTL4 was silenced in CLP mice or macrophages, followed by the determination of ANGPTL4 expression in bronchoalveolar lavage fluid (BALF) or macrophages. Lung histopathology was observed by H&E staining, with pathological injury scores evaluated and lung wet and dry weight ratio recorded. M1/M2 macrophage marker levels (iNOS/CD86/Arg1), inflammatory factor (TNF-α/IL-6/IL-1β/iNOS) expression in BALF, cell death and pyroptosis, NLRP3 inflammasome, cell pyroptosis-related protein (NLRP3/Cleaved-caspase-1/caspase-1/GSDMD-N) levels, NF-κB pathway activation were assessed by RT-qPCR/ELISA/flow cytometry/Western blot, respectively. ANGPTL4 was highly expressed in mice with sepsis-induced ALI, and ANGPTL4 silencing ameliorated sepsis-induced ALI in mice. In vivo, ANGPTL4 silencing repressed M1 macrophage polarization and macrophage pyroptosis in mice with sepsis-induced ALI. In vitro, ANGPTL4 knockout impeded LPS-induced activation and pyroptosis of M1 macrophages and hindered LPS-induced activation of the NF-κB pathway in macrophages. Knockdown of ANGPTL4 blocks the NF-κB pathway activation, hinders macrophage M1 polarization and pyroptosis, thereby suppressing sepsis-induced ALI. Show less

In order to comprehend the molecular basis of growth, nutrient composition, and color pigmentation in oysters, comparative proteome and metabolome analyses of two selectively bred oyster strains with contrasting growth rate and shell color were used in this study. A total of 289 proteins and 224 metabolites were identified differentially expressed between the two strains. We identified a series of specifically enriched functional clusters implicated in protein biosynthesis (RPL4, MRPS7, and CARS), fatty acid metabolism (ACSL5, PEX3, ACOXI, CPTIA, FABP6, and HSD17B12), energy metabolism (FH, PPP1R7, CLAM2, and RGN), cell proliferation (MYB, NFYC, DOHH, TOP2a, SMARCA5, and SMARCC2), material transport (ABCB1, ABCB8, VPS16, and VPS33a), and pigmentation (RDH7, RDH13, Retsat, COX15, and Cyp3a9). Integrated proteome and metabolome analyses indicate that fast-growing strain utilize energy-efficient mechanisms of ATP generation while promoting protein and polyunsaturated fatty acid synthesis, activating the cell cycle to increase cell proliferation and thus promoting their biomass increase. These results uncovered molecular mechanisms underlying growth regulation, nutrition quality, and pigmentation and provided candidate biomarkers for molecular breeding in oysters. SIGNIFICANCE: Rapid growth has always been the primary breeding objective to increase the production profits of Pacific oyster (Crassostrea gigas), while favorable nutritional quality and beautiful color add commercial value. In recent years, proteomic and metabolomic techniques have been widely used in marine organisms, although these techniques are seldom utilized to study oyster growth and development. In this study, two C. gigas strains with contrasted phenotypes in growth and shell color provided an ideal model for unraveling the molecular basis of growth and nutrient composition through a comparison of the proteome and metabolome. Since proteins and metabolites are the critical undertakers and the end products of cellular regulatory processes, identifying the differentially expressed proteins and metabolites would allow for discovering biomarkers and pathways that were implicated in cell growth, proliferation, and other critical functions. This work provides valuable resources in assistance with molecular breeding of oyster strains with superior production traits of fast-growth and high-quality nutrient value. Show less

Animal domestication, climate changes over time, and artificial selection have played significant roles in shaping the genome structure of various animal species, including cattle. These processes have led to the emergence of several indigenous cattle breeds with distinct genetic characteristics. This study focused on unraveling the genetic diversity and identifying candidate genomic regions in eight indigenous cattle breeds of Iran. The data consisted of ∼777 962 single nucleotide polymorphisms (SNPs) of 89 animals from Iranian indigenous cattle scattered throughout the country. We employed various methods, including integrated haplotype score, Show less

The function of hydroxysteroid dehydrogenase 12 (HSD17B12) in lipid metabolism is poorly understood. To study this further, we created mice with hepatocyte-specific knockout of HSD17B12 (LiB12cKO). From 2 months on, these mice showed significant fat accumulation in their liver. As they aged, they also had a reduced whole-body fat percentage. Interestingly, the liver fat accumulation did not result in the typical formation of large lipid droplets (LD); instead, small droplets were more prevalent. Thus, LiB12KO liver did not show increased macrovesicular steatosis with the increasing fat content, while microvesicular steatosis was the predominant feature in the liver. This indicates a failure in the LD expansion. This was associated with liver damage, presumably due to lipotoxicity. Notably, the lipidomics data did not support an essential role of HSD17B12 in fatty acid (FA) elongation. However, we did observe a decrease in the quantity of specific lipid species that contain FAs with carbon chain lengths of 18 and 20 atoms, including oleic acid. Of these, phosphatidylcholine and phosphatidylethanolamine have been shown to play a key role in LD formation, and a limited amount of these lipids could be part of the mechanism leading to the dysfunction in LD expansion. The increase in the Cidec expression further supported the deficiency in LD expansion in the LiB12cKO liver. This protein is crucial for the fusion and growth of LDs, along with the downregulation of several members of the major urinary protein family of proteins, which have recently been shown to be altered during endoplasmic reticulum stress. Show less

In the present study, a comparative global high-throughput proteomic analysis strategy was used to identify proteomic differences between estrus and diestrus stage of estrous cycle in dairy cows. Saliva was collected from cows during estrus and diestrus, and subjected to LC-MS/MS-based proteomic analysis. A total of 2842 proteins were detected in the saliva of cows, out of which, 2437 and 1428 non-redundant proteins were identified in estrous and diestrous saliva, respectively. Further, it was found that 1414 and 405 salivary proteins were specific to estrus and diestrus, respectively while 1023 proteins were common to both groups. Among the significantly dysregulated proteins, the expression of 56 proteins was down-regulated (abundance ratio <0.5) while 40 proteins were up-regulated (abundance ratio > 2) in estrous compared to diestrous saliva. The proteins, such as HSD17B12, INHBA, HSP70, ENO1, SRD5A1, MOS, AMH, ECE2, PDGFA, OPRK1, SYN1, CCNC, PLIN5, CETN1, AKR1C4, NMNAT1, CYP2E1, and CYP19A1 were detected only in the saliva samples derived from estrous cows. Considerable number of proteins detected in the saliva of estrous cows were found to be involved in metabolic pathway, PI3K-Akt signaling pathway, toll-like receptor signaling pathway, steroid biosynthesis pathway, insulin signaling pathway, calcium signaling pathway, estrogen signaling pathway, oxytocin signaling pathway, TGF-β signaling pathway and oocyte meiosis. On the other hand, proteins detected in saliva of diestrous cows were involved mainly in metabolic pathway. Collectively, these data provide preliminary evidence of a potential difference in salivary proteins at different stages of estrous cycle in dairy cows. Show less

In patients with prostate carcinoma as well as in some other cancer types, the reduction of testosterone levels is desired because the hormone stimulates cancer cell growth. One molecular target for this goal is the inhibition of 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3), which produces testosterone from its direct precursor androstenedione. Recent research in this field is trying to harness photopharmacological properties of certain compounds so that the inhibitory effect could be turned on and off by irradiation. Seven new light-switchable diazocines were investigated with regard to their inhibition of 17βHSD3. For this purpose, transfected HEK-293 cells and isolated microsomes were treated with the substrate and the potential inhibitors with and without irradiation for an incubation period of 3 or 5 h. The amount of generated testosterone was measured by UHPLC and compared between samples and control as well as between irradiated and non-irradiated samples. There was no significant difference between samples with and without irradiation. However, four of the seven diazocines led to a significantly lower testosterone production both in cell and in microsome assays. In some of the irradiated samples, a partial destruction of the diazocines was observed, indicated by an additional UHPLC peak. However, the influence on the inhibition is negligible, because the majority of the substance remained intact. In conclusion, new inhibitors of 17βHSD3 have been found, but so far without the feature of a light switch, since the configurational alteration of the diazocines by irradiation did not lead to a change in bioactivity. Further modification might help to find a light-switching molecule that inhibits only in one configuration. Show less

Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl Show less

Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism. Show less

Lymphoplasmacytic lymphoma (LPL) is a rare variant of non-Hodgkin lymphoma, accounting for <1% of cases. Skin involvement in LPL is quite rare-accounting for approximately 5% of extramedullary disease-and includes a variety of clinical morphologies, such as erythematous-to-violaceous plaques, violaceous nodules or tumors, and ulceration at various anatomical sites. Herein, we report the case of a 45-year-old Korean woman who presented with generalized erythematous indurated plaques and pendulous skin growths, which were asymptomatic, with marked diffuse infiltration of lymphocytes and plasma cells in the dermis. Immunohistochemical studies revealed that the lymphoid cells expressed CD3, CD79a, and cytoplasmic IgG, but lacked CD10 and IgM. Moreover, kappa light chain restriction and monoclonal immunoglobulin heavy chain gene rearrangement were observed. Upon further workup, lymphoma involvement was reported in multiple lymph nodes, including those in the cervical and axillary regions. This case shows a unique form of cutaneous LPL clinically presenting as acquired cutis laxa, emphasizing the dermatologists' need to be vigilant for variant forms of this disease. Show less

Blood lipid levels play a critical role in the progression of atherosclerosis. However, even with adequate lipid reduction, significant residual cardiovascular risk remains. Therefore, it is necessary to seek novel therapeutic strategies for atherosclerosis that can not only lower lipid levels but also inhibit inflammation simultaneously. The fusion protein FD03-IL-1Ra was designed by linking the Angiopoietin-like 3 (ANGPTL3) nanobody and human interleukin-1 receptor antagonist (IL-1Ra) sequences to a mutated human immunoglobulin gamma 1 (IgG1) Fc. This construct was transfected into HEK293 cells for expression. The purity and thermal stability of the fusion protein were assessed using SDS-PAGE, SEC-HPLC, and differential scanning calorimetry. Binding affinities of the fusion protein to ANGPTL3 and IL-1 receptor were measured using Biacore T200. The biological activity of the fusion protein was validated through in vitro experiments. The therapeutic efficacy of the fusion protein was evaluated in an ApoE-/- mouse model of atherosclerosis, including serum lipid level determination, histological analysis of aorta and aortic sinus sections, and detection of inflammatory and oxidative stress markers. ImageJ software was utilized for quantitative image analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post hoc test. The FD03-IL-1Ra fusion protein was successfully expressed, with no polymer formation detected, and it demonstrated good thermal and conformational stability. High affinity for both murine and human ANGPTL3 was exhibited by FD03-IL-1Ra, and it was able to antagonize hANGPTL3's inhibition of LPL activity. FD03-IL-1Ra also showed high affinity for both murine and human IL-1R, inhibiting IL-6 expression in A549 cells induced by IL-1β stimulation, as well as suppressing IL-1β-induced activity inhibition in A375.S2 cells. Our study revealed that the fusion protein effectively lowered serum lipid levels and alleviated inflammatory responses in mice. Furthermore, the fusion protein enhanced plaque stability by increasing collagen content within atherosclerotic plaques. These findings highlighted the potential of bifunctional interleukin-1 receptor antagonist and ANGPTL3 antibody fusion proteins for ameliorating the progression of atherosclerosis, presenting a promising novel therapeutic approach targeting both inflammation and lipid levels. Show less

In the current investigation, a new class of quinazolinone N-acetohydrazides 9a-v was designed as type II multi-kinase inhibitors. The target quinazolinones were tailored so that the quinazolinone moiety would occupy the front pocket of the binding sites of VEGFR-2, FGFR-1 and BRAF kinases, meanwhile, the phenyl group at position 2 would act as a spacer which was functionalized at position 4 with an N-acetohydrazide linker that could achieve the key interactions with the essential gate area amino acids. The hydrazide moiety was linked to diverse aryl derivatives to occupy the hydrophobic back pocket of the DFG-out conformation of target kinases. The synthesized quinazolinone derivatives 9a-v demonstrated moderate to potent VEGFR-2 inhibitory activity with IC Show less

Receptor tyrosine kinases (RTKs) serve as molecular targets for the development of novel personalized therapies in many malignancies. In the present study, expression pattern of receptor tyrosine kinases and its clinical significance in orbital RMS has been explored. Eighteen patients with histopathologically confirmed orbital RMS formed part of this study. Comprehensive q-PCR gene expression profiles of 19 RTKs were generated in the cases and controls. The patients were followed up for 59.53 ± 20.93 years. Clustering and statistical analysis tools were applied to identify the significant combination of RTKs associated with orbital rhabdomyosarcoma patients. mRNA overexpression of RTKs which included MET, AXL, EGFR was seen in 60-80% of cases; EGFR3, IGFR2, FGFR1, RET, PDGFR1, VEGFR2, PDGFR2 in 30-60% of cases; and EGFR4, FGFR3,VEGFR3 and ROS,IGFR1, EGFR1, FGFR2, VEGFR1 in 10-30% of cases. Immunoexpression of MET was seen in 89% of cases. A significant association was seen between MET mRNA and its protein expression. In all the cases MET gene expression was associated with worst overall survival (P = 0.03).There was a significant correlation of MET mRNA expression with RET, ROS, AXL, FGFR1, FGFR3, PDGFR1, IGFR1, VEGFR2, and EGFR3 genes. Association between MET gene and collective expression of RTKs was further evaluated by semi-supervised gene cluster analysis and Principal component analysis, which showed well-separated tumor clusters. MET gene overexpression could be a useful biomarker for identifying high risk orbital rhabdomyosarcoma patients. Well-separated tumor clusters confirmed the association between MET gene and collective expression of RTK genes. Therefore, the therapeutic potential of multi-kinase inhibitors targeting MET and the 9 other significant RTKs needs to be explored. Show less

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities. Show less

Alzheimer's disease (AD) hallmarks include amyloid-βeta (Aβ) and tau proteins aggregates, neurite degeneration, microglial activation with cognitive impairment. Phosphatidylinositol-3-kinase/protein kinase B/Glycogen synthase kinase-3-beta (PI3K/AKT/GSK-3) pathway is essential for neuroprotection, cell survival and proliferation by blocking apoptosis. This study aimed to assess protective role of nanocurcumin (NCMN) as strong antioxidant and anti-inflammatory agent with elucidating its synergistic effects with Donepezil as acetylcholinesterase inhibitor on AD in rats via modulating PI3K/AKT/GSK-3β pathway. The experiment was performed on 70 male Wistar albino rats divided into seven groups (control, NCMN, Donepezil, AD-model, Donepezil co-treatment, NCMN only co-treatment, and NCMN+Donepezil combined treatment). Behavioral and biochemical investigations as cholinesterase activity, oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxidedismutase, and catalase), tumor necrosis factor-alpha, Tau, β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), Phosphatase and tensin homolog (Pten), mitogen-activated protein kinase-1 (MAPK-1), Glycogen synthase kinase-3-beta (GSK-3β) and toll-like receptor-4 were evaluated. Treatment with NCMN improved memory, locomotion, neuronal differentiation by activating PI3K/AKT/GSK-3β pathway. These results were confirmed by histological studies in hippocampus. Show less

Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively. We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β. Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies. Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration. Show less

Acute myeloid leukemia (AML) is one of the hematological malignancies with a high recurrence rate. WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) is identified as a pivotal regulator of tumor progression. This study aimed to assess the possible role of WWP2 in AML. Analysis of the GEPIA database indicated an elevated WWP2 expression in AML. We established stable WWP2-overexpressed or WWP2-silenced cells using lentivirus loaded with cDNA encoding WWP2 mRNA or shRNA targeting WWP2. Notably, WWP2 overexpression facilitated cell proliferation and cell cycle progression, which was manifested as the increase of colony formation number, S-phase percentage and cell cycle related protein levels. As observed, WWP2 knockdown presented opposite effects, leading to inhibition of tumorigenicity. Strikingly, WWP2 knockdown induced apoptosis, accompanied by upregulation of pro-apoptosis proteins cleaved caspase-9, Bax and cleaved caspase-3 and downregulation of anti-apoptosis protein Bcl-2. Functionally, we further confirmed that WWP2 overexpression enhanced the NF-κB signaling and upregulated the levels of downstream genes, which may contribute to aggravating the development of AML. More importantly, by co-immunoprecipitation assay, we verified that WWP2 bound to NF-κB-repressing factor (NKRF) and promoted NKRF ubiquitylation. Dramatically, NKRF overexpression abolished the role of WWP2 in facilitating the process of AML. Overall, our observations confirm that WWP2 exerts a critical role in the tumorigenicity of AML, and NKRF is regarded as an essential factor in the WWP2-mediated AML progression. WWP2 may be proposed as a promising target of AML. Show less

Extra virgin olive oil has numerous cardiopreventive effects, largely due to its high content of (poly)phenols such as hydroxytyrosol (HT). However, some animal studies suggest that its excessive consumption may alter systemic lipoprotein metabolism. Because human lipoprotein metabolism differs from that of rodents, this study examines the effects of HT in a humanized mouse model that approximates human lipoprotein metabolism. Mice are treated as follows: control diet or diet enriched with HT. Serum lipids and lipoproteins are determined after 4 and 8 weeks. We also analyzed the regulation of various genes and miRNA by HT, using microarrays and bioinformatic analysis. An increase in body weight is found after supplementation with HT, although food intake was similar in both groups. In addition, HT induced the accumulation of triacylglycerols but not cholesterol in different tissues. Systemic dyslipidemia after HT supplementation and impaired glucose metabolism are observed. Finally, HT modulates the expression of genes related to lipid metabolism, such as Pltp or Lpl. HT supplementation induces systemic dyslipidemia and impaired glucose metabolism in humanized mice. Although the numerous health-promoting effects of HT far outweigh these potential adverse effects, further carefully conducted studies are needed. Show less

Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation of adult cardiomyocytes is crucially useful for cardiac repair after MI. Here, we found that miR-130b-5p was highly expressed in mouse embryonic and neonatal hearts and able to promote cardiomyocyte proliferation both in vitro and in vivo. Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, we found that overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after MI. These studies thus revealed the critical role of miR-130b-5p and its targeted MAPK-ERK signaling in the cardiomyocyte proliferation of adult hearts and proved that miR-130b-5p could be a potential target for cardiac repair after MI. Show less

The landscape of cancer therapy has been transformed by advances in clinical next-generation sequencing, genomically targeted therapies, and immunotherapies. Well designed clinical trials and efficient clinical trial conduct are crucial for advancing our understanding of cancer, improving patient outcomes, and identifying personalized treatments. Basket trials have emerged as one of the efficient modern clinical trial designs that evaluate the efficacy of these therapies across multiple cancer types based on specific molecular alterations or biomarkers, irrespective of histology or anatomic location. This review delves into the evolution of basket trials in cancer drug development, highlighting their potential prospects and current obstacles. The design of basket trials involves screening patients for specific molecular alterations or biomarkers and enrolling them in the trial to receive the targeted therapy under investigation. Statistical considerations play a crucial role in the design, analysis, and interpretation of basket trials. Several notable examples of basket trials that have led to US Food and Drug Administration approval for uncommon molecular alterations (e.g., NTRK fusions, BRAF mutations, RET and FGFR1 alterations) are discussed, including LOXO-TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT (ClinicalTrials.gov identifier NCT02637687)/NAVIGATE (ClinicalTrials.gov identifier NCT02576431)/STARTRK (ClinicalTrials.gov identifiers NT02097810, NT02568267), VE-BASKET (ClinicalTrials.gov identifier NCT01524978), ROAR Basket (ClinicalTrials.gov identifier NCT02034110), LIBRETTO-001 (ClinicalTrials.gov identifier NCT03157128), ARROW (ClinicalTrials.gov identifier NCT03037385), FIGHT-203 (ClinicalTrials.gov identifier NCT03011372), and the National Cancer Institute-Molecular Analysis for Therapy Choice trial (ClinicalTrials.gov identifier NCT02465060). Basket trials have the potential to revolutionize cancer treatment by identifying effective therapies for patients based on specific molecular alterations or biomarkers rather than traditional histology-based approaches. PLAIN LANGUAGE SUMMARY: To gain more knowledge about cancer, improve patient outcomes, and discover personalized treatments, it is crucial to conduct clinical trials efficiently. One effective type of clinical trial is called a basket trial. In basket trials, new treatments are tested on various types of cancer, regardless of their location in the body; instead, researchers focus on specific abnormalities in the cancer cells. Basket trials offer hope that we can find personalized treatments that are more effective for each individual battling cancer. Show less

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time. Show less

Apolipoprotein A4 (Apo-A4) is considered as a prospective molecular biomarker for diagnosis of depression due to its neurosynaptic toxicity. We develop a proximity hybridization-induced DNAzyme-driven bipedal DNA walker strategy for Apo-A4 quantification based on rolling circle amplification (RCA) triggered by poly adenine binding to Ag nanoparticles (AgNPs). With the help of DNAzyme, the free-running bipedal DNA walker can quickly and sequentially shear a molecular beacon that acts as a primer to initiate the RCA process, producing a large number of long DNA strands containing numerous adenines. The long repetitive adenine strands then absorb large amounts of AgNPs on the electrode interface, which is then electrochemically stripped of the AgNPs. The method has a linear detection range of 0.001 ∼ 100 ng mL Show less

The mitral valve undergoes structural modifications in response to cardiac functional changes, often predating cardiac decompensation and overt clinical signs. Our study assessed the potential of mitral valve morphological changes as early indicators for detecting carriers of hypertrophic cardiomyopathy (HCM)-associated gene mutations. We studied 505 participants: 189 without the pathogenic gene mutations and left ventricular hypertrophy (G-/LVH-), 149 carriers without LV hypertrophy (G+/LVH-), and 167 manifest HCM patients (G+/LVH+). We juxtaposed the mitral valve morphology and associated metrics across these groups, emphasizing those carrying MYH7 and MYBPC3 mutations. We discerned pronounced disparities in the mitral annulus and leaflet structures across the groups. The mitral valve apparatus in mutation carriers exhibited a tendency towards a flattened profile. Detailed analysis spotlighted MYBPC3 mutation carriers, whose mitral valves were notably flatter (with notably lower AHCWR values than non-carriers); this contrast was not evident in MYH7 mutation carriers. This mitral valve flattening, manifest in the mutation carriers, suggests it might be an adaptive response to incipient cardiac dysfunction in HCM's nascent stages. Three-dimensional echocardiography illuminates the initial mitral valve structural changes in HCM patients bearing pathogenic gene mutations. These morphological signatures hold promise as sensitive imaging markers, especially for asymptomatic carriers of the MYBPC3 mutation. Show less

This article provides an update for the practicing dentist and/or oral and maxillofacial surgeon on the recognition, identification, and treatment of burning mouth syndrome (BMS). We discuss the most common clinical findings and most common causes of BMS. This article provides a classification flowchart that assists the practitioner in diagnosing and classifying BMS. The article then discusses the pathophysiology and treatment of BMS updated in the literature from the latest studies and reviews. Treatment can vary from topical or systemic medication to behavioral therapy. Show less

As the field of implant dentistry continues to evolve, new techniques and technologies arise that can provide great benefits to the partial or completely edentulous patient. The purpose of this article is to review the history, definition, and rationale of immediate loading of dental implants with the goal of providing evidence-based recommendations for implementation into clinical practice. Relevant literature is summarized and includes discussion regarding prerequisites for immediate loading/restoration of an endosseous implant. Surgical techniques and methodologies to prevent implant failure in immediate-load cases are discussed as well. The greatest success has been demonstrated with 4 or more mandibular implants. Although there is support in the literature demonstrating successful outcomes in immediate functional loading of single implants, the opinion of the author is to opt for a nonfunctional load that does not have any occlusal contacts when considering immediate loading of a single dental implant. Show less

During the development of multimodal pain management protocols, practitioners need to consider the potential risks each treatment modality inherently carries in order to prevent or diminish harmful outcomes. As an example, the part dentists played in the early stages of the opioid epidemic in the United States of America should serve as a cautionary account. By understanding the roots of this crisis, as practitioners we are better equipped to implement the novel analgesic agents available today to optimize post-operative pain control while minimizing any risk of addiction and harm to our communities. It is therefore critical that our colleagues understand the variety of accessible options for pain management to assure that our profession is able to seek adequate and sustainable relief for our post-operative patients. This article will go in depth to explain the analgesic tools practitioners can implement for an effective low-risk protocol, including a combination of NSAIDS and acetaminophen approach, using long-acting local anesthetics such as Exparel, pregabalin, gabapentin, ketamine, dexmedetomidine, and corticosteroids, and enhanced recovery after surgery protocols. Show less

Increasing evidence has shown that implicit learning shapes visuospatial attention, yet how such learning interacts with top-down, goal-driven attention remains unclear. This study investigated the relationship between task goals and selection history using a location probability learning (LPL) paradigm. We tested whether a top-down spatial cue facilitates or interferes with the acquisition of implicit LPL. In a visual search task, participants were asked to give precedence to one of four, spatially cued, quadrants of the screen. Unbeknownst to them, there was an underlying uneven spatial probability in which the target appeared disproportionately often in the cued quadrant (37.5%) and a second, uncued quadrant (37.5%). To assess what participants had learned, neutral, uncued testing trials with an equal target location probability (25%) were used. Results revealed faster search times in the cued and the uncued high-probability quadrants compared to the two low-probability quadrants and these fast search times remained prevalent in the neutral testing blocks. Importantly, LPL was comparable between the cued and uncued locations in the testing blocks, suggesting that the spatial cue neither facilitated nor interfered with LPL. These results support the dual-system view of attention, revealing parallel systems supporting both goal-driven and experience-guided attention. (PsycInfo Database Record (c) 2024 APA, all rights reserved). Show less