Potential Target Research Articles

Insights Into Causal Effects of Genetically Proxied Lipids and Lipid-Modifying Drug Targets on Cardiometabolic Diseases.

The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships and underlying mechanisms. Genetic variants related to lipid profiles and targets for lipid modification were sourced from the Global Lipids Genetics Consortium. Summary data for 10 cardiometabolic diseases were compiled from both discovery and replication data sets. Expression quantitative trait loci data from relevant tissues were employed to evaluate significant lipid-modifying drug targets. Comprehensive analyses including colocalization, mediation, and bioinformatics were conducted to validate the results and investigate potential mediators and mechanisms. Significant causal associations were identified between lipids, lipid-modifying drug targets, and various cardiometabolic diseases. Notably, genetic enhancement of LPL (lipoprotein lipase) was linked to reduced risks of myocardial infarction (odds ratio [OR]1, 0.65 [95% CI, 0.57-0.75], P1=2.60×10-9; OR2, 0.59 [95% CI, 0.49-0.72], P2=1.52×10-7), ischemic heart disease (OR1, 0.968 [95% CI, 0.962-0.975], P1=5.50×10-23; OR2, 0.64 [95% CI, 0.55-0.73], P2=1.72×10-10), and coronary heart disease (OR1, 0.980 [95% CI, 0.975-0.985], P1=3.63×10-14; OR2, 0.64 [95% CI, 0.54-0.75], P2=6.62×10-8) across 2 data sets. Moreover, significant Mendelian randomization and strong colocalization associations for the expression of LPL in blood and subcutaneous adipose tissue were linked with myocardial infarction (OR, 0.918 [95% CI, 0.872-0.967], P=1.24×10-3; PP.H4, 0.99) and coronary heart disease (OR, 0.991 [95% CI, 0.983-0.999], P=0.041; PP.H4=0.92). Glucose levels and blood pressure were identified as mediators in the total effect of LPL on cardiometabolic outcomes. The study substantiates the causal role of lipids in specific cardiometabolic diseases, highlighting LPL as a potent drug target. The effects of LPL are suggested to be influenced by changes in glucose and blood pressure, providing insights into its mechanism of action.

Molecular Dynamics-Assisted Discovery of Novel Phosphodiesterase-5 Inhibitors Targeting a Unique Allosteric Pocket

Phosphodiesterase-5 (PDE5) is a potent therapeutic target for the treatment of male erectile dysfunction and pulmonary arterial hypertension with several drugs available on the market. However, most of the reported PDE5 inhibitors lack specificity over PDE6, a holoenzyme in eleven PDE families, which may cause various adverse effects. Targeting a unique allosteric pocket has proved to be an effective approach to designing selective PDE5 inhibitors. In the present study, an integrated virtual screening procedure consisting of pharmacophore modeling screening, molecular docking, molecular dynamics simulations, and binding free energy calculations was applied to the discovery of novel PDE5 inhibitors targeting the allosteric pocket. Seven out of thirty-three molecules purchased from the SPECS database (a hitting accuracy of 21%) with novel scaffolds were PDE5 inhibitors with enzymatic inhibition ratios of more than 50% at a concentration of 10 μM. Predicted binding patterns indicate these hits fit well in the allosteric pocket in PDE5. In particular, compound AI-898/12177002 (IC50 = 1.6 μM) demonstrates over 10-fold selectivity towards PDE6, providing a novel scaffold for the optimization of potent and selective PDE5 inhibitors with less adverse effects.

Interdependent roles for growth differentiation factor-15 (GDF15) and LIMS1 in regulating cell migration: Implications for colorectal cancer metastasis.

Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased LIMS1 expression, increased mRNA level of RhoGTPases RAC1 and RHOA but not CDC42, and increased migration. Conversely, GDF15 or LIMS1-siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of LIMS1 and GDF15 respectively, decreased RAC1, and RHOA as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in GDF15 and LIMS1-siRNA-treated cells. Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.

TBOPP, a DOCK1 Inhibitor, Potentiates Cisplatin Efficacy in Breast Cancer by Regulating Twist-mediated EMT.

DOCK1 has been reported to be involved in tumor progression and resistance. 1-(2-(30-(trifluoromethyl)-[1,10-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl2(1H)- pyridone (TBOPP) is a selective DOCK1 inhibitor; however, the role and molecular mechanisms of DOCK1 and its inhibition in breast cancer (BC) resistance remain poorly understood. This study aims toinvestigate the underlying mechanisms of DOCK1 in BC resistance. DOCK1 or Twist siRNA and Twist plasmid were used to explore the function of DOCK1 in vitro experiments. A mouse xenograft model was used for in vivo experiments. In the present study, we demonstrated that DOCK1 siRNA promoted cisplatin sensitivity in BC cells. Moreover, TBOPP also enhances the therapeutic effect of cisplatin both in vitro and in vivo. Mechanistically, DOCK1 siRNA inhibited EMT. Twist 1 is one of the EMT-inducing transcription factors and is known to induce EMT. To further reveal the effect of DOCK in BC cells, we co-transfected with DOCK1 and Twist1 siRNA to BC cells and found that co-transfection with DOCK1 and Twist siRNA could not further enhance the cisplatin sensitivity of BC cells. Moreover, DOCK1 siRNA failed to reverse the effect of Twist 1 up-regulation. Taken together, these results demonstrate that DOCK1 may function as a potential therapeutic target in BC and that combining cisplatin with TBOPP may provide a promising therapeutic strategy for cisplatin-resistant BC patients.

Dysregulated Long Non-coding RNAs in Myasthenia Gravis- A Mini-Review.

Myasthenia gravis (MG) is an acquired autoimmune disease that is mediated by humoral immunity, supplemented by cellular immunity, along with participation of the complement system. The pathogenesis of MG is complex; although autoimmune dysfunction is clearly implicated, the specific mechanism remains unclear. Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules with lengths greater than 200 nucleotides, with increasing evidence of their rich biological functions and high-level structure conservation. LncRNAs can directly interact with proteins and microRNAs to regulate the expression of target genes at the transcription and post-transcription levels. In recent years, emerging studies have suggested that lncRNAs play roles in the differentiation of immune cells, secretion of immune factors, and complement production in the human body. This suggests the involvement of lncRNAs in the occurrence and progression of MG through various mechanisms. In addition, the differentially expressed lncRNAs in peripheral biofluid may be used as a biomarker to diagnose MG and evaluate its prognosis. Moreover, with the development of lncRNA expression regulation technology, it is possible to regulate the differentiation of immune cells and influence the immune response by regulating the expression of lncRNAs, which will provide a potential therapeutic option for MG. Here, we review the research progress on the role of lncRNAs in different pathophysiological events contributing to MG, focusing on specific lncRNAs that may largely contribute to the pathophysiology of MG, which could be used as potential diagnostic biomarkers and therapeutic targets.

Integrating Network Pharmacology and In vivo Experimental Validation to Reveal the Mechanism of FuZheng YiLiu Formula on Estrogen Receptor Positive Breast Cancer.

FuZheng YiLiu Formula (FZYL) is a commonly used formula for postoperative estrogen receptor-positive (ER+) breast cancer and post-radiotherapy deficiency of both Qi and Yin. FZYL has been used in clinical practice for decades because of its ability to effectively improve the symptoms of deficiency in cancer patients. However, its mechanism needs to be further clarified. In this paper, we will observe the effect of FZYL on mice with ER+ breast cancer and explore the mechanism by which it improves the symptoms of ER+ breast cancer. A tumor xenograft mouse model was established to detect tumor growth in vivo in order to evaluate the pharmacological effects of FZYL on ER+ breast cancer. The main targets of FZYL were identified by extracting the FZYL components and the corresponding potential target genes of breast cancer from the established database and constructing a protein-protein interaction network of shared genes using the string database. GO functional annotation and KEGG pathway enrichment analysis were performed, and molecular docking, molecular dynamics simulations, western blotting analysis, and RT-qPCR were performed to confirm the validity of targets in the relevant pathways. FZYL was able to significantly reduce the size of tumors in vivo and had a significant therapeutic effect on tumor xenograft mice. GO and KEGG pathway enrichment analyses indicated that the effects of FZYL may be mediated by oxidative stress levels, apoptotic signaling pathways, and cell cycle proliferation. By RT-qPCR and protein blotting assays, FZYL targeted the key targets of TP53, JUN, ESR1, RELA, MYC, and MAPK1 to exert its effects. The key active components of FZYL are quercetin, luteolin, stigmasterol, and glycitein. Molecular docking and molecular dynamics simulation results further demonstrated that the key active components of FZYL are stably bound to the core targets. In this study, the potential active ingredients, potential core targets, key biological pathways, and signaling pathways involved in the treatment of breast cancer with FZYL were identified, providing a theoretical basis for further anti ER+ breast cancer research.

Epidermal growth factor receptor mutations in breast Cancer: Therapeutic challenges and way forward.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is upregulated in aggressive triple-negative breast cancer (TNBC). Ligands such as EGF, TGF-α, epigen, and amphiregulin activate the auto-phosphorylation activity of tyrosine residues on EGFR, which regulates the growth, proliferation, adhesion, migration, and survival of cancer cells. Our prior studies depicted that inhibition of EGFR modulates the chemosensitivity in breast cancer stem cells and, thus, serves as a potent therapeutic target in breast cancer. Small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) specifically targeting EGFR have been clinically approved for breast cancer treatment. However, intrinsic and acquired resistance generated due to EGFR mutations limits the applications of designed EGFR-TKIs in breast cancer patients. This review highlights the therapeutic approaches, and the challenges encountered in targeting EGFR-specific mutations. It suggests the need to develop more advanced higher-generation inhibitors for use in combinatorial therapy along with chemo-or-immune therapeutics in clinics as a breast cancer treatment strategy against relapse of the disease.

HLA is a potent immunoinflammatory target in asymptomatic Alzheimer’s disease

Alzheimer’s disease (AD) is a common neurodegenerative disease, neuroinflammation is an early pathological feature of AD. However, the alteration of the immune microenvironment in asymptomatic AD was not fully explained. In this study, we aimed to utilize the transcriptome data of AD patients in public databases to reveal the change of immune microenvironment in asymptomatic AD and screen the potential anti-AD drug. Through a series of bioinformatics analyses, differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification were done. Meanwhile, the hub genes were validated in APP/PS-1(AD) mice. Importantly, seven enrichment pathways and eight hub genes associated with inflammation were identified in asymptomatic AD. Early AD patients presented infiltration of immunoinflammatory cells to varying degrees in the four representative brain regions. Correspondingly, more hub genes changed in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammation cytokines were increased in the hippocampus of AD mice. Moreover, HLA-C was correlated with the activation of microglia, HLA-DRB1 with IL-6 and OAS2 with TGF-β1 in the hippocampus. Five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone and Pradaxa) were predicted as the common drug-targeted HLA-C and HLA-DRB1 by molecular docking. Taken together, the changes in the immune microenvironment of asymptomatic AD, and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment.

Molecular insights into the aspartate protease Plasmepsin II activity inhibition by fluoroquinolones: A pathway to antimalarial drug development

Plasmepsin II (PlmII) belongs to the aspartate proteases and is involved in hemoglobin degradation in Plasmodium falciparum. Due to its critical role in the survival of the Plasmodium, PlmII is considered as a potent drug target for antimalarial therapy. We have done recombinant protein production of pro-plasmepsin II (Pro-plmII). Pro-PlmII was further activated to mature form (mPlmII) and its activity was confirmed by enzyme kinetics studies. The fluorescence spectroscopic and isothermal titration calorimetric studies show that fluoroquinolone-based antibiotic drugs norfloxacin, ciprofloxacin, and sparfloxacin bind with mPlmII. Molecular docking results show that only norfloxacin and ciprofloxacin are able to bind at the active site of mPlmII via hydrogen binding and hydrophobic interactions. Enzyme kinetics analysis reveals that norfloxacin and ciprofloxacin effectively inhibit mPlmII activity, while sparfloxacin does not exhibit any inhibitory effect on the enzyme's catalytic function. The two methyl groups on the 3rd and 5th carbon atoms of the piperazine ring make sparfloxacin unable to go inside mPlmII and bind at its active site. Overall, the results here suggested that fluoroquinolone-based antibiotic drugs norfloxacin, and ciprofloxacin, can be repurposed as antimalarial inhibitors targeting aspartic proteases. These findings contribute to pave the way for potential therapeutic interventions targeted at malaria.

Mechanism of Compound Kushen Injection in the Treatment of Acute Myeloid Leukemia from the Analysis Perspectives

Background: Chemotherapy resistance often occurs in the conventional treatment with AML and results in poor cure rates. CKI was found to have a good therapeutic effect when it was combined with other chemotherapy drugs in the clinical treatment of AML. However, the underlying mechanism is unclear. Therefore, this study aims to preliminarily describe the pharmacological activity and mechanism of CKI through comprehensive network pharmacology methods. Objective: This study aimed to explore the possible mechanism of Compound Kushen Injection (CKI) in the treatment of acute myeloid leukemia (AML) by using network pharmacology, molecular docking, and molecular dynamics techniques. Methods: Active compounds of CKI were identified based on the Traditional Chinese Medicine Systems Pharmacy (TCMSP) database, and the related targets of the active compounds were predicted using Swiss Target Prediction; AML-related targets from Gene Cards and Online Mendelian Inheritance in Man (OMIM) were collected. Protein-protein interaction (PPI) network was constructed, and its mechanism was predicted through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. The protein-protein interaction (PPI) network construction, module partitioning, and hub node screening were visualized by using the Cytoscape software and its plugins. These module partitionings were also verified by using molecular docking and molecular dynamics modeling. Results: Fifty-six active ingredients corresponding to 223 potential targets were identified. Biological function analysis showed that 731, 70, and 137 GO entries were associated with biological processes, cellular components, and molecular functions, respectively. A total of 163 KEGG pathways were identified. Network analysis showed that the key anti-AML targets of CKI are MAPK3, EGFR, SRC, PIK3CA, and PIK3R1 targets, which are involved in the PI3K/Akt and Ras/MAPK signaling pathways or related crosstalk pathways. Conclusion: Our results suggested that the key anti-AML targets of CKI, such as MAPK3, EGFR, SRC, PIK3CA and PIK3R1, are involved in the PI3K/Akt and Ras/MAPK signaling pathways or related crosstalk pathways. Concentrating on the dynamic and complex crosstalk regulation between PI3K/Akt and Ras/MAPK signal pathways and related signal pathways may be a new direction in anti-AML therapy in the future.

Ramifloraolides A − D, four highly oxygenated picrotoxane-type sesquiterpenoids from the stems of Baccaurea ramiflora and their antithrombotic activity

A phytochemical investigation of the ethanol extract from air-dried stems of Baccaurea ramiflora led to the isolation of four highly oxygenated picrotoxane-type sesquiterpenoids, ramifloraolides A − D (1–4). Their structures were elucidated by comprehensive spectroscopic data (HRESIMS, IR, 1D, and 2D NMR), and their absolute configuration of them were unambiguously determined by single-crystal X-ray diffraction. Structurally, all compounds possess a unique [4.3.0] bicyclic core along with a characteristic γ-lactone. Notably, compound 1 is a picrotoxane sesquiterpenoid incorporating a rare oxygen bridge and a pentadecolactone. Compounds 2–4 possess a five-membered ether ring and the pentadecolactone, while ramifloraolides C (3) and D (4) were nor-picrotoxane. Then, the isolated phytochemicals were evaluated for antithrombotic activity in vivo. Interestingly, compounds 1 and 2 displayed potent antithrombotic activity at 30 μM in a zebrafish model. Additionally, 1 and 2 demonstrated certain antithrombotic effects in a mouse model of thrombosis. This marked the first report on the anti-thrombotic activity of picrotoxane-type sesquiterpenoids. Furthermore, network pharmacological and molecular docking analysis revealed potent target of those compounds associated with thrombotic disease. These finding initially demonstrate the potential of picrotoxanes as naturally derived antithrombotic lead compounds, and highlight the significant research values of sesquiterpenoids from the Baccaurea genus for comprehensive exploration of their application in antithrombotic therapy.

MCL-1 as a potent target for cancer: Recent advancements, structural insights and SAR studies

MCL-1 as a potent target for cancer: Recent advancements, structural insights and SAR studies

Bushen Huoxue Recipe inhibits endometrial epithelial-mesenchymal transition through the transforming growth factor-β/nuclear factor kappa-B pathway to improve polycystic ovary syndrome-mediated infertility

Objective To investigate the target and mechanism of action of Bushen Huoxue Recipe (BSHX) for the treatment of infertility in polycystic ovary syndrome (PCOS), to provide a basis for the development and clinical application of herbal compounds. Methods Prediction and validation of active ingredients and targets of BSHX for the treatment of PCOS by using network pharmacology-molecular docking technology. In an animal experiment, the rats were randomly divided into four groups (control group, model group, BSHX group, metformin group, n = 16 in each group), and letrozole combined with high-fat emulsion gavage was used to establish a PCOS rat model. Body weight, vaginal smears, and number of embryos were recorded for each group of rats. Hematoxylin-eosin (HE) staining was used to observe the morphological changes of ovarian and endometrial tissues, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the serum inflammatory factor levels. Expression levels of transforming growth factor-β (TGF-β), transforming growth factor beta activated kinase 1 (TAK1), nuclear factor kappa-B (NF-κB), Vimentin, and E-cadherin proteins were measured by western blot (WB). Results Ninety active pharmaceutical ingredients were obtained from BSHX, involving 201 protein targets, of which 160 were potential therapeutic targets. The active ingredients of BSHX exhibited lower binding energy with tumor necrosis factor-α (TNF-α), TGF-β, TAK1, and NF-κB protein receptors (< −5.0 kcal/mol). BSHX significantly reduced serum TNF-α levels in PCOS rats (p < .01), effectively regulated the estrous cycle, restored the pathological changes in the ovary and endometrium, improved the pregnancy rate, and increased the number of embryos. The results of WB suggested that BSHX can down-regulate protein expression levels of TGF-β and NF-κB in endometrial tissue (p < .05), promote the expression level of E-cadherin protein (p < .001), intervene in the endometrial epithelial-mesenchymal transition (EMT) process. Conclusions TGF-β, TAK1, NF-κB, and TNF-α are important targets of BSHX for treating infertility in PCOS. BSHX improves the inflammatory state of PCOS, intervenes in the endometrial EMT process through the TGF-β/NF-κB pathway, and restores endometrial pathological changes, further improving the pregnancy outcome in PCOS.

Structure-guided discovery of novel dUTPase inhibitors with anti-Nocardia activity by computational design

The zoonosis caused by Nocardia is increasing seriously. But commonly used antibiotic drugs often lead to resistance. N. seriolae dUTPase (NsdUTPase) plays a key role in the proliferation of Nocardia, and was regarded as a potent drug target. However, there was little report about the NsdUTPase inhibitors. In this study, we discovered a series of novel NsdUTPase inhibitors to fight against Nocardia. The first crystal structure of NsdUTPase was released, and a structure-based computational design was performed. Compounds 4b and 12b exhibited promising activities towards NsdUTPase (IC50 = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti-Nocardia activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that NsdUTPase inhibitors might be a useful way to repress Nocardia.

Network pharmacology-integrated molecular modeling analysis of Aquilaria malaccensis L. (agarwood) essential oil phytocompounds.

A network pharmacology approach was used to construct comprehensive pharmacological networks, elucidating the interactions between agarwood compounds and key biological targets associated with cancer pathways. We have employed a combination of network pharmacology, molecular docking and molecular dynamics to unravel agarwood plants' active components and potential mechanisms. Reported 23 molecules were collected from the agarwood plants and considered to identify molecular targets. Further, we identified ten potent targets related to cancer through network pharmacology analysis. The key targets include EGFR, JUN, TP53, SRC, MAPK3, ACTB, GAPDH, AKT1, MYC and CTNNB1. The biological processes include the negative regulation of fibroblast proliferation, metabolic, oxidative, and more. Subsequently, molecular docking results have indicated that 7-isopropenyl-1, 4a-dimethyl-4, 4a, 5,6,7,8-hexahydro-3 H-naphthalen-2-one showed an excellent binding affinity for all ten targets. This is the first study; we employed a novel integrated approach that combines network pharmacology, molecular docking and molecular dynamics simulation (MDS). The GO and KEGG, pathway enrichment analyses, shed light on biological processes relevant to cancer treatment. Moreover, molecular docking studies results indicated that the molecule 7-isopropenyl-1,4a-dimethyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one exhibited strong binding affinity among all ten cancer targets, with a docking score ranging from - 9.9 to - 6.7kcal/mol and found to have hydrogen bond interaction with Lys168, Ser322, Thr336 and Ala946 residues. MDS sheds light on the stability of their binding, the longevity of their interactions, and their overall effect on the enzyme's active site throughout the simulation. The current work signifies the initial report using bioinformatics approaches to assess the anticancer properties of compounds derived from the agarwood plant.

Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader

Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.

Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy.

The cell membrane transport capacity and surface targets of multiple myeloma (MM) cells heavily influence chemotherapy and immunotherapy. Here, it is found that caveolin-1 (CAV1), a primary component of membrane lipid rafts and caveolae, is highly expressed in MM cells and is associated with MM progression and drug resistance. CAV1 knockdown decreases MM cell adhesion to stromal cells and attenuates cell adhesion-mediated drug resistance to bortezomib. CAV1 inhibition in MM cells enhances natural killer cell-mediated cytotoxicity through increasing CXCL10, SLAMF7, and CD112. CAV1 suppression reduces mitochondrial membrane potential, increases reactive oxygen species, and inhibits autophagosome-lysosome fusion, resulting in the disruption of redox homeostasis. Additionally, CAV1 knockdown enhances glutamine addiction by increasing ASCT2 and LAT1 and dysregulates glutathione metabolism. As a result of CAV1 inhibition, MM cells are more sensitive to starvation, glutamine depletion, and glutamine transporter inhibition, and grow more slowly in vivo in a mouse model treated with bortezomib. The observation that CAV1 inhibition modulated by 6-mercaptopurine, daidzin, and statins enhances the efficacy of bortezomib in vitro and in vivo highlights the translational significance of these FDA-approved drugs in improving MM outcomes. These data demonstrate that CAV1 serves as a potent therapeutic target for enhancing chemotherapy and immunotherapy for MM.

CK2B is a Prognostic Biomarker and a Potential Drug Target for Hepatocellular Carcinoma.

Although casein kinase II subunit beta (CK2B) was previously reported to be involved in human cancers, such as hepatocellular carcinoma (HCC), there has been no systematic assessment of CK2B in HCC. To assess the potential function of CK2B as a prognostic biomarker and possible druggable target in HCC. The Cancer Genome Atlas database was accessed to investigate the potential oncogenic and prognostic roles of CK2B in HCC. Diverse analytical methods were used to obtain a fuller understanding of CK2B, including CIBERSORT, The Tumor Immune Estimation Resource (TIMER), gene set enrichment analyses (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene ontology (GO). Furthermore, the Comparative Toxicogenomic Database (CTD) was used to identify potential drugs to treat CK2B-overexpressing HCC. Patents for these drugs were reviewed using Patentscope® and Worldwide Espacenet®. Upregulated CK2B expression was markedly associated with more aggressive pathological features, including G3, G4 (vs. G1, G2), and T2, T3 (vs. T1). Kaplan-Meier survival curves indicated that patients with HCC with higher expression of CK2B had worse overall survival (P = 0.005), progression-free interval (P = 0.001), and disease-specific survival (P = 0.011). GO and KEGG analysis revealed that CK2B dysregulation affects mitotic chromosome condensation, protein stabilization and binding, regulation of signal transduction of p53 class mediator, and cancer-related pathways. GSEA identified six well-known pathways, including MAPK, WNT, Hedgehog, and TGFβ signaling pathways. Finally, CTD identified six compounds that might represent targeted drugs to treat HCC with CK2B overexpression. A review of patents indicated these compounds showed promising anticancer results; however, whether CK2B interacts with these drugs and improves drug outcomes for patients with HCC was not confirmed. CK2B is a biomarker for HCC prognosis and could be a potential new drug target. Moreover, the association between infiltrating immune cells and CK2B in the HCC tumor microenvironment might provide a solid basis for further investigation and a potent strategy for immunotherapy of HCC.

Hibiscus sabdariffa Linn. Extract Increases the mRNA Expression of the Arcuate Nucleus Leptin Receptor and is Predicted in silico as an Anti-obesity Agent.

Leptin is predominant in regulating body weight by stimulating energy expenditure through its neuronal action in the brain. Moreover, it is projected to adipose tissue and induces adipocyte browning by activating the β3-adrenergic receptor (β3AR). However, the expression of leptin receptor (Lep-R) and β3AR in people with obesity is downregulated. We hypothesized that Hibiscus sabdariffa Linn. extract (HSE) would increase hypothalamus arcuate nucleus (ARC) Lep-R and white adipose tissue (WAT) β3AR mRNA expression in DIO rats. This study also analyzed the potency of H. sabdariffa bioactive compounds as activators of Lep-R and β3AR by an in-silico experiment. Twenty-four male Sprague-Dawley rats were divided into four groups: Control (standard food), DIO (high-fat diet), DIO-Hib200 (HFD+HSE 200 mg/kg BW), and DIO-Hib400 (HFD+HSE400 mg/kg BW). HSE was administered orally for five weeks, once a day. HSE administration significantly (p <0,05) increased the ARC Lep-R expression. The Lee index significantly decreased to the normal range (≤ 310) with p <0,001 for DIO-Hib200 and p <0,01 for DIO-Hib400. Among 39 bioactive compounds, 5-O-caffeoyl shikimic acid exhibited high free binding scores (-8,63) for Lep-R, and myricetin_3_arabinogalactoside had high free binding scores (-9,39) for β3AR. These binding predictions could activate Lep-R and β3AR. This study highlights that HSE could be a potential therapeutic target for obesity by increasing LepR mRNA and leptin sensitivity, enhancing energy expenditure, and reducing obesity.

Identify Diabetes-related Targets based on ForgeNet_GPC.

Research on potential therapeutic targets and new mechanisms of action can greatly improve the efficiency of new drug development. Polygenic genetic diseases, such as diabetes, are caused by the interaction of multiple gene loci and environmental factors. In this study, a disease target identification algorithm based on protein recognition is proposed. In this method, the related and unrelated targets are collected from literature databases for treating diabetes. The transcribed proteins corresponding to each target are queried in order to construct a protein dataset. Six protein feature extraction algorithms (AAC, CKSAAGP, DDE, DPC, GAAP, and TPC) are utilized to obtain the feature vectors of each protein, which are merged into the full feature vectors. A novel classifier (forgeNet_GPC) based on forgeNet and Gaussian process classifier (GPC) is proposed to classify the proteins. In forgeNet_GPC, forgeNet is utilized to select the important features, and GPC is utilized to solve the classification problem. The experimental results reveal that forgeNet_GPC performs better than 22 classifiers in terms of ROC-AUC, PR-AUC, MCC, Youden Index, and Kappa.