Drug Design, Discovery and Therapy
Two Decades Rituximab Therapy in Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis
Remission failure and relapse numerate as one of the main problems in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAVs). The need for new agents that provide effective and safe induction accompanied by sustained remission seems to be urgent in clinical care. The efficacy and safety of rituximab (RTX) for AAVs therapy has been reported in various studies. RTX therapy offers several advantages to treating AAVs patients compared to other therapeutic approaches including reduction of Glucocorticoids (GCs) and conventional Immunosuppressive therapy (IST) usage during both the induction of remission and maintenance phases. This reduction can lead to a lower rate of serious complications making RTX therapy a safer option. It seems that RTX may provide improved clinical outcomes in these patients mediated via B-lymphocyte depletion Proteinase 3-antineutrophilic cytoplasmic antibody (PR3-ANCA) and myeloperoxidase-antineutrophilic cytoplasmic antibody (MPO-ANCA) titers reduction. In this regard some uncertainties have been reported to validate the association between such depletion and clinical improvement as suggested by other sources of autoreactive B cells that did not target with RTX. Due to the prolonged B cell depletion fixed intervals and adjusted dosage of RTX may be required in patients with AAVs. In this narrative review we aimed to insight better understand regarding the efficacy of RTX for effective induction and sustained remission in patients with AAVs. It seems that discovering new biomarkers predicting relapse in AAVs patients can lead to future targeted therapy.
Statin Therapy and C-reactive Protein in Patients with Kidney Disease: A Systematic Review and Meta-analysis of Randomized Clinical Trials
Increased levels of inflammation markers in patients with kidney disease particularly chronic kidney disease (CKD) is an important risk factor. This study explored whether the effect of more potent statins on inflammation in CKD patients is dose-dependent whether there is any difference between the hydrophilic and lipophilic statins concerning their effects on inflammation markers in patients with CKD and whether the duration of treatment with statins has any effect on markers of inflammation in these patients.
A systematic literature search of Scopus PubMed and ISI Web of Science databases from inception to August 2022 was performed. Eligible studies were stratified based on a target population intervention duration dosage and type of statins (high intensity statin and moderate/low intensity) and solubility of statins. Publication bias was evaluated using Begg’s regression asymmetry test for visual inspection of funnel plots. Non-linear effects of dosage of statins and treatment duration were also examined by fractional polynomial modeling.
Meta-analysis of 10 RCTs (12 studies) on 264 patients with kidney disease and 254 controls showed a significant hs-CRP lowering effect of the dose of statin. Both hydrophilic and lipophilic statins had significant hs-CRP lowering effects. Meta-analysis of 6 publications (7 studies) evaluating the impact of statins on CRP in 235 patients and 197 control subjects showed a significant negative association between treatment with statins group and CRP levels.
Statin treatment decreases significantly the levels of CRP and hs-CRP in patients with kidney disease.
Advances in Cysteine Protease B Inhibitors for Leishmaniasis Treatment
The expression and release of cysteine proteases by Leishmania spp. and their virulence factors significantly influence the modulation of host immune responses and metabolism rendering cysteine proteases intriguing targets for drug development. This review article explores the substantial role of cysteine protease B (CPB) in medicinal chemistry from 2001 to 2024 particularly concerning combatting Leishmania parasites. We delve into contemporary advancements and potential prospects associated with targeting cysteine proteases for therapeutic interventions against leishmaniasis emphasizing drug discovery in this context. Computational analysis using the pkCSM tool assessed the physicochemical properties of compounds providing valuable insights into their molecular characteristics and drug-like potential enriching our understanding of the pharmacological profiles and aiding rational inhibitor design. Our investigation highlights that while nonpeptidic compounds constitute the majority (69.2% 36 compounds) of the dataset peptidomimetic-based derivatives (30.8% 16 compounds) also hold promise in medicinal chemistry. Evaluating the most promising compounds based on dissociation constant (Ki) and half maximal inhibitory concentration (IC50) values revealed notable potency with 41.7% and 80.0% of nonpeptidic compounds exhibiting values < 1 µM respectively. On the other hand all peptidic compounds evaluated for Ki (43.8%) and IC50 (31.3%) obtained values < 1 µM respectively. Further analysis identified specific compounds within both categories (nonpeptidic: 1 2 and 4; peptidic: 48-52) as particularly promising warranting deeper investigation into their structure-activity relationships. These findings underscore the diverse landscape of inhibitors in medicinal chemistry and highlight the potential of both nonpeptidic and peptide-based compounds as valuable assets in therapeutic development against leishmaniasis.
Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach
Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival proliferation and metastasis. Abnormal regulation of these transporters which exhibit varying affinities for hexoses could enable cancer cells to efficiently manage their energy supply offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters GLUTs and Sodium Linked Glucose Transporters (SGLTs) could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.
Pioneering the Battle Against Breast Cancer: The Promise of New Bcl-2 Family
Currently breast cancer is the most common cancer type accounting for 1 in every 4 cancer cases. Leading both in mortality and incidence breast cancer causes 1 in 4 cancer deaths. To decrease the burden of breast cancer novel therapeutic agents which target the key hallmarks of cancer are being explored. The Bcl-2 family of proteins has a crucial role in governing cell death making them an attractive target for cancer therapy. As cancer chemotherapies lead to oncogenic stress cancer cells upregulate the Bcl-2 family to overcome apoptosis leading to failure of treatment. To fix this issue Bcl-2 family inhibitors which can cause cell death have been introduced as novel therapeutic agents. Members of this group have shown promising results in in-vitro studies and some are currently in clinical trials. In this review we will investigate Bcl-2 family inhibitors which are already in trials as monotherapy or combination therapy for breast cancer and we will also highlight the result of in vitro studies of novel Bcl-2 family inhibitors on breast cancer cells. The findings of these studies have yielded encouraging outcomes regarding the identification of novel Bcl-2 family inhibitors. These compounds hold significant potential as efficacious agents for employment in both monotherapy and combination therapy settings.
In silico-driven identification of Pranlukast as a Stabilizer of PD-L1 Homodimers
Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. Multiple small-molecule drugs have been developed as inhibitors of the PD-1/PD-L1 axis. Those drugs promote the formation of PD-L1 homodimers causing their stabilization internalization and subsequent degradation. Drug repurposing is a strategy that expedites the clinical translation by identifying new effects of drugs with clinical use. Herein we aimed to repurpose drugs as inductors of PD-L1 homodimerization and therefore as potential inhibitors of PD-L1.
We generated a hybrid pharmacophore model by analyzing the structures of reported ligands that induce PD-L1 homodimerization and their target-binding mode. Pharmacophore-matching compounds were selected from a chemical library of Food and Drug Administration (FDA)-approved drugs. Their binding modes to PD-L1 homodimers were assessed by molecular docking and the stability of the complexes and the corresponding binding energies were evaluated by molecular dynamics (MD) simulations. Finally the activity of one drug as promoter of PD-L1 homodimerization was assessed in protein crosslinking assays.
We identified 12 pharmacophore-matching compounds but only 4 reproduced the binding mode of the reference inhibitors. Further characterization by MD showed that pranlukast an antagonist of leukotriene receptors that is used to treat asthma generated stable and energy-favorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1.
Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis meriting its repurposing as an antitumor drug.
Therapeutic Effects of Crocin Nanoparticles Alone or in Combination with Doxorubicin against Hepatocellular Carcinoma In vitro
Crocin (CRO) the primary antioxidant in saffron is known for its anticancer properties. However its effectiveness in topical therapy is limited due to low bioavailability poor absorption and low physicochemical stability. This study aimed to prepare crocin nanoparticles (CRO-NPs) to enhance their pharmaceutical efficacy and evaluate the synergistic effects of Cro-NPs with doxorubicin (DOX) chemotherapy on two cell lines: human hepatocellular carcinoma cells (HepG2) and non-cancerous cells (WI38).
CRO-NPs were prepared using the emulsion diffusion technique and characterized by transmission electron microscopy (TEM) scanning electron microscopy (SEM) Zeta potential and Fourier transform infrared spectroscopy (FT-IR). Cell proliferation inhibition was assessed using the MTT assay for DOX CRO CRO-NPs and DOX+CRO-NPs. Apoptosis and cell cycle were evaluated by flow cytometry and changes in the expression of apoptotic gene (P53) and autophagic genes (ATG5 & LC3) were analyzed using real-time polymerase chain reaction.
TEM and SEM revealed that CRO-NPs exhibited a relatively spherical shape with an average size of 9.3 nm and zeta potential analysis indicated better stability of CRO-NPs compared to native CRO. Significantly higher antitumor effects of CRO-NPs were observed against HepG2 cells (IC50 = 1.1 mg/ml and 0.57 mg/ml) compared to native CRO (IC50 = 6.1 mg/ml and 3.2 mg/ml) after 24 and 48 hours respectively. Annexin-V assay on HepG2 cells indicated increased apoptotic rates across all treatments with the highest percentage observed in CRO-NPs accompanied by cell cycle arrest at the G2/M phase. Furthermore gene expression analysis showed upregulation of P53 ATG5 and LC3 genes in DOX/CRO-NPs co-treatment compared to individual treatments. In contrast WI38 cells exhibited greater sensitivity to DOX toxicity but showed no adverse response to CRO-NPs.
Although more in vivo studies in animal models are required to corroborate these results our findings suggest that CRO-NPs can be a potential new anticancer agent for hepatocellular carcinoma. Moreover they have a synergistic effect with DOX against HepG2 cells and mitigate the toxicity of DOX on normal WI38 cells.
Advancements in Pyrazine Derivatives as Anticancer Agents: A Comprehensive Review (2010-2024)
Cancer an intricate and formidable disease continues to challenge Medical Science with its diverse manifestations and relentless progression. In the pursuit of novel therapeutic strategies organic heterocyclic compounds have emerged as promising candidates due to their versatile chemical structures and intricate interactions with biological systems. Among these pyrazine derivatives are characterized by a six-membered aromatic ring containing four carbon and two nitrogen atoms situated in a 14-orientation. These compounds garnered significant attention for their potential as anticancer agents. This comprehensive review provides a detailed analysis of the advancements made during this timeframe encompassing the chemical diversity of pyrazine derivatives their mechanisms of action at the cellular level and structure-activity relationships spanning the years 2010 to 2024. By examining their therapeutic potential challenges and future prospects this review offers valuable insights into the evolving landscape of pyrazine derivatives as potent tools in the fight against cancer.
Anticancer Properties Against Select Cancer Cell Lines and Metabolomics Analysis of Tender Coconut Water
Tender Coconut Water (TCW) is a nutrient-rich dietary supplement that contains bioactive secondary metabolites and phytohormones with anti-oxidative and anti-inflammatory properties. Studies on TCW’s anti-cancer properties are limited and the mechanism of its anti-cancer effects have not been defined.
In the present study we investigate TCW for its anti-cancer properties and using untargeted metabolomics we identify components form TCW with potential anti-cancer activity.
Cell viability assay BrdU incorporation assay soft-agar assay flow-cytometery and Western blotting were used to analyze TCW’s anticancer properties and to identify mechanism of action. Liquid chromatography-Tandem Mass Spectroscopy (LC-MS/MS) was used to identify TCW components.
TCW decreased the viability and anchorage-independent growth of HepG2 hepatocellular carcinoma (HCC) cells and caused S-phase cell cycle arrest. TCW inhibited AKT and ERK phosphorylation leading to reduced ZEB1 protein increased E-cadherin and reduced N-cadherin protein expression in HepG2 cells thus reversing the ‘epithelial-to-mesenchymal’ (EMT) transition. TCW also decreased the viability of Hep3B hepatoma HCT-15 colon MCF-7 and T47D luminal A breast cancer (BC) and MDA-MB-231 and MDA-MB-468 triple-negative BC cells. Importantly TCW did not inhibit the viability of MCF-10A normal breast epithelial cells. Untargeted metabolomics analysis of TCW identified 271 metabolites primarily lipids and lipid-like molecules phenylpropanoids and polyketides and organic oxygen compounds. We demonstrate that three components from TCW: 3-hydroxy-1-(4-hydroxyphenyl)propan-1-one iondole-3-carbox aldehyde and caffeic acid inhibit the growth of cancer cells.
TCW and its components exhibit anti-cancer effects. TCW inhibits the viability of HepG2 hepatocellular carcinoma cells by reversing the EMT process through inhibition of AKT and ERK signalling.
Doramectin Induces Apoptosis in B16 Melanoma Cells
Metastatic melanoma resists current pharmacological regimens that act through apoptosis. This indicates that therapies acting via non-apoptotic cell-death pathways could be pursued. Doramectin has shown promising results in another cancer of neural crest origin neuroblastoma through the inhibition of growth via autophagy. Our research hypothesis is that doramectin induces autophagy in B16F10 melanoma cells.
Cells were treated with doramectin (15 uM) or a combination of both doramectin and a cell-death inhibitor compared to untreated control cells (media) and then analyzed with MTT analysis. Likewise MDC analysis was completed to detect autophagy involvement with doramectin treatment. Flow cytometry and TUNEL Assay were conducted to observe cell death-related effects.
MTT analysis of doramectin-treated cells displayed a decrease in cell growth compared to control. Apoptotic morphology was prominent in melanoma cells treated with doramectin. Increased autophagy was not detected by fluorometric microscopic analysis. Flow cytometry analysis of doramectin-treated cells showed apoptosis as a major mode of cell death with some necrosis.
Doramectin induces a novel cell-death mechanism in melanoma compared to other forms of cancer and should be studied as an effective anti-cancer agent for melanoma treatment.
PEGylated Titanium Dioxide Nanoparticle-bound Doxorubicin and Paclitaxel Drugs Affect Prostate Cancer Cells and Alter the Expression of DUSP Family Genes
Prostate cancer (PC) is among the cancer types with high incidence and mortality. New and effective strategies are being sought for the treatment of deadly cancers such as PC. In this context the use of nanocarrier systems containing titanium dioxide (TiO2) can improve treatment outcomes and increase the effectiveness of anticancer drugs.
This study aimed to evaluate the cytotoxic activity of doxorubicin (DOX) and paclitaxel (PTX) drugs on the PC cell line by attaching them to PEGylated TiO2 nanoparticles and to examine their effect on the expression levels of dual-specificity phosphatase (DUSP) genes.
Free DOX and PTX drugs DOX and PTX compounds bound to the pegylated TiO2 system were applied to DU-145 cells a PC cell line under in vitro conditions and MTT analysis was performed. Additionally the IC50 values of these compounds were analyzed. In addition the expression levels of DUSP1 DUSP2 DUSP4 DUSP6 and DUSP10 genes were measured using RT-PCR. Additionally bioinformatics and molecular docking analyses were performed on DUSP proteins.
The cytotoxic activity of PTX compound bound to PEGylated TiO2 was found to be higher than that of DOX compound bound to PEGylated TiO2. Additionally when the expression levels were compared to the control group the expression levels of DUSPs were found to be lower in the drugs of the drug carrier systems.
Accordingly it was predicted that the PEGylated TiO2 nano-based carrier could be effective in PC.
Anti-inflammatory and Anti-proliferative Role of Essential Oil of Leaves of Cleistocalyx operculatus (Roxb.) Merr. & Perry
Phytochemicals have long remained an essential component of the traditional medicine system worldwide. Advancement of research in phytochemicals has led to the identification of novel constituents and metabolites from phytochemicals performing various vital functions ranging from antimicrobial properties to anticarcinogenic roles. Cleistocalyx operculatus is traditionally used by local people to manage inflammation. In this study we aim to extract and chemically profile the essential oil from the leaves of Cleistocalyx operculatus (Roxb.) Merr. & Perry and study of the anti-inflammatory and anti-proliferative role of essential oil.
The hydro distillation method was used for the extraction of essential oil and the GC-MS was applied for the chemical profiling. The percentage of cell viability was calculated using a crystal violet assay colony formation assay was performed using Semiquantitative PCR Propodium iodite staining was used for cell death assay and Western blotting was used to determine antibodies and proteins. Schrodinger 2015 software was used for molecular docking.
Myrcene a monoterpene constitutes 56% of the oil and could be attributed to its anti-inflammatory potential. Treatment of LPS-challenged mouse macrophages RAW264.7 cells with essential oil resulted in a decline in the inflammatory markers such as IL-1β TNFα iNOS COX-2 and NFκB. Further essential oil inhibited cancer PC-3 A431 A549 and MCF-7 cell lines at concentrations lower than normal PNT2 and HEK-293 cell lines. This decline in proliferative potential can be attributed to a decline in anti-apoptotic proteins such as procaspase 3 and PARP an increase in CKIs such as p21 and a decline in the Akt signaling responsible for survival.
The essential oil of the plant Cleistocalyx operculatus may be a potential lead for anti-inflammatory and anti-proliferative function.
Emerging Claudin18.2-targeting Therapy for Systemic Treatment of Gastric Cancer: Seeking Nobility Amidst Danger
Gastric cancer in advanced stages lacked effective treatment options. claudin18.2 (CLDN18.2) is a membrane protein that is crucial for close junctions in the differentiated epithelial cells of the gastric mucosa playing a vital role in barrier function and can be hardly recognized by immune cells due to its polarity pattern. As the polarity of gastric tumor cells changes claudin18.2 is exposed on the cell surface resulting in immune system recognition and making it an ideal target. In this review we summarized the expression regulation mechanism of claudin18.2 both in normal cells and malignant tumor cells. Besides we analyzed the available clinical results and potential areas for future research on claudin18.2-positive gastric cancer and claudin18.2-targeting therapy. In conclusion claudin18.2 is an ideal target for gastric cancer treatment and the claudin18.2-targeting therapy has changed the treatment pattern of gastric cancer.
Novel Quinoline Nitrate Derivatives: Synthesis, Characterization, and Evaluation of their Anticancer Activity with a Focus on Molecular Docking and NO Release
Nitric Oxide (NO) has recently gained recognition as a promising approach in the field of cancer therapy. The quinoline scaffold is pivotal in cancer drug research and is known for its versatility and diverse mechanisms of action.
This study presents the synthesis characterization and evaluation of novel quinoline nitrate derivatives as potential anticancer agents.
The compounds were synthesized through a multi-step process involving the preparation of substituted 1-(2-aminophenyl) ethan-1-one followed by the synthesis of substituted 2-(chloromethyl)-34-dimethylquinolines and finally the formation of substituted (34-dimethylquinolin-2-yl) methyl nitrate derivatives. The synthesized compounds were characterized using various spectroscopic techniques. Molecular docking studies were conducted to assess the binding affinity of the compounds to the EGFR tyrosine kinase domain.
The docking scores revealed varying degrees of binding affinity with compound 6k exhibiting the highest score. The results suggested a correlation between molecular docking scores and anticancer activity. Further evaluations included MTT assays to determine the cytotoxicity of the compounds against Non-Small Cell Lung Cancer (A-549) and pancreatic cancer (PANC-1) cell lines. Compounds with electron-donating groups displayed notable anticancer potential and there was a correlation between NO release and anticancer activity. The study also investigated nitric oxide release from the compounds revealing compound 6g as the highest NO releaser.
The synthesized quinoline nitrate derivatives showed promising anticancer activity with compound 6g standing out as a potential lead compound. The correlation between molecular docking NO release and anticancer activity suggests the importance of specific structural features in the design of effective anticancer agents.
MG132-mediated Suppression of the Ubiquitin-proteasome Pathway Enhances the Sensitivity of Endometrial Cancer Cells to Cisplatin
Tumor cell resistance to cisplatin is a common challenge in endometrial cancer chemotherapy stemming from various mechanisms. Targeted therapies using proteasome inhibitors such as MG132 have been investigated to enhance cisplatin sensitivity potentially offering a novel treatment approach.
The aim of this study was to investigate the effects of MG132 on cisplatin sensitivity in the human endometrial cancer (EC) cell line RL95-2 focusing on cell proliferation apoptosis and cell signaling.
Human endometrial cancer RL95-2 cells were exposed to MG132 and cell viability was assessed in a dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition and apoptosis correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines IL-1β IL-6 IL-8 and IL-13 during MG132 and cisplatin co-administration.
MG132 exposure significantly reduced cell viability in a dose-dependent manner. It augmented cisplatin-induced proliferation inhibition and enhanced apoptosis correlating with caspase-3 activation and ROS upregulation. Molecular analysis revealed a profound inhibition of the ubiquitin-proteasome system. MG132 also significantly increased the expression of cisplatin-induced pro-inflammatory cytokines suggesting a transition from chronic to acute inflammation.
MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin-proteasome pathway reducing cell viability enhancing apoptosis and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.
Emerging Combinatorial Drug Delivery Strategies for Breast Cancer: A Comprehensive Review
Breast cancer remains the second most prevalent cancer among women in the United States. Despite advancements in surgical radiological and chemotherapeutic techniques multidrug resistance continues to pose significant challenges in effective treatment. Combination chemotherapy has emerged as a promising approach to address these limitations allowing multiple drugs to target malignancies via distinct mechanisms of action. Increasingly the use of phytoconstituents alongside chemotherapeutic agents has shown promise in enhancing treatment outcomes. This combination therapy acts on key signaling pathways such as Hedgehog Notch Wnt/β- catenin tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) which play critical roles in cellular proliferation apoptosis angiogenesis differentiation invasion and metastasis. This review explores various signaling pathways involved in breast cancer progression discusses conventional treatment methods like surgery adjuvant radiotherapy hormonal therapy and chemotherapy and highlights emerging nanocarrier-based drug delivery systems (DDS). Liposomes dendrimers exosomes polymeric micelles and nanoparticles (organic inorganic gold magnetic carbon-based and quantum dots) are examined as innovative strategies for enhancing drug delivery efficacy. Furthermore stimuli-responsive DDSs including reactive oxygen species (ROS) enzyme- and hypoxia-responsive systems are presented as cutting-edge approaches to overcoming drug resistance. Special emphasis is placed on the co-delivery of chemotherapeutic agents and plant-based compounds particularly in estrogen receptor-positive (ER+) breast cancer. This review aims to provide a comprehensive overview of novel combinatorial strategies and advanced nanocarriers for the effective and targeted treatment of breast cancer.
Signaling Dynamics in Osteogenesis: Unraveling Therapeutic Targets for Bone Generation
Diseases affecting bone encompass a spectrum of disorders from prevalent conditions such as osteoporosis and Paget's disease collectively impacting millions to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs such as bisphosphonates synthetic hormones and antibodies are utilized in the treatment of bone diseases their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems. Consequently the selection of an appropriate target is a complicated process despite the significant demand for novel medications to address bone diseases. Research has shown the role of various cell signaling pathways including Wnt PTHR1 CASR BMPRs OSCAR and TWIST1 in the regulation of osteogenesis bone remodeling and homeostasis. Disruptions in bone homeostasis can result in decreased bone density and the onset of osteoporosis. There remains a need for the development of drugs that can enhance bone remodeling with improved side effects profiles. The exploration of promising targets to stimulate bone formation has the potential to significantly advance the field of bone-related medical care thereby improving the quality of life for millions. Additionally a deeper understanding of anabolic and catabolic pathway mechanisms could enable future studies to explore synergistic effects between unrelated pathways. Herein we explore potential drug targets that may be exploited therapeutically using small molecule agonists or antagonists to promote bone remodeling and discuss their advantages and limitations.
Repurposing Nano Curcumin: Unveiling its Therapeutic Potential in Diabetic Nephropathy
Currently diabetic nephropathy (DN) stands as the predominant global cause of end- stage renal disease. Many scientists believe that diabetes will eventually spread to pandemic levels due to the rising prevalence of the disease. While the primary factor leading to diabetic nephropathy is vascular dysfunction induced by hyperglycemia several other pathological elements such as fibrosis inflammation and oxidative stress also contribute to the progression of the disease. The primary targets of current DN therapy approaches are the underlying abnormalities of hypertension and glucose. With several targets and fewer side effects curcumin is a commonly utilized antioxidant in DN. The present study emphasizes the critical role of oxidative stress and inflammation in the development of diabetic nephropathy. It reveals how these factors induce damage in key kidney cell types highlighting their potential as therapeutic targets for this disease. In addition by concentrating on Nrf2 SIRT1 HMGB1 NF-κB and NLRP3 of curcumin has strong anti-inflammatory and antioxidant characteristics. This review describes the role of curcumin in the therapeutic application of diabetic nephropathy. In this attempt we tried to elaborate on the bench-to-bedside aspects of curcumin in DN including clinical and preclinical investigations. The rationales of curcumin’s mechanisms in alleviating symptoms of the DN were discussed. Curcumin could serve as the potential therapeutic agent for the patient seeking to recover from DN.
Design and Evaluation of 5-Oxo-1,2,4-triazole-3-carboxamide Compounds as Promising Anticancer Agents: Synthesis, Characterization, In vitro Cytotoxicity and Molecular Docking Studies
Cancer presents a significant global health challenge necessitating effective treatment strategies. While chemotherapy is widely employed its non-specific nature can induce adverse effects on normal cells prompting the exploration of targeted therapies. The 124-triazole scaffold has emerged as a promising element in anticancer drug development due to its structural diversity and potential to target cancer cells.
This study aims to synthesize and evaluate novel derivatives derived from the 124-triazole scaffold for their potential as anticancer agents. Molecular docking techniques are employed to investigate the interactions between the designed derivatives and specific cancer-related targets providing insights into potential underlying mechanisms.
The synthesis involves a three-step process to produce 5-oxo-124-triazole-3-carboxamide derivatives. Various analytical techniques including NMR and HRMS validate the successful synthesis. Molecular docking studies utilize X-ray crystal structures of EGFR and CDK-4 obtained from the Protein Data Bank employing the Schrödinger suite for ligand preparation and Glide's extra-precision docking modes for scoring.
The synthesis yields compounds with moderate to good yields supported by detailed characterization. Molecular docking scores for the derivatives against EGFR and CDK-4 revealed diverse affinities influenced by distinct substituents. Compounds with hydroxyl and halogen substitutions exhibited notable binding affinities while alkyl and amino substitutions showed varying effects. The 124-triazole derivatives demonstrated potential for targeted cancer therapy.
The study highlights the successful synthesis of 5-oxo-124-triazole-3-carboxamides and their diverse interactions with cancer-related targets. The findings emphasized the potential of these derivatives as candidates for further development as anticancer agents offering insights into structure-activity relationships. The 124-triazole scaffold stands out as a promising platform for advancing cancer treatment with enhanced precision and efficacy.
Anti-metastasis Effects and Mechanism of Action of Curcumin Analog (2E,6E)-2,6-bis(2,3-dimethoxybenzylidene) Cyclohexanone (DMCH) on the SW620 Colorectal Cancer Cell Line
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths. Curcumin has been reported to have suppressive effects in CRC and to address the physiological limitations of curcumin a chemically synthesized curcuminoid analog known as (2E6E)-26-Bis (23-Dimethoxy benzylidine) cyclohexanone (DMCH) was developed and the anti-metastatic and anti-angiogenic properties of DMCH in colorectal cell line SW620 were examined.
The anti-metastatic effects of DMCH were examined in the SW620 cell line by scratch assay migration and invasion assay while for anti-angiogenesis properties of the cells the mouse aortic ring assay and Human Umbilical Vein Endothelial Cells (HUVEC) assay were conducted. The mechanism of action was determined by microarray-based gene expression and protein analyses.
The wound healing assay demonstrated that wound closure was decreased from 63.63 ± 1.44% at IC25 treatment to 4.54 ± 0.62% at IC50 treatment. Significant (p<0.05) reductions in the percentage of migrated and invaded cells were also observed in SW620 with values of 36.39 ± 3.86% and 44.81 ± 3.54% respectively. Mouse aortic ring assays demonstrated a significant reduction in the formation of tubes and microvessels. Microarray and protein profiler results revealed that DMCH treatment has modulated several metastases angiogenesis-related transcripts and proteins like Epidermal Growth Factor Receptor (EGFR) TIMP-1 (TIMP Metallopeptidase Inhibitor 1) and Vascular Endothelial Growth Factor (VEGF).
DMCH could be a potential anti-cancer agent due to its capability to impede metastasis and angiogenesis activities of the SW620 colorectal cancer cell line in vitrovia regulating genes and protein in metastases and angiogenesis-related signalling pathways.