Unique Mechanism Of Action Research Articles

Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview ofits Chemistry, Pharmacology, and Toxicology.

Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.

Antibacterial Activity of Clindamycin/BPO in Combination With Adapalene

Introduction: Acne guidelines recommend the addition of benzoyl peroxide (BPO) to antibiotics to reduce resistance in Cutibacterium acnes (C. acnes). Pairing the antibiotic/BPO combination with a retinoid, such as adapalene, may further increase treatment efficacy, although research on adapalene’s antibacterial activity is limited. To determine if adapalene improves antimicrobial activity, this in vitro study evaluated minimum inhibitory concentration (MIC) of clindamycin, adapalene, and BPO alone or in combination against both susceptible and resistant C. acnes isolates. Methods: Part 1a: C. acnes sensitivity to clindamycin, adapalene, or BPO was assessed via MIC values obtained by the broth microdilution method, with lower MIC indicating higher susceptibility. Part 1b: The effect (synergistic, additive, antagonistic, or indifferent [no interaction]) of combining adapalene with clindamycin or BPO on C. acnes inhibition was evaluated using a checkerboard assay, wherein two test compounds are combined in varying concentrations. Part 2: Susceptibility to single formulations of clindamycin, adapalene, and BPO, and fixed-dose combination formulations of an antibiotic (clindamycin or erythromycin) with BPO was determined by measuring antibacterial zone of inhibition using agar diffusion method, with larger diameter indicating increased bacterial inhibition. Results: Part 1a: Clindamycin demonstrated strain-dependent activity (MIC range: <0.125-64 μg/ml), while BPO and adapalene had no/low activity as indicated by high MIC (>512 and >64, respectively) against the 6 acne-associated strains tested. Part 1b: The combination of adapalene with clindamycin resulted in an additive effect for 3 and no interaction for 1 strain, whereas adapalene with BPO did not result in any interaction against the 4 acne-associated strains tested. Part 2: Activity of single formulations varied, with adapalene 0.1% having no activity (zone of inhibition: 0 cm) against any of the 8 acne-associated C. acnes strains tested. The fixed-dose combination formulations had generally similar activity against all strains tested (range: 0.9-5 cm). Conclusions: In these in vitro analyses, adapalene and BPO had no/low activity against C. acnes, whereas clindamycin alone or in combination formulations demonstrated strain-dependent activity. The relatively high MIC of BPO is not unexpected and aligns with previous studies in which the in vitro activity of BPO was low compared to its high in vivo antimicrobial activity. Further, addition of the retinoid adapalene had an additive effect on the antimicrobial activity of clindamycin against 3 out of 4 C. acnes strains tested, but no effect on the activity of BPO in vitro. Taken together, these data suggest that when combined with clindamycin/BPO, adapalene may enhance antimicrobial activity, while also bringing its own, unique retinoid mechanism of action to the triple combination, adding to clindamycin's bacteriostatic and anti-inflammatory properties. Funding: Ortho Dermatologics

Discovery of new AMR drugs targeting modulators of antimicrobial activity using in vivo silkworm screening systems.

Global concerns about drug-resistant bacteria have underscored the need for new antimicrobial drugs. Emerging strategies in drug discovery include considering the third factors that influence drug activity. These factors include host-derived elements, adjuvants, and drug combinations, which are crucial in regulating antimicrobial efficacy. Traditional in vivo assessments have relied on animal models to study drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). Alternative models, such as silkworms, are being explored to overcome the ethical and financial barriers associated with mammalian models. The silkworm has been proven effective in evaluating ADMET and in highlighting the therapeutic potential enhanced by third factors. Host factors (either mammalian or non-mammalian) enhance the antimicrobial activity of antimicrobial agents such as lysocin E. Additionally, using D-cycloserine to potentiate vancomycin has successfully combated vancomycin-resistant infections in silkworms. Leveraging silkworms in drug discovery could establish a novel screening method incorporating interactions with third factors, whether host related or non-host-related, thus promising new pathways for identifying antimicrobial drugs with unique mechanisms of action.

Levosimendan, a Promising Pharmacotherapy in Cardiogenic Shock: A Comprehensive Review

Cardiogenic shock (CS) is a critical condition with high mortality rate, as the current management of CS presents significant challenges. Exploration of more effective therapies is necessitated. This review article comprehensively examines the efficacy and safety of levosimendan in the management of CS. By synthesising evidence from numerous studies, a comparison of levosimendan over traditional inotropic agents, such as enoximone, dobutamine, dopamine and norepinephrine, is highlighted. The unique mechanism of action of levosimendan enhances myocardial contractility without increasing oxygen demand, offering a promising alternative for patients with CS. This review also delves into comparative studies that demonstrate the superiority of levosimendan in improving survival rates, haemodynamic parameters, and reducing the incidence of CS complications. Safety profiles and adverse effects are critically assessed to provide a balanced view of the therapeutic window provided by levosimendan. The review concludes that levosimendan is a valuable addition to the therapeutic strategy against CS, with the potential to improve patient outcomes.

CSIG-04. ANTI-TUMOR RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. RESULTS OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for OMT stimulation and provide a strong rationale for standalone OMT for GBM.

Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease.

Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ. Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.

The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans

The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) is known for protecting dopaminergic neurons and functioning in various other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants exhibit defects such as increased endoplasmic reticulum (ER) stress, dopaminergic neurodegeneration, and abnormal protein aggregation. These findings suggest an essential role for MANF in cellular processes. However, the mechanisms by which intracellular and extracellular MANF regulate broader cellular functions remain unclear. We report a unique mechanism of action for MANF-1 that involves the transcription factor HLH-30/TFEB-mediated signaling to regulate autophagy and lysosomal function. Multiple transgenic strains overexpressing MANF-1 showed extended lifespan of animals, reduced protein aggregation, and improved neuronal survival. Using fluorescently tagged MANF-1, we observed tissue-specific localization of the protein, which was dependent on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes and utilizes the endosomal pathway. Consistent with the lysosomal localization, our transcriptomic study of MANF-1 and analyses of autophagy regulators demonstrated that MANF-1 promotes proteostasis by regulating autophagic flux and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of stress response, proteostasis, and aging.

Safety and efficacy of up to 60h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial.

Cardiogenic shock (CS) is linked to high morbidity and mortality rates, posing a challenge for clinicians. Interventions to improve tissue perfusion and blood pressure are crucial to prevent further deterioration. Unfortunately, current inotropes, which act through adrenergic receptor stimulation, are associated with malignant arrhythmias and poorer outcomes. Due to its unique mechanism of action, istaroxime should improve haemodynamics without adrenergic overactivation. The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients. The SEISMiC study is a multinational, multicentre, randomized, double-blind, placebo-controlled safety and efficacy study with two parts (A and B). The study enrols patients hospitalized for decompensated heart failure (pre-CS, not related to myocardial ischaemia) with persistent hypotension [systolic blood pressure (SBP) 70-100mmHg for at least 2h] and clinically confirmed congestion, NT-proBNP ≥1400pg/mL, and LVEF≤40%. Subjects must not have taken intravenous (iv) vasopressors, inotropes or digoxin in the past 6h. Eligible patients are randomized to receive IV infusion of istaroxime (different doses and regimens in Parts A and B) or placebo for up to 60h. Central haemodynamics, ECG Holter monitoring, cardiac ultrasound and biomarkers are recorded at predefined time points during the trial. The study's primary efficacy endpoint is the SBP area under the curve from baseline curve from baseline to 6 and 24h in the combined SEISMiC Parts A and B population. Key secondary efficacy endpoints include haemodynamic, laboratory and clinical measures in SEISMiC B alone in the combined SEISMiC A and B studies. The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population.

From Concept to Cure: The Road Ahead for Ruthenium-Based Anticancer Drugs.

The evolution of chemotherapy, especially the dawn of metal-based drugs, represents a transformative era in cancer treatment. From the serendipitous discovery of mustard gas's cytotoxic effects to the sophisticated development of targeted therapies, chemotherapy has significantly refined. Central to this progression is the incorporation of metal-based compounds, such as platinum (Pt), ruthenium (Ru), and gold (Au), which offer unique mechanisms of action, distinguishing them from organic therapeutics. Among these, Ru complexes, exemplified by BOLD-100 and TLD1433, have shown exceptional promise due to their selective activity, lower propensity for resistance, and the ability to target spescific cellular pathways. This paper explores the journey of such Ru candidates, focusing on the mechanisms, efficacy, and clinical potential of these Ru-based drugs, which stand at the forefront of current research, aiming to provide more targeted, less toxic, and highly effective cancer treatments.

Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

The Diverse Activities and Mechanisms of the Acylphloroglucinol Antibiotic Rhodomyrtone: Antibacterial Activity and Beyond.

Background/Objectives: The rose myrtle Rhodomyrtus tomentosa is a medicinal plant used in traditional Asian medicine. The active compound in R. tomentosa leaf extracts is rhodomyrtone, a chiral acylphloroglucinol. Rhodomyrtone exhibits an impressive breadth of activities, including antibacterial, antiviral, antiplasmodial, immunomodulatory, and anticancer properties. Its antibacterial properties have been extensively studied. Methods: We performed a comprehensive literature review on rhodomyrtone and summarized the current knowledge about this promising acylphloroglucinol antibiotic and its diverse functions in this review. Results: Rhodomyrtone shows nano to micromolar activities against a broad range of Gram-positive pathogens, including multidrug-resistant clinical isolates, and possesses a unique mechanism of action. It increases membrane fluidity and creates hyperfluid domains that attract membrane proteins prior to forming large membrane vesicles, effectively acting as a membrane protein trap. This mechanism affects a multitude of cellular processes, including cell division and cell wall synthesis. Additionally, rhodomyrtone reduces the expression of inflammatory cytokines, such as TNF-α, IL-17A, IL1β, and IL8. Generally showing low toxicity against mammalian cells, rhodomyrtone does inhibit the proliferation of cancer cell lines, such as epidermal carcinoma cells. The primary mechanism behind this activity appears to be the downregulation of adhesion kinases and growth factors. Furthermore, rhodomyrtone has shown antioxidant activity and displays cognitive effects, such as decreasing depressive symptoms in mice. Conclusions: Rhodomyrtone shows great promise as therapeutic agent, mostly for antibacterial but also for diverse other applications. Yet, bottlenecks such as resistance development and a better understanding of mammalian cell toxictiy demand careful assessment.

Synergistic Potential of Nanomedicine in Prostate Cancer Immunotherapy: Breakthroughs and Prospects.

Given the global prevalence of prostate cancer in men, it is crucial to explore more effective treatment strategies. Recently, immunotherapy has emerged as a promising cancer treatment due to its unique mechanism of action and potential long-term effectiveness. However, its limited efficacy in prostate cancer has prompted renewed interest in developing strategies to improve immunotherapy outcomes. Nanomedicine offers a novel perspective on cancer treatment with its unique size effects and surface properties. By employing targeted delivery, controlled release, and enhanced immunogenicity, nanoparticles can be synergized with nanomedicine platforms to amplify the effectiveness of immunotherapy in treating prostate cancer. Simultaneously, nanotechnology can address the limitations of immunotherapy and the challenges of immune escape and tumor microenvironment regulation. Additionally, the synergistic effects of combining nanomedicine with other therapies offer promising clinical outcomes. Innovative applications of nanomedicine include smart nanocarriers, stimulus-responsive systems, and precision medicine approaches to overcome translational obstacles in prostate cancer immunotherapy. This review highlights the transformative potential of nanomedicine in enhancing prostate cancer immunotherapy and emphasizes the need for interdisciplinary collaboration to drive research and clinical applications forward.

Clinical Pharmacology Of Selective Oestrogen Receptor Modulators In The Prevention Of Breast Cancer, Osteoporosis, Coronary Heart Disease, Alzheimer's Disease, Use In Hormone Replacement Therapy, Cholesterol Metabolism

Oestrogen is the key regulatory hormone for the development and maintenance of reproductive functions and affects various physiological systems, including the skeletal, cardiovascular, and central nervous systems. oestrogen replacement therapy (ERT) is highly effective in postmenopausal women, addressing menopausal symptoms and providing beneficial effects on osteoporosis and coronary heart disease. However, ERT is associated with significant side effects, such as an increased risk of breast cancer. To mitigate these risks, selective oestrogen receptor modulators (SERMs) have been developed. SERMs are a growing class of synthetic nonsteroidal compounds that act as oestrogen receptor agonists or antagonists in a tissue-specific manner. They can selectively activate or inhibit oestrogen receptors in different tissues throughout the body. SERMs are used to treat a variety of conditions, including ER-positive breast cancer, osteoporosis, coronary heart disease, Alzheimer’s disease, and cholesterol metabolism disorders in postmenopausal women. Specific SERMs are employed for different conditions: raloxifene for osteoporosis, tamoxifen and toremifene for breast cancer, clomiphene for the induction of ovulation, and ormeloxifene for oral contraception. Arzoxifene is used for altering cholesterol metabolism. Each SERM forms a unique complex with oestrogen receptors, influencing target tissues and resulting in a tissue-selective pharmacological profile. This unique mechanism of action translates into specific safety and efficacy profiles for each SERM. The surprising pharmacology of SERMs has sparked interest in developing new selective medications, allowing for precise treatment of various diseases. This article reviews the pharmacological properties of SERMs and explains how they differ from oestrogen in their actions.

RUTHENIUM ORGANOMETALLIC COMPOUNDS IN CANCER TREATMENT

Organometallic complexes with ruthenium have shown promise as potential anticancer agents. These complexes represent a class of compounds that can exhibit unique mechanisms of action, and they may offer advantages or overcome some limitations associated with platinum-based drugs, such as cisplatin. Ruthenium-based complexes can have diverse mechanisms of action. They may interact with DNA, proteins, or other cellular components, leading to cytotoxic effects on cancer cells. The versatility of ruthenium coordination chemistry allows for the design of complexes with specific properties. Some cancers that become resistant to platinum-based drugs may still respond to ruthenium-based compounds. This reduced cross-resistance is attributed to differences in the mechanisms of action between platinum and ruthenium complexes. Researchers can design ruthenium complexes to target specific cellular pathways or processes associated with cancer. This targeted approach aims to enhance the selectivity of the treatment for cancer cells while minimizing the impact on normal cells. Ruthenium complexes often have unique structural features that contribute to their stability and reactivity. These features can be tailored to optimize the pharmacological properties of the compounds. Ruthenium-based complexes may be explored in combination with other anticancer agents to achieve synergistic effects and enhance overall treatment efficacy. Ongoing research continues to explore the potential of ruthenium-based organometallic complexes, and preclinical studies have demonstrated promising results. As with any emerging field, further investigations and clinical trials are needed to fully understand the therapeutic potential and safety profiles of these compounds for various types of cancers.

Finding potential targets in cell-based immunotherapy for handling the challenges of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hostile hematological malignancy under great danger of relapse and poor long-term survival rates, despite recent therapeutic advancements. To deal with this unfulfilled clinical necessity, innovative cell-based immunotherapies have surfaced as promising approaches to improve anti-tumor immunity and enhance patient outcomes. In this comprehensive review, we provide a detailed examination of the latest developments in cell-based immunotherapies for AML, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR)-engineered T-cell therapy, and natural killer (NK) cell-based therapies. We critically evaluate the unique mechanisms of action, current challenges, and evolving strategies to improve the efficacy and safety of these modalities. The review emphasizes how promising these cutting-edge immune-based strategies are in overcoming the inherent complexities and heterogeneity of AML. We discuss the identification of optimal target antigens, the importance of mitigating on-target/off-tumor toxicity, and the need to enhance the persistence and functionality of engineered immune effector cells. All things considered, this review offers a thorough overview of the rapidly evolving field of cell-based immunotherapy for AML, underscoring the significant progress made and the ongoing efforts to translate these innovative approaches into more effective and durable treatments for this devastating disease.

A Comprehensive Review of the Antitumor Properties and Mechanistic Insights of Duocarmycin Analogs.

The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins' unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin's mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody-drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics.

Alkyl Pyridinol Compounds Exhibit Antimicrobial Effects against Gram-Positive Bacteria.

Background/Objectives. The rise of antibiotic-resistant pathogens represents a significant global challenge in infectious disease control, which is amplified by the decline in the discovery of novel antibiotics. Staphylococcus aureus continues to be a highly significant pathogen, causing infections in multiple organs and tissues in both healthcare institutions and community settings. The bacterium has become increasingly resistant to all available antibiotics. Consequently, there is an urgent need for novel small molecules that inhibit the growth or impair the survival of bacterial pathogens. Given their large structural and chemical diversity, as well as often unique mechanisms of action, natural products represent an excellent avenue for the discovery and development of novel antimicrobial treatments. Anaephene A and B are two such naturally occurring compounds with significant antimicrobial activity against Gram-positive bacteria. Here, we report the rapid syntheses and biological characterization of five novel anaephene derivatives, which display low cytotoxicity against mammalian cells but potent antibacterial activity against various S. aureus strains, including methicillin-resistant S. aureus (MRSA) and the multi-drug-resistant community-acquired strain USA300LAC. Methods. A Sonogashira cross-coupling reaction served as the key step for the synthesis of the alkyl pyridinol products. Results/Conclusions. Using the compound JC-01-074, which displays bactericidal activity already at low concentrations (MIC: 16 μg/mL), we provide evidence that alkyl pyridinols target actively growing and biofilm-forming cells and show that these compounds cause disruption and deformation of the staphylococcal membrane, indicating a membrane-associated mechanism of action.

Cariprazine in Psychiatry: A Comprehensive Review of Efficacy, Safety, and Therapeutic Potential.

This article provides a comprehensive review of recent developments regarding a new atypical antipsychotic drug - cariprazine - considering the mechanism of action, efficacy, safety, and promising therapeutic option for various psychiatric disorders, including schizophrenia and bipolar disorder, therapy of addictions, and treatment in the pediatric population. Its distinct pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as serotonin receptors - 5HT1A with a preference for the D3 receptor - sets it apart from other antipsychotics. The unique mechanism of action contributes to cariprazine's positive impact on negative symptoms in schizophrenia and an antidepressant effect. Its relatively low risk of adverse effects, such as sedation, metabolic issues, and hypotension, enhances its tolerability. In bipolar affective disorder, cariprazine exhibits effectiveness in managing both depressive and manic episodes. Ongoing research in pediatric populations suggests potential benefits in schizophrenia, bipolar I disorder, and autism spectrum disorder, but further research is necessary to establish safety and efficacy. Moreover, cariprazine shows promise in addiction therapy, particularly with coexisting psychiatric disorders. Continued research and clinical exploration may discover additional insights, broadening its use in diverse patient populations. This article aims to review the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illnesses, including schizophrenia, bipolar disorder, addiction therapy, and pediatric treatment.

GC-MS profiling of the leaf extract of Garcinia pedunculata, molecular docking, ADME/drug likeness predictions and toxicity analysis

Medicinal plants have long been valued for their efficacy, cultural acceptance and lower side effects. Amidst rising concerns about multidrug-resistant bacteria, there is an increasing push to identify novel plant-based drugs with unique mechanisms of action. Garcinia pedunculata, commonly used as food and traditional medicine among tribal communities in North Eastern India, was investigated for its potential medicinal properties. The study involved analyzing the phytoconstituents of the methanolic leaf extract using GC-MS (Gas Chromatography- Mass Spectrometry), which identified 30 compounds. These compounds were further evaluated through in silico studies, including drug-likeness assessments and molecular docking. Molecular docking results indicated that the compounds strongly interacted with Penicillin Binding Protein 4 (PBP4) of Staphylococcus aureus (S aureus), a well-known drug target. Notably, ethane-1,1-diol dipropanoate demonstrated favorable drug-like properties, meeting four out of five drug filters and exhibiting promising physiochemical characteristics, lipophilicity, solubility and pharmacokinetic profiles with minimal toxicity. This suggests its potential for development into novel antimicrobial formulations. Further research using animal models is underway to validate these findings in vivo.

Approach Bias and Tobacco Craving as Mechanisms of the Effect of Approach Bias Retraining on Smoking Cessation.

Approach bias, the automatic tendency to advance toward, rather than move away from appetitive cues, has been associated with greater tobacco cravings, dependence, and likelihood of smoking relapse. Approach bias retraining (ABR) has emerged as one way to reduce approach bias and promote avoidance toward smoking cues. Yet, additional research is needed to identify the mechanisms that may help explain the effect of ABR on smoking cessation. The current study uses data collected as part of a randomized controlled trial to test two unique mechanisms of action ([1] approach bias and [2] tobacco craving) for the efficacy of standard smoking cessation treatment (ST) augmented by ABR on smoking abstinence. Participants were 96 adult daily smokers (Mage=43.1, SD=10.7) motivated to quit smoking. Results showed that lower approach bias and lower cravings at a treatment session were significantly related to next session smoking abstinence (p's<.018). Further, deviations in approach bias partially mediated the effect of ABR on smoking abstinence (ab=-12.17, 95%CI: [-29.67, -0.53]). However, deviations in tobacco craving did not mediate this relation (ab=.40, 95%CI: [-.27, 1.34]). The current findings add to extant literature by identifying approach bias as a mechanism of action of the effect of ABR on smoking abstinence during smoking cessation treatment. The current study adds to our knowledge on the effectiveness of approach bias retraining (ABR) as a part of smoking cessation treatment. Results indicate that reductions in approach bias partially mediate the effect of ABR on smoking abstinence. These findings are consistent with previous research on alcohol-dependent adults and underline the potential of ABR to reduce approach bias and promote smoking cessation among smokers. Such findings could inform the development of future research exploring more targeted and effective smoking cessation interventions, ultimately improving outcomes for individuals attempting to quit smoking.