In Silico Analysis of Selective Bioactive Compounds from Acronychia Pedunculata as a Potential Inhibitor of HER2 in Colorectal Cancer.

Colorectal cancer (CRC) is a pervasive malignancy that stands as a prominent contributor to global cancer-related mortality. Among the numerous causative factors, the overexpression of human epidermal growth factor receptor 2 (HER2) is notably linked to CRC progression. Acronychia (A.) pedunculata has a longstanding history in folk medicine due to its multifaceted medicinal attributes. This study aimed to assess the potential of specific bioactive compounds derived from A. pedunculata for their inhibition of HER2 in CRC, utilizing in silico analysis. The compounds were systematically evaluated through a series of computational analyses. Drug-likeness assessment, pharmacokinetic evaluation, and toxicity analysis were conducted. Molecular docking studies were performed to investigate binding affinities with the HER2 target. Additionally, bioavailability radar analysis was employed to predict oral bioavailability, while molecular target prediction provided insights into potential protein interactions. All 12 compounds demonstrated favorable drug-likeness properties and adherence to Lipinski's rule of five, indicative of the potential for good oral bioavailability. Four compounds were found to have no toxicological endpoints. Molecular docking revealed two compounds, namely caryophylla-4 (14), 8 (15)-dien-5alpha-ol and (-)-globulol, which showed promising binding affinities between several compounds and HER2. From this study, two leads were identified from A. pedunculata. Further experimental studies are required to validate the action of leads.

Antimicrobials: An update on new strategies to diversify treatment for bacterial infections.

Ninety-five years after Fleming's discovery of penicillin, a bounty of antibiotic compounds have been discovered, modified, or synthesised. Diversification of target sites, improved stability and altered activity spectra have enabled continued antibiotic efficacy, but overwhelming reliance and misuse has fuelled the global spread of antimicrobial resistance (AMR). An estimated 1.27 million deaths were attributable to antibiotic resistant bacteria in 2019, representing a major threat to modern medicine. Although antibiotics remain at the heart of strategies for treatment and control of bacterial diseases, the threat of AMR has reached catastrophic proportions urgently calling for fresh innovation. The last decade has been peppered with ground-breaking developments in genome sequencing, high throughput screening technologies and machine learning. These advances have opened new doors for bioprospecting for novel antimicrobials. They have also enabled more thorough exploration of complex and polymicrobial infections and interactions with the healthy microbiome. Using models of infection that more closely resemble the infection state in vivo, we are now beginning to measure the impacts of antimicrobial therapy on host/microbiota/pathogen interactions. However new approaches are needed for developing and standardising appropriate methods to measure efficacy of novel antimicrobial combinations in these contexts. A battery of promising new antimicrobials is now in various stages of development including co-administered inhibitors, phages, nanoparticles, immunotherapy, anti-biofilm and anti-virulence agents. These novel therapeutics need multidisciplinary collaboration and new ways of thinking to bring them into large scale clinical use.

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

Novel therapeutics to treat chronic pancreatitis: targeting pancreatic stellate cells and macrophages.

INTRODUCTION: Chronic pancreatitis (CP) is a persistent, recurrent, and progressive disorder that is characterized by chronic inflammation and irreversible fibrosis of the pancreas. It is associated with severe morbidity, resulting in intense abdominal pain, diabetes, exocrine and endocrine dysfunction, and an increased risk of pancreatic cancer. The etiological factors are diverse and the major risk factors include smoking, chronic alcoholism, as well as other environmental and genetic factors. The treatment and management of CP is challenging, and no definitive curative therapy is currently available. AREAS COVERED: This review paper aims to provide an overview of the different cell types in the pancreas that is known to mediate disease progression and outline potential novel therapeutic approaches and drug targets that may be effective in treating and managing CP. The information presented in this review was obtained by conducting a NCBI PubMed database search, using relevant keywords. EXPERT OPINION: In recent years, there has been an increased interest in the development of novel therapeutics for CP. A collaborative multi-disciplinary approach coupled with a consistent funding for research can expedite progress of translating the findings from bench to bedside.

Identification and In Vivo Validation of Unique Anti-Oncogenic Mechanisms Involving Protein Kinase Signaling and Autophagy Mediated by the Investigational Agent PV-10.

PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future.

Novel Therapeutic Targets in Acute Myeloid Leukemia (AML).

PURPOSE OF REVIEW: This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML). RECENT FINDINGS: Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.

Addressing a Pre-Clinical Pipeline Gap: Development of the Pediatric Acute Myeloid Leukemia Patient-Derived Xenograft Program at Texas Children's Hospital at Baylor College of Medicine.

The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children's Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML.

miRNAs in pancreatic cancer progression and metastasis.

Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of diseases including cancer. They play a complex role in cancers, having both tumour suppressor and promoter properties. In addition, a single miRNA can be involved in regulating several mRNAs or many miRNAs can regulate a single mRNA, therefore assessing these roles is essential to a better understanding in cancer initiation and development. Pancreatic cancer is a leading cause of cancer death worldwide, in part due to the lack of diagnostic tools and limited treatment options. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by major genetic mutations that drive cancer initiation and progression. The regulation or interaction of miRNAs with these cancer driving mutations suggests a strong link between the two. Understanding this link between miRNA and PDAC progression may give rise to novel treatments or diagnostic tools. This review summarises the role of miRNAs in PDAC, the downstream signalling pathways that they play a role in, how these are being used and studied as therapeutic targets as well as prognostic/diagnostic tools to improve the clinical outcome of PDAC.

Immunotherapy of microsatellite stable colorectal cancer: resistance mechanisms and treatment strategies.

In recent years, immunotherapy strategies based on immune checkpoint inhibitors have yielded good efficacy in colorectal cancer (CRC)especially in colorectal cancer with microsatellite instability-high. However, microsatellite-stable (MSS) CRCs account for about 85% of CRCs and are resistant to immunotherapy. Previous studies have shown that compared with MSS CRC, high microsatellite instability CRC possesses a higher frequency of mutations and can generate more neoantigens. Therefore, improving the sensitivity of immunotherapy to MSS CRC is a hot topic which is crucial for the treatment of MSS CRC. This review aims to discuss the factors contributing to MSS CRC insensitivity to immunotherapy and explored potential solutions to overcome immunotherapy resistance.

Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.

Background: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes. Methods: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses. Findings: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 µmol/L to 86.4 µmol/L at Week 24 vs 464.7 to 426.6 µmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity. Interpretation: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility. Funding: Aeglea BioTherapeutics.

Novel Pharmacotherapies for Hyperlipidemia.

The link between elevated LDL-C, low HDL-C, elevated triglycerides, and an increased risk for cardiovascular disease has solidified over the past decades. Concomitantly, the number of agents to treat dyslipidemia proliferated in clinical trials, proving or refuting their clinical efficacy. Many of these agents' role in reducing cardiovascular disease morbidity and mortality is now clear. Recently, there has been an explosion in emerging therapeutics for the primary and secondary prevention of cardiovascular disease through the control of dyslipidemia. This article reviews standard, new, and emerging treatments for hyperlipidemia.

Pharmacotherapy for the treatment of recurrent cervical cancer: an update of the literature.

INTRODUCTION: Cervical cancer is the fourth most common cause of cancer-related death worldwide. High-risk locally advanced or recurrent/metastatic cervical cancers have a poor prognosis with routine treatments. The objective of this study is to analyze the data available in the literature on therapies and molecules currently in use to improve the prognosis of recurrent cervical cancer. AREAS COVERED: An extensive literature search was conducted by authors to identify relevant trials on various databases. Articles in English published until September 2023 that investigate different pharmacotherapy strategies for the treatment of recurrent cervical cancer, were included. Results of various pharmacological regimens including different combinations of chemotherapy, immune checkpoint inhibitors, DNA damage repair inhibitors and antibody-drug conjugates were analyzed. EXPERT OPINION: In recent years, there have been significant improvements in the outcomes of recurrent/metastatic cervical cancer. However, these improvements do not address the unmet need in terms of oncological outcomes. The introduction of immunotherapy and targeted therapies showed advantages in cervical cancer patients. New therapies and combination strategies must be implemented. Centralization of care and enrollment in clinical trials are of paramount importance. Primary and secondary prevention remains the fundamental goal to reduce the burden of cervical cancer.

Chemical Probes Review: Choosing the Right Path Towards Pharmacological Targets in Drug Discovery, Challenges and Future Perspectives.

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and ß-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries.

Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.

Liquid-liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.

Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma.

Introduction: Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. Methods: ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. Results: ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. Discussion: These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

Familial Hypercholesterolemia: A Literature Review of the Pathophysiology and Current and Novel Treatments.

Familial hypercholesterolemia (FH) is a genetically transmitted disorder. It shows an autosomal dominant mode of inheritance. It is a metabolic disorder. Mutation in chromosome 19 leads to this disorder. Chromosome 19 codes data for low-density lipoprotein (LDL) receptor (LDLR). LDLR either reduces increased LDL levels from the circulation or maintains a normal level of LDL. It precipitates the risk of cardiovascular disease at an early age. Characteristic features of FH are elevated levels of LDL in the blood because of sudden changes in LDLR, which causes a decrease in the clearance of LDL from the blood. Plaque gets deposited in the lumen of the arteries, called atherosclerosis, which occurs at an early young age. If both genes are affected then it is homozygous FH (HoFH); such a case is very rare. When a single gene is affected then that condition is known as heterozygous FH (HeFH). HoFH comes up with more severe cardiac disease than HeFH at an early age. The major cause of FH is a mutation in the LDLR gene while other causes include mutation in various genes like apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), LDLR adaptor protein 1 (LDLRAP 1). In order to prevent cardiovascular crises due to FH, it must be diagnosed early and treated effectively. With increasing research and advances in medical sciences, many kinds of current and novel therapies are emerging that aim to reduce the level of LDL in blood.

Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin. AREAS COVERED: Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved. EXPERT OPINION: Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.

Investigating the Therapeutic Potential of Plants and Plant-Based Medicines: Relevance to Antioxidant and Neuroprotective Effects.

Oxidative stress is a common characteristic of psychiatric, neurological, and neurodegenerative disorders. Therefore, compounds that are neuroprotective and reduce oxidative stress may be of interest as novel therapeutics. Phenolic, flavonoid and anthocyanin content, ORAC and DPPH free radical scavenging, and Cu2+ and Fe2+ chelating capacities were examined in variations (fresh/capsule) of Queen Garnet plum (QGP, Prunus salicina), black pepper (Piper nigrum) clove (Syzygium aromaticum), elderberry (Sambucus nigra), lemon balm (Melissa officinalis) and sage (Salvia officinalis), plus two blends (Astralagus membranaceus-lemon balm-rich, WC and R8). The ability of samples to prevent and treat H2O2-induced oxidative stress in SH-SY5Y cells was investigated. Pre-treatment with WC, elderberry, QGP, and clove prevented the oxidative stress-induced reduction in cell viability, demonstrating a neuroprotective effect. Elderberry increased cell viability following oxidative stress induction, demonstrating treatment effects. Clove had the highest phenolic and flavonoid content, DPPH, and Cu2+ chelating capacities, whereas QGP and elderberry were highest in anthocyanins. Black pepper had the highest ORAC and Fe2+ chelating capacity. These findings demonstrate that plant extracts can prevent and treat oxidative stress-induced apoptosis of neuron-like cells in vitro. Further research into phytochemicals as novel therapeutics for oxidative stress in the brain is needed.