Pharmacological Studies Research Articles

An ethnobotanical survey investigating medicinal plants used by Cape bush doctors to treat dermatophyte infections.

Introduction: Over the past few years, the incidence of dermatophyte infections has increased at an alarming rate. The treatment for these infections is becoming more difficult especially because fungal pathogens have developed resistance to conventional treatments. The Cape Metropole region in South Africa has an abundance of plant species and is the residence of herbalists, called Cape bush doctors who use some of these diverse plants to treat various skin-related conditions. There are limited ethnobotanical studies that have been conducted on the medicinal plants they use to treat dermatophyte infections. Therefore, this study aimed to report on the knowledge and practices of Cape bush doctors concerning their use of medicinal plants for treating dermatophyte infections. MethodologyA cross-sectional study was performed using an interview-based questionnaire to investigate 1) the knowledge of bush doctors regarding skin infections, 2) the practices of bush doctors along with the medicinal plants used when treating fungal skin infections, and 3) selected plants identified with potential anti-fungal activity in vitro, were further explored to assess their application in the treatment of fungal infections by bush doctors. Results: Participants confirmed the use of the fifteen selected medicinal plants identified in the literature. Additionally, twenty other plant species were mentioned as having antifungal properties. Most plants reported belonged to the Xanthorrhoeaceae, Amaryllidaceae, Asteraceae, Lamiaceae, and Rutaceae families. Conclusion: This study shows that bush doctors use a vast array of plant species to treat dermatophyte conditions. This indicates the diversity of medicinal plant species used and that these doctors associated indigenous knowledge is of great value. Therapeutic uses of the documented plants provide data for further pharmacological studies.

The Perpetual Impact of COVID-19 on the Geriatric Population's Quality of Life and Potential Preventive and Therapeutic Measures in Unani Medicine: An Evidence-based Review

Background: COVID-19 pandemic has affected the elderly population more severely than many other patient groups. Due to their constitutional weakness and co-morbidities, geriatric populations are more prone to complications and adverse outcomes, especially with a high viral load. The Unani system of medicine encompasses several guidelines for the prevention and treatment of epidemics, which are stratified for different types of people with respect to age, geography, and health status, among others. Objective: Since Unani drugs are both safe and efficient, it has been found that demand for them has surged since COVID. This paper aims to discuss the various immunomodulatory, longevity-promoting agents, and organ-specific tonics specified in Unani medicine for the care of the elderly, which may be helpful during epidemics, and also, to present the scientific evidence of their efficacy. Methods: A thorough assessment of the available literature was carried out utilizing several electronic databases, including PubMed, Science Direct, Web of Science, Wiley Online, Google Scholar, and Springer Link, using the terms "Geriatrics," "Elderly," "SARS-CoV-2," "Unani," and many others, up until October 2022. A total of 61 pertinent reviews were included. To gather information on epidemics and their specific response in geriatrics, monographs in Urdu, Arabic, and English were explored in addition to classic Unani texts such Al-Qanun fit Tibb (The Canon of Medicine), Kamil-us-Sana'at (Liber Regius), Kitab al-Hawi fit Tibb (Liber Continence), and others. Plant names were confirmed by “The Plant List” (www.theplantlist.org). Results: During pandemics, Unani medicine aims to promote and preserve the health of the elderly by regulating six important factors (Asbāb Sitta Ḍarūriyya), which include adopting a specific diet, regimen and drugs as effective prophylactic strategies. However, the role of Unani medicine in immunological regulation relies on major organ protection, viz., general body tonic, nervine tonic, heart tonic, and liver tonic. Several Unani single drugs, such as Sibr (Aloe barbadensis Mill.), Zafran (Crocus sativus L.), and Mur (Commiphora myrrh Nees.), and formulations, such as Khameera Marwareed, Tiryaq-i- Arba, and Habb-i- Jadawar have also been found to be very effective in validated scientific preclinical and clinical studies. Furthermore, Unani drugs have anti-inflammatory, analgesic, and tonic actions, contributing to their holistic efficacy. Conclusion: It is observed in this review that Unani medicine employs a holistic approach to the health protection of the elderly. There are various dietary recommendations, lifestyle modifications, regimental therapy, and pharmacotherapy prescribed as per the individual’s requirements and needs to reduce geriatric mortality in times of epidemics. Modern pharmacological studies have discovered many bioactive compounds in health-protective drugs prescribed in Unani medicine, such as Vitis vinifera L., Ziziphus jujube Mill., and many others, further substantiating the literature.

Exploring the therapeutic potential of achyranthes aspera: A comprehensive review

Achyranthes aspera, commonly known as "Prickly Chaff Flower," is a medicinal plant extensively used in traditional medicine systems worldwide. This review provides a comprehensive overview of the phytochemical constituents, pharmacological properties, and therapeutic potential of Achyranthes aspera. The phytochemical analysis reveals the presence of various bioactive compounds such as alkaloids, flavonoids, saponins, and terpenoids, among others, which contribute to its medicinal properties. Pharmacological studies have demonstrated the diverse therapeutic effects of Achyranthes aspera, including anti-inflammatory, analgesic, antioxidant, antimicrobial, antidiabetic, hepatoprotective, and anticancer activities. Furthermore, the plant has been utilized in the management of various ailments such as arthritis, diabetes, respiratory disorders, gastrointestinal disorders, and skin diseases. However, despite its promising therapeutic potential, further research is warranted to elucidate the underlying mechanisms of action and evaluate its safety and efficacy for clinical applications. This review aims to consolidate the existing knowledge on Achyranthes aspera, providing insights for future research and potential development of novel therapeutic agents.

PHARMACOLOGICAL EFFECTS OF MELATONIN AND ITS POTENTIAL APPLICATION IN THERAPY OF GOUT AND ASSOCIATED DISEASES

Introduction. The disturbance in biosynthetic activity of pinealocytes of the pineal gland and subsequent melatonin deficiency in the body are linked to the progression of certain chronic diseases. This has prompted research into correcting chrono-biological dysfunctions, particularly in conditions such as gout and its comorbidities. This study aims to analyze the potential use of melatonin in correcting metabolic disorders in gout and to justify its use as a pharmacotherapeutic agent for treating metabolic and cardiovascular diseases. Materials and methods. We conducted a comprehensive analysis of modern scientific literature from specialized domestic and foreign sources. Emphasis was placed on studies exploring the pharmacological and pharmacotherapeutic aspects of melatonin use in both experimental and clinical settings, particularly those conducted in the last 5-6 years. Results. The research data revealed three main aspects of the problem that must be addressed to understand the experimental, biological, pharmacological, and pharmacotherapeutic foundations for the long-term use of melatonin in clinical practice. The first part of the review highlighted the significant impact of melatonin homeostasis disruption on the pathogenesis of gout and its progression in comorbidity with other conditions such as hypertension, obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The role of chronobiological disorders and desynchronosis in the progression of these diseases was also established. Pharmacological studies demonstrated the pivotal role of melatonin, as an important factor in neuroendocrine regulation, in organizing the circadian rhythm of the body's vital functions under normal and pathological conditions. Melatonin was found to normalize the pathological processes underlying gout development and comorbid diseases, providing a scientific basis for its use in the treatment of gout, cardiovascular diseases, disturbed metabolic processes, and normalization of circadian rhythms in patients with these conditions. Conclusions. This paper presents data on the causes of gout development and progression, as well as some comorbid diseases, from the perspective of chronobiological disruptions in the body's functions. The review sections delve into the pharmacological and pharmacotherapeutic aspects of melatonin's therapeutic action. The findings confirm the importance of melatonin in effectively treating gout and other comorbid diseases and metabolic disorders.

Ecology, Cultivation, and Utilization of the Dittany of Crete (Origanum dictamnus L.) from Ancient Times to the Present: A Short Review

Medicinal and aromatic plants are a consistent component of the biodiversity heritage in numerous countries worldwide. Origanum dictamnus L. (Lamiaceae family), also known as Dittany, an endemic plant of the Greek island of Crete, has been widely used as traditional medicine since antiquity, all over Europe. The aim of the present review is to provide a thorough and detailed account of Dittany in antiquity, the plant’s physical characteristics and ecology, and its cultivation methods, as well as its chemical components, biological properties, and pharmacological studies. The information is presented and analyzed in a critical manner. A total of 86 research studies were systematically reviewed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The findings indicate that Dittany is one of the most important medicinal and aromatic plants, with many uses not only in pharmacology but also in gastronomy. While a large body of literature exists regarding the application of essential oils, the number of publications concerning the plant’s cultivation is rather small. Therefore, the main focus of this review is on the cultivation methods and the significance of cultivating and employing Dittany in Greece and the wider Mediterranean region in the future. Further research on this plant species is warranted since it has significant medicinal, economic, and environmental value.

Application of microphysiological systems for nonclinical evaluation of cell therapies.

Microphysiological systems (MPS) are gaining broader application in the pharmaceutical industry but have primarily been leveraged in early discovery toxicology and pharmacology studies with small molecules. The adoption of MPS offers a promising avenue to reduce animal use, improve in-vitro-to-in-vivo translation of pharmacokinetics/pharmacodynamics and toxicity correlation, and provide mechanistic understanding of model species suitability. While MPS have demonstrated utility in these areas with small molecules and biologics, cell therapeutic MPS models in drug development have not been fully explored, let alone validated. Distinguishing features of MPS, including long-term viability and physiologically relevant expression of functional enzymes, receptors, and pharmacological targets make them attractive tools for nonclinical characterization. However, there is currently limited published evidence of MPS being utilized to study the disposition, metabolism, pharmacology, and toxicity profiles of cell therapies. This review provides an industry perspective on the nonclinical application of MPS on cell therapies, first with a focus on oncology applications followed by examples in regenerative medicine.

Phytochemistry of genus Buxus and pharmacology of Cyclovirobuxine D.

Genus Buxus plants, commonly known as "boxwood", are widely distributed in China. The stems, branches, and leaves of the plant are traditionally used for rheumatism, toothache, chest pain, abdominal gas, and other diseases. However, an overview of the genus Buxus remains to be provided. To provide a scientific basis for the appropriate use and further research the recent advancements in the traditional usage, phytochemistry, and, pharmacology of Buxus. Chemical composition and pharmacological correlation studies through a literature review. Between 1970 and 2023, the available data concerning Buxus was compiled from online scientific sources, such as Sci-Finder, PubMed, CNKI, Google Scholar, and the Chinese Pharmacopoeia. Plant names were verified from "The Plant List'.Results: To date, 266 structurally diverse chemicals have been extracted and identified from the genus Buxus. Alkaloids constitute one of its primary bioactive phytochemicals. A summary of the channels of action of Cyclovirobuxine D on the cytotoxicity of a variety of cancers has been provided. Numerous findings from contemporary phytochemical and pharmacological studies support the traditional use, facilitating its application. Further research is necessary to address various shortcomings, including the identification of the active ingredients and quality control of the genus Buxus.

Deciphering characteristics of Macaranga tanarius leaves extract with electron shuttle-associated anti-inflammatory activity via microbial fuel cells, molecular docking, and network pharmacology

Recent studies have shown that the potential disease-treating characteristics of traditional Chinese medicine (TCM) were associated with electron-shuttling and bioenergy-stimulating capabilities. These redox-mediating characteristics are possibly even beneficial in the treatment of a wide variety of diseases ranging from viral infections to inflammations. This first-attempt study tended to investigate electron-mediating and bioenergy-extracting potentials of Macaranga tanarius leaves extract using dual chamber microbial fuel cells (MFCs) to unveil correlations of the anti-inflammatory potential for value-added applications. Network pharmacology and molecular docking studies were conducted with compounds identified to own electron-shuttling capabilities in the leaves extract to determine inhibitory activity with inflammation receptors. M. tanarius has shown significant bioenergy-stimulating characteristics, with the water extract having a 1.72±0.21-fold power generation. The underlying mechanism of action of M. tanarius was proposed via network pharmacology, suggesting how it targets specific proteins to inhibit potential diseases, such as kidney nephropathy. The findings revealed that major flavonoids bound to receptors via hydrogen bonds and π-interactions stabilizing the protein-ligand complex. Thus, exhibiting a high binding affinity with inflammation receptors, suggesting how it targets specific proteins to inhibit potential diseases.

Identification of Scutebarbatine B metabolites in rats using UHPLC-Q-Orbitrap-MS/MS and exploration of its mechanism of reversal multidrug resistance in breast cancer by network pharmacology and molecular docking studies

Scutebarbatine B (SBT-B) is a neo-clerodane diterpenic compound isolated from Scutellaria barbata D. Don (S. barbata), which has been reported to exhibit inhibitory P-glycoprotein (P-gp) property in MCF-7/ADR cells. However, its metabolism and molecular mechanism of reversal multidrug resistance (MDR) in breast cancer remains unclear. This study investigated the metabolite profile of SBT-B in rats by UHPLC-Q-Orbitrap-MS/MS, and explored its mechanism of reversal MDR through network pharmacology and molecular docking studies. A total of 16 Phase I metabolites and 2 Phase II metabolites were identified, and 18 metabolites were all newly discovered metabolites as novel compounds. The metabolic pathway of SBT-B mainly includes oxidization, reduction, hydrolysis, acetylation and glycination. Meanwhile, network pharmacology analyses showed that SBT-B mainly regulated p27 phosphorylation during cell cycle progression, p53 signaling pathway, influence of Ras and Rho proteins on G1 to S Transition. Molecular docking studies revealed that SBT-B exhibits the potential to inhibit P-gp expression by selectively binding to GLN721 and ALA981 residue sites at the interface of P-gp. In addition, SBT-B exhibits moderate binding affinity with CDK2 and E2F1. This study illustrated the major metabolic pathways of SBT-B in vivo, clarified detailed information on SBT-B metabolites in rats, and uncovered the potential mechanism of SBT-B reversal MDR in breast cancer, providing new insights for the development of P-gp inhibitors.

Integrated transcriptome and metabolome analysis reveals the regulation of phlorizin synthesis in Lithocarpus polystachyus under nitrogen fertilization

BackgroundNitrogen (N) is essential for plant growth and development. In Lithocarpus polystachyus Rehd., a species known for its medicinal and food value, phlorizin is the major bioactive compound with pharmacological activity. Research has revealed a positive correlation between plant nitrogen (N) content and phlorizin synthesis in this species. However, no study has analyzed the effect of N fertilization on phlorizin content and elucidated the molecular mechanisms underlying phlorizin synthesis in L. polystachyus.ResultsA comparison of the L. polystachyus plants grown without (0 mg/plant) and with N fertilization (25, 75, 125, 175, 225, and 275 mg/plant) revealed that 75 mg N/plant fertilization resulted in the greatest seedling height, ground diameter, crown width, and total phlorizin content. Subsequent analysis of the leaves using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) detected 150 metabolites, including 42 flavonoids, that were differentially accumulated between the plants grown without and with 75 mg/plant N fertilization. Transcriptomic analysis of the L. polystachyus plants via RNA sequencing revealed 162 genes involved in flavonoid biosynthesis, among which 53 significantly differed between the N-treated and untreated plants. Fertilization (75 mg N/plant) specifically upregulated the expression of the genes phenylalanine ammonia-lyase (PAL), 4-coumarate-CoA ligase (4CL), and phlorizin synthase (PGT1) but downregulated the expression of trans-cinnamate 4-monooxygenase (C4H), shikimate O-hydroxycinnamoyltransferase (HCT), and chalcone isomerase (CHI), which are related to phlorizin synthesis. Finally, an integrated analysis of the transcriptome and metabolome revealed that the increase in phlorizin after N fertilization was consistent with the upregulation of phlorizin biosynthetic genes. Quantitative real-time PCR (qRT‒PCR) was used to validate the RNA sequencing data. Thus, our results indicated that N fertilization increased phlorizin metabolism in L. polystachyus by regulating the expression levels of the PAL, PGT1, 5-O-(4-coumaroyl)-D-quinate 3’-monooxygenase (C3’H), C4H, and HCT genes.ConclusionsOur results demonstrated that the addition of 75 mg/plant N to L. polystachyus significantly promoted the accumulation of flavonoids, including phlorizin, and the expression of flavonoid synthesis-related genes. Under these conditions, the genes PAL, 4CL, and PGT1 were positively correlated with phlorizin accumulation, while C4H, CHI, and HCT were negatively correlated with phlorizin accumulation. Therefore, we speculate that PAL, 4CL, and PGT1 participate in the phlorizin pathway under an optimal N environment, regulating phlorizin biosynthesis. These findings provide a basis for improving plant bioactive constituents and serve as a reference for further pharmacological studies.

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation

BackgroundAccording to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. MethodsComputational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. ResultsThe XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were –14.261, –13.475, –13.074, –13.045, –12.978, –12.659, –12.354 and –12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were −69.093, −62.950, and −53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 μg/ml, and for that of pure acarbose it was 89.16 μg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. ConclusionIn summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

Potential mechanisms of traditional Chinese medicine in treating insomnia: A network pharmacology, GEO validation, and molecular-docking study.

The purpose of this study is to investigate the potential mechanisms of Chinese herbs for the treatment of insomnia using a combination of data mining, network pharmacology, and molecular-docking validation. All the prescriptions for insomnia treated by the academician Qi Wang from 2020 to 2022 were collected. The Ancient and Modern Medical Case Cloud Platform v2.3 was used to identify high-frequency Chinese medicinal herbs and the core prescription. The Traditional Chinese Medicine Systems Pharmacology and UniProt databases were utilized to predict the effective active components and targets of the core herbs. Insomnia-related targets were collected from 4 databases. The intersecting targets were utilized to build a protein-protein interaction network and conduct gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using the STRING database, Cytoscape software, and clusterProfiler package. Gene chip data (GSE208668) were obtained from the Gene Expression Omnibus database. The limma package was applied to identify differentially expressed genes (DEGs) between insomnia patients and healthy controls. To create a "transcription factor (TF)-miRNA-mRNA" network, the differentially expressed miRNAs were entered into the TransmiR, FunRich, Targetscan, and miRDB databases. Subsequently, the overlapping targets were validated using the DEGs, and further validations were conducted through molecular docking and molecular dynamics simulations. Among the 117 prescriptions, 65 herbs and a core prescription were identified. Network pharmacology and bioinformatics analysis revealed that active components such as β-sitosterol, stigmasterol, and canadine acted on hub targets, including interleukin-6, caspase-3, and hypoxia-inducible factor-1α. In GSE208668, 6417 DEGs and 7 differentially expressed miRNAs were identified. A "TF-miRNA-mRNA" network was constructed by 4 "TF-miRNA" interaction pairs and 66 "miRNA-mRNA" interaction pairs. Downstream mRNAs exert therapeutic effects on insomnia by regulating circadian rhythm. Molecular-docking analyses demonstrated good docking between core components and hub targets. Molecular dynamics simulation displayed the strong stability of the complex formed by small molecule and target. The core prescription by the academician Qi Wang for treating insomnia, which involves multiple components, targets, and pathways, showed the potential to improve sleep, providing a basis for clinical treatment of insomnia.

Network Pharmacology Combined with Animal Models to Investigate the Mechanism of ChangPu YuJin Tang in the Treatment of Tourette Syndrome.

ChangPu YuJin Tang (CPYJT) is a Chinese herbal formula that has been shown to be an effective therapeutic strategy for pediatric patients with Tourette Syndrome (TS). Using an integrated strategy of network pharmacology and animal model, the aim of this study was to investigate the mechanism of CPYJT in the treatment of TS. Compound libraries of CPYJT were established using databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The TCMSP database and Swiss Target Prediction database were used to predict the targets. The above results were constructed into a CPYJT-Drug-Component-Target network. Moreover, TS targets were predicted using GeneCards and other databases. The targets corresponding to the potential ingredients in CPYJT and the targets corresponding to TS were taken as the intersections to construct the CPYJT-TS network. The target network was analysed by PPI using the string database. GO and KEGG enrichment analyses were performed on the target network. The whole process was performed using Cytoscape 3.7.2 to make visual network diagrams of the results. CPYJT was characterised by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS). Transmission Electron Microscopy (TEM) was used to observe the structural changes of CPYJT on the neuronal cells of the IDPN model rats. RT-PCR and Western Blot were used to analyse the changes in the mRNA and protein expression levels of BDNF, TrkB, PI3K, and AKT in the cortex, striatum, and thalamus brain regions after CPYJT administration in IDPN model rats. Network pharmacology and UHPLC-MS studies revealed that CPYJT acted on the TS through multiple neurotransmitters and the BDNF/TrkB and PI3K/AKT signalling pathways. CPYJT ameliorated neurocellular structural damage in the cortex, striatum, and thalamus of TS model rats. Additionally, CPYJT up-regulated the levels of BDNF, TrkB, PI3k, and AKT in the cortex, striatum, and thalamus of TS model rats. It was found that CPYJT protected neuronal cells from structural damage in multiple brain regions and affected the expression levels of BDNF, TrkB, PI3K, and Akt in the cortex, striatum, and thalamus during TS treatment.

A Review on Khubbāzī (Malva sylvestris L.): Phytochemical, Pharmacological Properties and Therapeutic Applications

Traditional system of medicine, especially Unani, highly value Khubbāzī (Malva sylvestris L.) for its therapeutic properties. Its leaves, seeds and flowers are utilized medicinally as Barg-i-Khubbāzī, Tukhm-i-Khubbāzī and Gul-i-Khubbāzī since time immemorial. It is used in Unani Medicine for various activities like concoctive, diuretic, anti-inflammatory, hepatoprotective, hence used to treat several ailments related to respiratory, skin and digestive systems such as cough, cold, coryza, sore throat, chronic bronchitis, intestinal ulcer and urinary issues like strangury, irritation in micturition etc. Pharmacological studies on various parts of the plant have been reported such as hepatoprotective, antioxidant, anti-inflammatory etc. which are supported by the bioactive compounds, alkaloid, glycosides, flavone etc. present in the plant. Scientific studies validated several actions documented in Unani literature, but further researches needed to explore the hidden properties of the plant. This review focuses on the plant’s traditional uses, pharmacological properties.

Abstract PO5-18-06: On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit the the in vitro and in vivo action of human PGRN/GP88 has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. The presentation will provide an update on the number of patients enrolled in this on-going phase 1A trial. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-06.

Mechanism of Si Ni San Combined with Astragalus in Treating Hepatic Fibrosis: A Network Pharmacology and Molecular Docking Study.

Si Ni San combined with Astragalus (SNSQ) has demonstrated significant efficacy in the treatment of hepatic fibrosis (HF), as confirmed by clinical practice. However, its pharmacological mechanism remains unclear. This study employs network pharmacology to identify key targets and proteins for molecular docking. Additionally, animal experiments were conducted to validate the network pharmacology results, providing further insights into the mechanism of SNSQ in treating HF. Effective compounds of SNSQ were screened from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopedia of Traditional Chinese Medicine (ETCM) databases. Molecular formula structures of these effective compounds were obtained from the PubChem database. Partial target proteins with a probability greater than 0.6 were sourced from the SWISS database. Uniprot IDs corresponding to these target proteins were retrieved from the SUPERPRED database. The remaining target proteins of the compounds were obtained from the Uniprot database based on the Uniprot IDs. The drug target proteins were then summarized. Target points related to HF were selected from the GeneCards and OMIM databases. Common target points were identified in the Venn diagram and imported into Cytoscape 3.9.1 software to construct the "SNSQ-effective compound-target pathway-HF" network. AutoDock software was used for molecular docking of compounds and target proteins with high-degree values. The common target points underwent GO function enrichment and KEGG pathway enrichment analysis using the DAVID database. An HF rat model was established, and serum AST and ALT activities were measured. The Hyp assay kit was utilized to detect the Hyp content in liver tissue. To the transcription levels of pro-inflammatory factors (IL-1β, TNF-α, IL-6) and anti-inflammatory factors (IL-10, TGF-β1, IL-4) in rat serum and liver.IL-1β, TNF-α, IL-10, and TGF-β1 were chosen for validation through ELISA. Western blotting and qRT-PCR were used to assess the expression of related proteins, namely NFKB1, NF-κBp65, NF-κBp50, α-SMA, and Col-1 in liver tissue. qRT-PCR was also employed to study the expression of ECM synthesis and proliferation-related genes, including Cyclin D1, TIMP1, COL1A1 in HSC-T6 cells and rat liver tissue, as well as the inhibition of the ECM-related gene MMP13 in HSC-T6 cells and rat liver tissue. A total of 16 valid compounds were predicted, with kaempferol, sitosterol, and isorhamnetin exhibiting high-degree values. KEGG enrichment analysis revealed that the target genes of SNSQ were enriched in multiple pathological pathways, with the NF-Kappa B signaling pathway being predominant. Molecular docking simulations indicated strong affinities between SNSQ's primary components-kaempferol, sitosterol, isorhamnetin-and NFKB1. Experimental results demonstrated significant reductions in AST, ALT, and Hyp levels in the SNSQ group. Pro-inflammatory factors (IL-1β, TNF-ɑ) were markedly reduced, while anti-inflammatory factors (IL-10, TGF-β1) were substantially increased. The protein expression and transcription levels of α-SMA and Col-1 were significantly decreased, whereas those of NFKB1, NF-κBp65, and NF-κBp50 were notably elevated. mRNA expression levels of Cyclin D1, TIMP1, COL1A1 in HSC-T6 cells and rat liver tissue were significantly decreased, whereas MMP13 mRNA expression level was significantly increased. Treatment of HF with SNSQ involves multiple targets and pathways, with a close association with the overexpression of NFKB1 and activation of the NF-Kappa B signaling pathway. Its mechanism is closely linked to the activation of inflammatory responses, HSC activation, and proliferation.

Bibliometric analysis of traditional Chinese medicine in the treatment of inflammatory bowel disease

Objective: This study conducts a bibliometric analysis of literature on the treatment of inflammatory bowel disease (IBD) with traditional Chinese medicine (TCM) to explore its research status, hotspots, and development trends, providing ideas and references for further research. Method: We screened literature for treating IBD with TCM from the Web of Science Core Collection (WOSCC), and used the VOSviewer software (1.6.18) to discover cooperation among countries, institutions, authors, and information on journals, keywords, etc. We use the CiteSpace software (6.2.R2) to analyze co-citation and burst discovery of references. Results: In all, 440 relevant literature papers were searched and screened from the WOSCC database. The results showed that the number of publications concerning treating IBD with TCM has shown a significant growth in the past decade. China is far ahead in terms of article output, occupying a dominant position. The institution with the most published articles is Nanjing University of Traditional Chinese Medicine. The authors who have published most of the articles are Dai Yancheng, Shi Rui, and Zhou Lian. The Journal of Ethnopharmacology published maximum articles in this field, while Gastroenterology was the most cited journal. Ungaro et al.’s article entitled “Ulcerative colitis” (https://doi.org/10.1016/S0140-6736(16)32126-2), published in The Lancet in 2017 was the most cited study. The high-frequency keywords mainly include ulcerative colitis, inflammation, NF-κB, expression, traditional Chinese medicine, gut microbiota, activation, mice, cells, etc. Conclusions: The research heat for treating IBD with TCM has risen over the past decade, with studies focusing on three main aspects: clinical studies of TCM, basic pharmacology, and animal experimental research. The research hotspot shifted from pathogenesis, clinical study of TCM, basic pharmacology, and complementary therapies to the study of network pharmacology and the mechanism of action of TCM related to gut microbiota. Network pharmacology and gut microbiota are at the frontiers of research and turning to be the future research trends to provide new insights and ideas for further research for treating IBD with TCM.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet

AimsEpidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. MethodsB16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). Key findingsEGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. ConclusionTaken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Revealing the potential bioactive components and mechanism of Qianhua Gout Capsules in the treatment of gouty arthritis through network pharmacology, molecular docking and pharmacodynamic study strategies

Recent clinical studies have confirmed the effectiveness of Qianhua Gout Capsules (QGC) in the treatment of gouty arthritis (GA). However, the specific regulatory targets and mechanisms of action of QGC are still unclear. To address this gap, we utilized network pharmacology, molecular docking, and pharmacodynamic approaches to investigate the bioactive components and associated mechanisms of QGC in the treatment of GA. By employing UPLC-Q Exactive-MS, we identified the compounds present in QGC, with active ingredients defined as those with oral bioavailability ≥30 % and drug similarity ≥0.18. Subsequently, the targets of these active compounds were determined using the TCMSP database, while GA-related targets were identified from DisGeNET, GeneCards, TTD, OMIM, and DrugBank databases. Further analysis including PPI analysis, GO analysis, and KEGG pathway enrichment was conducted on the targets. Validation of the predicted results was performed using a GA rat model, evaluating pathological changes, inflammatory markers, and pathway protein expression. Our results revealed a total of 130 components, 44 active components, 16 potential shared targets, GO-enriched terms, and 47 signaling pathways related to disease targets. Key active ingredients included quercetin, kaempferol, β-sitosterol, luteolin, and wogonin. The PPI analysis highlighted five targets (PPARG, IL-6, MMP-9, IL-1β, CXCL-8) with the highest connectivity, predominantly enriched in the IL-17 signaling pathway. Molecular docking experiments demonstrated strong binding of CXCL8, IL-1β, IL-6, MMP9, and PPARG targets with the top five active compounds. Furthermore, animal experiments confirmed the efficacy of QGC in treating GA in rats, showing reductions in TNF-α, IL-6, and MDA levels, and increases in SOD levels in serum. In synovial tissues, QGC treatment upregulated CXCL8 and PPARG expression, while downregulating IL-1β, MMP9, and IL-6 expression. In conclusion, this study applied a network pharmacology approach to uncover the composition of QGC, predict its pharmacological interactions, and demonstrate its in vivo efficacy, providing insights into the anti-GA mechanisms of QGC. These findings pave the way for future investigations into the therapeutic mechanisms underlying QGC's effectiveness in the treatment of GA.

Behavioral and pharmacological characterization of planarian nociception.

Pain mostly arises because specialized cells called nociceptors detect harmful or potentially harmful stimuli. In lower animals with less convoluted nervous system, these responses are believed to be purely nociceptive. Amongst invertebrate animal models, planarians are becoming popular in a wide range of pharmacological and behavioral studies beyond the field of regeneration. Recent publications led the way on pain studies by focusing on nociceptive behaviors such as the 'scrunching' gait displayed under various noxious stimuli, as opposed to the 'gliding' gait planarians usually adopt in normal conditions. In this study, we adapted commonly used nociceptive tests to further explore nociception in planarians of the species Girardia dorotocephala. By using behavioral analysis in open fields and place preferences, we managed to set up chemical, thermal and mechanical nociceptive tests. We also adapted RNA interference protocols and explored the effects of knocking down TRPA1 ion channels, one of the main effectors of chemically and thermally-induced nociceptive responses in vertebrates. Consequently, we demonstrated the reliability of the scrunching gait in this planarian species, which they displayed in a dose-dependent manner when exposed to the irritant AITC. We also showed that suppressing the expression of TRPA1 ion channels completely suppressed the scrunching gait, demonstrating the involvement of TRPA1 nociceptors in this nociceptive reaction. Besides, we also explored the effects of two common analgesics that both displayed strong antinociceptive properties. First, morphine reduced the chemically-induced nociceptive scrunching gaits by more than 20% and shifted the of the dose-response curve by approximately 10 μM. Secondly, the NSAID meloxicam drastically reduced chemically-induced scrunching by up to 60% and reduced heat avoidance in place preference tests. Thus, we managed to characterize both behavioral and pharmacological aspects of G. dorotocephala's nociception, further developing the use of planarians as a replacement model in pain studies and more globally the study of invertebrate nociception.