Pharmaceutical Biology最新文献

Context: Botanicals, including products derived from plants, fungi, and algae, are increasingly consumed worldwide. Their complex compositions and variable phytochemical profiles present significant challenges for safety assessment. Traditional toxicology methods are time and resource intensive, and the variability of botanicals makes it difficult to test one lot as representative.

Objective: The Botanical Safety Consortium (BSC), launched in 2019, was established to advance fit-for-purpose toxicity testing strategies for botanicals. This manuscript summarizes the progress of the BSC, with emphasis on the activities of its Working Groups.

Methods: The BSC Working Groups evaluate established new approach methodologies (NAMs), including in vitro assays, in silico models, and non-protected whole organisms such as C. elegans, for their applicability to botanical hazard assessment. Case studies of botanicals were selected based on known toxicity profiles to test assay performance and determine whether botanicals behave differently from single chemicals in these systems.

Results: The evaluations address toxicological endpoints such as hepatotoxicity, genotoxicity, developmental and reproductive toxicity, neurotoxicity, cardiotoxicity, and dermal toxicity. Early findings have identified fit-for-purpose screening tools that can generally be applied to botanical testing, with some nuances and considerations.

Conclusion: Future work will focus on refining and enhancing the tool-kit through assay refinement, filling endpoint gaps with additional assays, and incorporating ADME data and in silico modeling approaches. This collaborative, science-driven framework aims to modernize botanical safety evaluation, address regulatory needs, and ultimately protect public health while supporting the global demand for botanical-based dietary supplements, cosmetics, and other products.

Context: Kratom (Mitragyna speciosa), native to Southeast Asia, has traditionally been consumed as fresh leaves or teas. Under those conditions, exposure to 7-hydroxymitragynine (7-OH)-a potent μ-opioid receptor agonist-is minimal, as it occurs only at trace levels in leaf material. By contrast, the U.S. market offers chemically enriched or semi-synthetic 7-OH products, often marketed as 'kratom' yet chemically distinct from botanical preparations.

Methods: '7-OH', '7-hydroxymitragynine', and 'kratom' were used as keywords; relevant literature was obtained from PubMed, Web of Science, and Google Scholar.

Results: Pharmacological studies consistently identify 7-OH as a partial μ-opioid receptor agonist with nanomolar affinity, greater efficacy than mitragynine, and often exceeding the potency of morphine. Animal experiments demonstrate robust antinociceptive effects, respiratory depression, tolerance, dependence, and reinforcing properties characteristic of opioids. Human pharmacokinetic studies show systemic exposure after kratom ingestion, but concentrated 7-OH products bypass metabolic formation, producing markedly higher exposures. Regulatory surveillance, poison-center data, and marketplace audits confirm a rapid increase in availability and use of these products. State health departments have reported severe intoxications and fatalities. Clinical cases describe escalating use, medically managed withdrawal, and psychiatric destabilization, while forensic investigations document postmortem concentrations consistent with fatal opioid toxicity. Pediatric risk is amplified by developmental susceptibility, absence of age restrictions, and marketing in confectionary formats. Emerging analogues such as MGM-15 further extend this trajectory.

Conclusion: Collectively, the evidence demonstrates that concentrated 7-OH products are pharmacologically and toxicologically distinct from kratom leaf and pose significant risks of morbidity and mortality under typical conditions of use.

Aim: Insufficient quality control and limited dissolution of Andrographis paniculata extract capsules restricts their bioavailability and hinder the clinical use for treating mild coronavirus disease 2019 (COVID-19) patients.

Objective: This study aims to investigate pharmacokinetics and safety of high-dosage A. paniculata ethanolic extract (equivalent to 180 or 360 mg/day of andrographolide), relevant dosages used for mild COVID-19 treatment.

Methods: An open-label, single-dose, and repeated-dose conducted in healthy volunteers. Subjects received capsules containing ethanolic extract equivalent to andrographolide dosage of either 60 or 120 mg per dose, taken every eight hours daily (totaling 180 or 360 mg/day). Safety was assessed through blood chemical analysis and adverse event monitoring after 7 days of ethanolic extract administration.

Results: Pharmacokinetics of ethanolic extract indicated low plasma levels of the major diterpenoids. The maximum plasma concentration (Cmax) of andrographolide did not exhibit a dose-proportional increase, reaching 6.44 and 11.62 µg/L for single and repeated doses of 60 mg/day, respectively. Doubling the dose (120 mg/day) only resulted in slightly higher Cmax (6.97 and 15.03 µg/L for single and repeated doses, respectively). Safety evaluation revealed mild, transient adverse events, but all parameters remained within normal ranges.

Conclusions: This study highlights limitations in the pharmacokinetics of the ethanolic extract of A. paniculata. It indicated non-linear proportionality in the oral bioavailability of andrographolide. These findings suggest that current extraction process of ethanolic extract may hinder its effectiveness. Further research is warranted to explore alternative extraction methods or formulation developments that can enhance the bioavailability of andrographolide and its potential therapeutic effects for COVID-19 treatment.

Context: The discovery of plants and bioactive compounds with the potential to become botanical or pharmaceutical drugs remains a cornerstone of drug innovation. Many of these valuable molecules originate from traditional botanical pharmacopeias, repositories of centuries-old knowledge that are often underappreciated in modern research.

Objective: This review highlights the medicinal plants identified in Sabah from 1922 to 2024, analyzing their taxonomical distribution, uses, utilization among ethnic groups, and their potential for clinical uses.

Methods: The data for this review were gathered from Google Scholar, PubMed, ScienceDirect, Web of Science, PubMed, the Internet Archive, and Google Books. A keyword combination of "Medicinal" and "Plants" and "Sabah" yielded 21,700 results. Each result was examined, and articles that did not contain information relevant to the topic or came from non-peer-reviewed journals were excluded. Each of the remaining 87 selected articles was critically reviewed to extract pertinent information.

Results: A review of the available data indicates that 696 plant species are used in Sabah, including 412 angiosperms. These plants are primarily utilized to treat diseases or symptoms related to infections, digestive issues, injuries, and pains. Notably, 156 species employed by local Sabahan Dusunic, Murutic, and Kelabit ethnic groups remain unstudied in terms of their phytochemical and pharmacological properties, highlighting their potential for further investigation.

Conclusion: Sabah's medicinal plants offer tremendous potential for discovering natural products of therapeutic value.

Context: The advent of tissue engineering and biomedical techniques has significantly advanced the development of three-dimensional (3D) cell culture systems, particularly tumor organoids. These self-assembled 3D cell clusters closely replicate the histopathological, genetic, and phenotypic characteristics of primary tissues, making them invaluable tools in cancer research and drug screening.

Objective: This review addresses the challenges in developing in vitro models that accurately reflect tumor heterogeneity and explores the application of tumor organoids in cancer research, with a specific focus on the screening of natural products for antitumor therapies.

Methods: This review synthesizes information from major databases, including Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, ScienceDirect, Google Scholar, Scopus, PubMed and Springer Link. Publications were selected without date restrictions, using terms such as 'organoid', 'natural product', 'pharmacological', 'extract', 'nanomaterial' and 'traditional uses'. Articles related to agriculture, ecology, synthetic work or published in languages other than English were excluded.

Results and conclusions: The review identifies key challenges related to the efficiency and variability of organoid generation and discusses ongoing efforts to enhance their predictive capabilities in drug screening and personalized medicine. Recent studies utilizing patient-derived organoid models for natural compound screening are highlighted, demonstrating the potential of these models in developing new classes of anticancer agents. The integration of natural products with patient-derived organoid models presents a promising approach for discovering novel anticancer compounds and elucidating their mechanisms of action.

Context: Obesity induces alterations in adipocyte size, tissue inflammation, vascularization, and extracellular matrix composition. Previous studies have shown that a leaf extract of Eucalyptus tereticornis Sm. (Myrtaceae), with ursolic acid, oleanolic acid, and ursolic acid lactone mixed with minor metabolites, provided a superior antiobesity effect than reconstituted triterpenoid mixtures in adipocyte cell lines and a pre-diabetic mouse model. Further identification of the molecular mechanisms of action of this mixture of triterpenes is required.

Objective: This study analyzes the effect of the natural extract and its components on early RNA expression profiles in human primary cultured adipocytes and a mouse cell line.

Materials and methods: RNA was sequenced using the DNBseq platform and the EnrichR software to perform gene enrichment analysis using the Gene Ontology database, Kyoto Encyclopedia of Genes and Genomes, and Reactome. To conduct clustering analysis, the normalized counts of each gene and applied k-means clustering were standardized.

Results: The combination of molecules in the natural extract has an additive or synergic effect that increases the number of genes regulated associated with the biological functionality of differentiating adipocytes, with UAL playing a central role. The natural extract modulates PPAR, Wnt, and Extracellular Matrix organization pathways significantly in both cellular models. Remarkably, the extract downregulates the expression of genes involved in lipid metabolism, adipogenesis, and adipocyte fat load, such as PRKAR2B, LPIN1, FABP4, Scd1, MC5R, CD36, PEG10, and HMGCS1.

Discussion and conclusions: Our study shows that Eucalyptus tereticornis extract is a promising option for treating adipocyte tissue dysfunction derived from obesity.

Context: Melanoma's aggressiveness and resistance to radiotherapy highlight an urgent need for innovative treatments. Traditional Chinese medicine (TCM) offers a unique approach through its 'four natures' theory-cold, cool, warm, and hot.

Objective: This review aims to explore the potential of TCM's 'four natures' herbal monomers in melanoma treatment, providing an alternative to conventional therapies.

Materials & methods: A systematic literature review was conducted by accessing various databases, including Baidu Scholar, PubMed, Science Citation Index Expanded (SCIE), and China National Knowledge Infrastructure (CNKI), to synthesize the most recent findings on traditional Chinese medicine monomers. Furthermore, this review elucidated the mechanisms underlying their role in melanoma retention.

Results: TCM's multi-component, multi-target approach has shown promise in addressing melanoma's complexity, with specific monomers demonstrating the ability to modulate tumor behavior.

Discussion and conclusions: The 'four natures' theory in TCM presents a novel perspective for melanoma treatment, warranting further investigation into its clinical applications and potential integration with modern oncology.

Background: Botanical dietary supplements derived from the fruit of the tree Garcinia gummi-gutta (L.) N. Robson (commonly known as Garcinia cambogia or Garcinia) are used to support weight loss but are increasingly linked to adverse events and case reports of liver injury.

Objective: Clinical case reports of liver injury associated with Garcinia dietary supplements were reviewed that had prompted the United States Pharmacopeia (USP) to revise the USP Garcinia family of dietary ingredient monographs to include a cautionary statement regarding potential risk of liver damage.

Methods: The terms 'Garcinia cambogia,' 'Garcinia gummi-gutta,' or 'Garcinia' were searched in multiple databases of adverse events. PubMed and Google Scholar were searched for peer-reviewed papers describing preclinical and clinical studies of Garcinia toxicity.

Results: More than 200 adverse events of liver injury resulting from Garcinia consumption were identified. A total of 34 case reports of Garcinia hepatotoxicity indicated one death and nine liver transplants, with 17 cases receiving CIOMS/RUCAM scores that indicated possible to highly probable causality due to Garcinia dietary supplements. In one case, causality was confirmed by rechallenge with Garcinia.

Discussion and conclusions: Garcinia toxicity was consistent with drug-induced liver injury and included elevated serum liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase with a high ratio of ALT to alkaline phosphatase. Proposed mechanisms of toxicity include genetic predisposition to immune-mediated reactions involving the human leucocyte antigen HLA-B*35:01 allele, induction of hepatocyte oxidative stress and inflammation, and hepatocyte apoptosis caused by the active constituent, hydroxycitric acid, which inhibits mitochondria ATP-citrate lyase.

Context: Recent research has revealed significant advancements in the field of traditional Chinese medicine (TCM) for skin diseases. However, there is a lack of visualization analysis within this research domain.

Objective: To analyze the research directions and advancements in TCM research in skin diseases.

Materials and methods: Publications related to TCM in skin diseases from 2014 to 2024 were searched on the Web of Science Core Collection (WoSCC), VOSviewer, CiteSpace, and the R package "bibliometrix" were employed to visualize and analyze the retrieved data.

Results: The study included 527 articles published in 25 countries. The number of publications consistently increased from 2014 to 2024. The Guangzhou University of Chinese Medicine was the most noteworthy institution in this field. Among the journals in this domain, the Journal of Ethnopharmacology was the most popular, and most frequently co-cited journal. Chuanjian Lu published the most papers and Yin-Ku Lin was the most frequently co-cited author. Among keywords, "psoriasis" appeared the most frequently. Additionally, several emerging research hotspots were identified, indicating the transition from traditional Chinese therapies to investigations of the molecular interactions and network pharmacology of Chinese herbs in treatment of skin diseases over the past decade.

Discussion and conclusion: This visualization analysis summarizes the research directions and advancements in TCM research on skin diseases. It presents a comprehensive examination of the latest research frontiers and trends and serves as a valuable reference for scholars engaged in the study of TCM research.

Background: Apium graveolens L. (celery) is a dietary vegetable with anti-inflammatory properties. It has the potential to treat acute lung injury (ALI) caused by COVID-19 or other diseases.

Objective: To investigate the effects of Apium graveolens water extract (AGWE) on ALI in human lung A-549 cells induced by lipopolysaccharide (LPS).

Materials and methods: A-549 cells were treated with AGWE for 24 h and then stimulated with 10 μg/mL LPS for another 24 h. The effects of AGWE on cell viability, the inflammatory response, oxidative stress, and apoptosis and their regulatory factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation were analyzed.

Results: Treatment with 5-50 μg/mL AGWE reversed the decrease in cell viability caused by LPS (p < 0.05). AGWE can reduce interleukin (IL)-1β, IL-6, IL-18, and TNF-α levels; their EC₅₀ values are 61.4, 65.7, 37.8, and 79.7 μg/mL, respectively. AGWE can reduce reactive oxygen species and thiobarbituric acid reactive substances in A-549 cells induced by LPS. AGWE also reduced the levels of apoptosis (EC50 of 74.8 μg/mL) and its regulators (Bid; Caspase-9, -8, and -3; Bax) and increased the levels of the mitochondrial membrane potential in A-549 cells induced by LPS. AGWE can also decrease the protein levels of NLRP3 and Caspase-1 and the activation of NF-κB signaling in A-549 cells induced by LPS.

Conclusions: These results show that 10 and 50 μg/mL AGWE can reduce the acute inflammation induced by LPS by reducing NF-κB and NLRP3 inflammasome signaling and mitochondria-dependent apoptosis pathways.