Pharmaceutical Biology最新文献

Context: The marine macroalga, Halymenia hawaiiana, holds significant commercial potential due to its culinary uses among various ethnic groups in Hawai'i and its success in aquaculture.

Objective: To investigate the chemical components and potential medicinal properties of H. hawaiiana.

Materials and methods: Dried, ground H. hawaiiana was sequentially extracted with three solvents: ethyl acetate, methanol, and n-butanol. Chromatographic procedures were sequentially applied, leading to the isolation of several compounds. Structure determination of these compounds was performed using spectroscopic methods. The isolated compounds were then assessed through several in vitro assays.

Results: A total of 11 compounds were isolated and identified: two nucleosides (1 and 2), a cytosine analog (3), five saturated long-chain fatty acids (4-8), cholesterol (9), and two of its derivatives (10-11) were isolated. Compounds 10 and 11 displayed promising antimicrobial activity against Staphylococcus aureus, both exhibiting MIC values of 8 μg/mL, and methicillin-susceptible S. aureus, with MIC values of 32 and 64 μg/mL, respectively. Furthermore, using a cell culture model, compounds 9, 10, and 11 exhibited significant anti-inflammatory effects as indicated by their inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with IC₅₀ values ranging from 50.2 to 60.8 µM. These compounds also effectively inhibited the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) in RAW 264.7 mouse macrophage cells with IC₅₀ values of 55-73.7 µM without inducing cytotoxicity. Compounds 9-11 also exhibited mild cytotoxicity against the non-small cell lung cancer cell line A549, with compound 10 eliciting the strongest response (IC₅₀ 86.1 µM).

Conclusions: This study uncovered a diverse array of constituents from H. hawaiiana. Notably, compounds 10 and 11, which feature peroxide side chains, show significant promise as lead compounds for the development of novel anti-inflammatory and antimicrobial agents.

Context: Diabetes mellitus represents a group of metabolic disorders that can adversely affect numerous organ systems, including the skeletal system. It elevates bone fragility and causes secondary osteoporosis, known as diabetic bone disease (DBD). The treatment of DBD depends on the control of hyperglycemia supplemented with anti-osteoporotic agents, but this has unsatisfactory efficiency.

Objective: This article provides a comprehensive review on the effects of Elaeagnus rhamnoides (L.) A. Nelson (sea buckthorn; family Elaeagnaceae), a prospective anti-diabetic and osteoprotective supplement, and its most abundant flavonoids (quercetin, isorhamnetin, kaempferol) on major mechanisms related to DBD.

Methods: 'Sea buckthorn' (SB), 'quercetin', 'isorhamnetin', 'kaempferol', 'DBD', 'hyperglycemia', 'inflammatory state', 'insulin resistance' (IR), 'advanced glycation end products' (AGEs) were used as keywords, and relevant literature was obtained from online databases (PubMed, Web of Science, Scopus).

Results and conclusions: SB and flavonoids mentioned above exert hypoglycemic and anti-inflammatory properties, attenuate IR, inhibit AGEs formation, thereby positively affecting the main DBD-related mechanisms. The direct effect of SB on DBD has not been investigated yet, but the beneficial impact of quercetin on DBD has been revealed. Therefore, it can be assumed that SB could favorably influence DBD, as its great potential to treat other bone-related diseases (osteoporosis, rheumatoid arthritis) has been reported. Further research, including high-quality in vitro and animal model studies, as well as large-scale clinical trials, is needed to confirm such a putative positive effect and to identify more efficient therapies against various diabetic complications, including DBD.

Context: Modified Xiao-Qing-Long-decoction (MXQLD) is believed to have the potential to alleviate lung diseases.

Objective: We explored the effects and mechanisms of MXQLD in acute respiratory distress syndrome (ARDS).

Materials and methods: Thirty male C57BL/6 mice were randomized into sham (distilled water), model (distilled water), MXQLD (1 g/kg MXQLD), DEX (distilled water + 0.7 mg/kg dexamethasone), MXQLD + oe-HDAC7 (HDAC7 over-expression + 1 g/kg MXQLD) groups. Except for HDAC7 over-expression on day 0 and dexamethasone injection on day 12, all treatments were administered every two days from day 0 to day 10. On day 12, except for the sham group, all mice underwent cecal ligation and puncture surgery to establish ARDS models. After surgery, pulmonary functions, protein concentration of bronchoalveolar lavage fluid (BALF) and lung tissue morphology in mice were detected. Furthermore, pro-inflammatory cytokine concentrations (IL-6, IL-1β, and TNF-α) in BALF supernatant and serum were quantified. Additionally, HDAC7, Nur77, ZO-1, occludin, and claudin protein expressions were detected.

Results: MXQLD treatment improved pulmonary functions and alleviated lung injury for ARDS mice. Furthermore, MXQLD treatment decreased protein concentration in BALF, and inhibited pro-inflammatory cytokine release in BALF supernatant and serum for ARDS mice. Additionally, MXQLD treatment down-regulated HDAC7 expression, but up-regulated Nur77, ZO-1, occludin, and claudin expressions for ARDS mice. Importantly, the preventive effects of MXQLD in ARDS mice were reversed by HDAC7 over-expression.

Discussion and conclusion: MXQLD may prevent inflammation and promote Nur77 expression in ARDS by inhibiting HDAC7 expression, indicating that MXQLD may be a promising drug for preventing ARDS.

Context: Macrophages play a critical role in the pathogenesis of ulcerative colitis (UC). Indirubin (IDR), a natural ligand of the aryl hydrocarbon receptor (AhR), has been shown to ameliorate DSS-induced colitis in our previous study (Liu Z et al.).

Objective: To investigate whether IDR exerts its protective effects by regulating M1/M2 polarization and inhibiting ferroptosis in macrophages.

Materials and methods: Immunohistochemistry staining targeting CD206 and F4/80 was performed to evaluate the effect of IDR on the polarization of M1/M2 macrophages in colitis. Subsequently, the effects of IDR on the M1- or M2-polarization of THP-1-derived macrophages were investigated. Furthermore, the effects of IDR on ferroptosis in the colon tissue of mice and on RSL3-induced ferroptosis in THP-1-derived macrophages were assessed. The results were verified in mouse peritoneal macrophages.

Results: In addition to reducing the infiltrated macrophages, IDR treatment preserved CD206+ macrophages in DSS-induced colitis. Using cultured THP-1 cells, we demonstrated that IDR inhibited M1 polarization and prompted M2 polarization. Furthermore, we showed that IDR treatment decreased levels of 4-HNE while increasing GPX4 and NRF2 in DSS-induced colitis and THP-1 cells. IDR treatments also reduced cellular reactive oxygen species (ROS) and iron content, and mitigated RSL3-induced ferroptosis in THP-1-derived macrophages. Similarly, IDR augmented M2-polarization and alleviated ferroptosis in peritoneal macrophages.

Discussion and conclusion: IDR skews the polarization of macrophages from M1 to M2. Furthermore, it inhibits ferroptosis in both mice and THP-1-derived macrophages. These mechanisms may contribute to the therapeutic effects of IDR in the treatment of UC.

Context: The Atlas Pistachio (Pistacia atlantica Desf.) possesses numerous applications for therapeutic purposes.

Objective: We set out to test various extracts from Pistacia atlantica Desf. fruits and leaves for their anticancer and acetylcholinesterase inhibitory effects. In addition to discovering the phytochemical profile of P. atlantica extracts responsible for the pharmacological effects that were researched.

Materials and methods: The anti-acetylcholinesterase activity was performed against the acetylcholinesterase (AChE) enzyme. Anticancer assays were investigated by evaluating the antiproliferative and cytotoxicity potentials against five cancerous cell lines using the [3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MMT:Medical training therapy) assay. The phenolic profile was established against phenolic standards using high-performance liquid chromatography with diode-array detection (HPLC-DAD).

Results: In anticholinesterase activity, the extracts of P. atlantica inhibited AChE activity in a dose-dependent manner. The stronger AChE inhibition activity was obtained for the n-BuOH extract of the fruits (IC₅₀ 47.80 ± 1.03 µg/mL) and compared to the leaf extracts. The results, compared with galantamine, showed a close inhibition activity. P. atlantica extracts also showed the most optimal antiproliferative and cytotoxic effect against cancer cell lines compared to positive control 5FU (Fluorouracil); the best antiproliferative activity was obtained for the fruit extracts compared to the leaf extracts. The spotted biological activities can be attributed to flavonoids and phenolic compounds in the extracts. The HPLC-DAD analysis identified the presence of 18 phytochemicals. The main compounds detected were luteolin, gallic acid, epicatechin, and protocatechuic acid.

Discussion and conclusion: This study demonstrated moderate anticholinesterase and suitable antiproliferative activities of P. atlantica Desf. extracts, which opens up new possibilities for the pharmaceutical and food industries.This study suggests that the concentrations of phenolic compounds, along with the results of anticholinesterase and antiproliferative activities found in the fruit and leaf extracts of P. atlantica Desf, indicate this plant holds promise for pharmaceutical and food application industries.

Context: Tagetes erecta is widely cultivated for its ornamental flowers and has traditionally been used as a diuretic and antihypertensive. However, its effects on blood pressure have not yet been studied.

Objective: To evaluate the vasorelaxant potential of ethanolic extract of T. erecta from two cultivars of edible flowers, yellow and orange.

Materials and methods: The pharmacological effects of T. erecta extracts as vasorelaxant agents were evaluated using isolated rat aorta rings in an organ bath and by measuring the pharyngeal pumping rate in the Caenorhabditis elegans model.

Results: The extracts induced relaxation in endothelium-intact aortic rings pre-contracted with different agents. Vasorelaxant effect was attenuated by endothelial removal and by pretreatment with L-NAME or ODQ, but not by indomethacin. Statistically significant effects were observed only at low concentrations. Atropine and H-89 reduced the extract-induced response, whereas okadaic acid had no effect. In a calcium-free medium, the extracts reduced contractions induced by CaCl₂ and phenylephrine. Relaxation was significantly attenuated by iberiotoxin, glibenclamide, BaCl₂, and 4-aminopyridine, while apamin and TRAM-34 had mild effect. The extracts also significantly decreased the pharyngeal pumping rate in C. elegans.

Discussion and conclusion: The extracts induced concentration-dependent vasorelaxation though both endothelium-dependent and -independent mechanisms. At low concentrations, relaxation was mediated by nitric oxide, while at higher concentrations it involved inhibition of intracellular Ca²⁺, opening of K⁺ channels, and activation of protein kinase A. In C. elegans, the extracts significantly reduced pharyngeal pumping. This study is the first to suggest that T. erecta could be beneficial in treating pathologies associated with endothelial dysfunction, such as hypertension.

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.