Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

The poor vascularization of solid tumors results in oxygen-deprived areas within the tumor mass. This phenomenon is defined as tumor hypoxia and is considered to be a major contributor to tumor progression in breast and ovarian cancers due to hypoxia-cascade-promoted increased metastasizing capacity. Hence, targeting hypoxia is a strategic cancer treatment approach, however, the hypoxia-modulating drugs face several limitations in monotherapies. Here, we investigated the impact of the potent hypoxia-inducible factor inhibitory compound acriflavine on tumor cell proliferation, migration, and metabolism under hypoxic conditions. We identified that acriflavine inhibited the proliferation of breast and ovarian tumor cells. To model the potential benefits of additional hypoxia response inhibition next to standard chemotherapy, we combined acriflavine with a frequently used chemotherapeutic agent, paclitaxel. In most breast and ovarian cancer cell lines used, we identified additive effects between the two drugs. The most significant findings were detected in triple-negative breast cancer cell lines, where we observed synergism. The drug combination effectively impeded tumor growth and metastasis formation in an in vivo orthotopic triple-negative breast cancer model as well. Additionally, we demonstrated that an epithelial-mesenchymal transition inhibitory drug, rolipram, combined with acriflavine and paclitaxel, notably reduced the motility of hypoxic triple-negative breast cancer cells. In conclusion, we identified novel drug combinations that can potentially combat triple-negative breast cancer by inhibiting hypoxia signaling and hindering cell migration and metastasis formation.

Background: Natural compounds offer promising targets for cardioprotection, which could lead to enhanced clinical outcomes. We aimed to determine the cardioprotective effects of Fruitflow®, a water-soluble tomato extract known for its anti-platelet effects in doxorubicin-induced toxicity in rat cardiomyoblast cell line pathological alteration in heart tissue of high fat-fed Wistar Albino rats.

Methods: The cardioprotective effect of Fruitflow® was investigated using H9c2 (2-1) cells (rat cardiomyoblast cell line) and high-fat diet-fed Wistar Albino rats. We evaluated morphological changes, cell proliferation, cell migration, antioxidant activity, cell cycle progression, and mitochondrial membrane potential after the Fruitflow® treatment in the Doxorubicin-injured H9c2 (2-1) cell line. We studied lipid profiles, inflammation, oxidative stress, and cardiac function regulatory enzyme activity in the rat model.

Results: Fruitflow® dose-dependently stimulated cell proliferation and migration in Doxorubicin-injured H9c2 (2-1) cells, potentially promoting cardiac regeneration and supporting tissue repair. Fruitflow® modulated the cell cycle, improved mitochondrial function, and reduced oxidative stress. Furthermore, it significantly improved lipid profiles and enzyme activities and reduced inflammation and oxidative stress in high-fat-fed rats. Fruitflow® also modulated the expression of genes involved in cardiac remodeling, mitochondrial biogenesis, inflammation, and vascular function.

Conclusion: Our findings suggest Fruitflow® may have cardioprotective effects, making it a potential treatment option for cardiac ailments. Larger-scale clinical trials were recommended further to determine the efficacy and safety of Fruitflow® as a potential therapeutic agent for cardiac diseases, potentially in combination with other cardioprotective medications.

Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.

Background: Disorders of glutamate metabolism and excessive release participat in multiple neuronal pathologies including ischemic stroke (IS), Alzheimer's disease (AD), or Parkinson's disease (PD). Recently, herbal medicines have been widely used and have shown satisfactory results in the treatment of neurological disorders. Gastrodin is a traditional Chinese medicine (TCM) used for the treatment of nerve injuries, spinal cord injuries, and some central nervous system diseases as well. This research examines the neuroprotective effects of Gastrodin against glutamate-induced neurotoxicity in neuronal cells.

Methods: The HERB database was used to explore the active ingredients and target genes of Gastrodia Elata. The STRING database and Cytoscape software were used to screen and construct the Protein-Protein Interaction (PPI). Furthermore, we used molecular docking to predict the potential targets of Gastrodin. The effects of Gastrodin were revealed by western blot, calcium imaging, membrane clamp, CCK8 and flow cytometry. Neuronal oxidative stress and damage were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Neuronal morphology was examined using Golgi-Cox staining. Finally, animal behavior was examined using novel object recognition and fear conditioning tests.

Results: We have obtained 22 components such as TM10, TM17, TM25 (Gastrodin), and 281 targets such as AKT, EGFR, and CDK1 through network pharmacology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed these genes were significantly enriched in protein phosphorylation, protein serine/threonine/tyrosine kinase activity, apoptosis and HIF-1 signaling pathways, etc. A higher affinity between Gastrodin and AKT was revealed by PPI analysis and molecular docking. Further, Gastrodin significantly inhibited Ca²⁺ influxes and excitatory synaptic transmission in cortical neurons. In addition, Gastrodin effectively alleviated neuron apoptosis, oxidative stress and damage.

Conclusion: Gastrodin has neuroprotective effects against glutamate-induced neurotoxicity.

The incidence of inflammatory bowel disease (IBD) is rising globally, increasing interest in food ingredients for its prevention and control. This study evaluated the effect of farnesol (FAR), a key component of pomelo flower volatile oil, on dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice. FAR significantly alleviated DSS-induced colitis and secondary liver injury, as shown by improved body weight, DAI, colon length, and pathology, as well as liver function and blood lipid indices. The mechanism involves FAR-mediated regulation of inflammatory cytokines, increased expression of tight junction protein genes, and decreased expression of lipid metabolism-related proteins. FAR also enhanced gut microbiota diversity, balancing harmful and probiotic bacteria. Fecal metabolome analysis indicated FAR's role in reversing metabolic disturbances related to inflammation and liver lipid metabolism. These findings support developing functional foods for IBD treatment using pomelo flower volatile oil.

Aims: To investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets.

Methods: We systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models.

Results: Behavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level.

Conclusions: Semaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.

Neuroblastoma, a pediatric cancer originating from neural crest tissues of the sympathetic nervous system, poses significant treatment challenges due to its molecular diversity and restricted druggable targets. While chemotherapy is a common treatment, its drawbacks, including poor targeting of cancer cells and nonspecific cytotoxicity, highlight the urgent need for innovative and effective therapeutic strategies. Herein, we developed a novel drug by coupling the receptor binding domain of botulinum neurotoxin type A (Hc) fused with monomeric streptavidin (mSA) to biotin coated doxorubicin (Dox)-loaded liposome, via interaction between mSA and biotin. The resultant Hc-coated liposome (Hc-Lipo@Dox) actively targeted the recycling synaptic vesicle 2 protein (SV2) abundantly expressed on the surface of neuroblastoma cells. Our results revealed that Hc-Lipo@Dox more effectively entered the neuroblastoma SH-SY5Y cells, inducing apoptosis compared to non-targeted liposome and free Dox. Moreover, Hc-Lipo@Dox rapidly enriched Dox in the subcutaneously implanted neuroblastoma tumor in nude mice, resulting potent anti-neuroblastoma effect compared to non-targeted liposomes or free Dox. Importantly, Hc-Lipo@Dox significantly improved the survival rate of treated mice, while also exhibiting a favorable safety profile with no discernible impact on mobility or observable side effects. These findings highlight the potential of SV2-targeted Dox liposome as a promising and well-tolerated chemotherapy approach for neuroblastoma treatment. Moreover, the technology established here has broader applications for various cancer therapies by substituting the Hc moiety with other tumor-specific targeting moieties.

Pulmonary fibrosis (PF) is a progressive and debilitating respiratory condition characterized by excessive deposition of extracellular matrix proteins and scarring within the lung parenchyma. Despite extensive research, the pathogenesis of PF remains incompletely understood, and effective therapeutic options are limited. Emerging evidence suggests a potential link between gut microbiota dysbiosis and the development of PF, highlighting the gut-lung axis as a promising therapeutic target. Akkermansia muciniphila (A. muciniphila), a mucin-degrading bacterium residing in the gut mucosal layer, has garnered considerable interest due to its immunomodulatory and anti-inflammatory properties. This study investigates the therapeutic potential of live and pasteurized A. muciniphila, as well as its extracellular vesicles (EVs), in mitigating inflammation and fibrosis in a murine model of carbon tetrachloride (CCl4)-induced PF exacerbated by a high-fat diet (HFD). Male C57BL/6 mice were divided into groups receiving either a normal diet or an HFD, with or without CCl4 administration. The mice were then treated with live or pasteurized A. muciniphila, or its EVs. Lung tissue was analyzed for the expression of inflammatory markers and fibrosis markers using real-time PCR and ELISA. Administration of live and pasteurized A. muciniphila, as well as its EVs, significantly downregulated the expression of inflammatory and fibrosis markers in the lung tissue of CCl4-induced PF mice. Furthermore, these treatments ameliorated the increased production of IL-6 and reduced IL-10 levels observed in the HFD and CCl4-treated groups. These findings suggest that A. muciniphila and its derivatives exert protective effects against pulmonary inflammation and fibrosis, potentially through modulation of the gut-lung axis. The study highlights the therapeutic potential of A. muciniphila and its derivatives as novel interventions for the management of PF, warranting further preclinical and clinical investigations.

Obesity is a complex disease with numerous molecular and metabolic implications that could be prevented through proper diet and lifestyle. Native corn is a promissory underutilized plant species containing bioactive compounds that could reduce the impact of obesity. This research aimed to characterize and evaluate the anti-obesogenic effect of a polyphenols-rich extract of native corn ('Elotes Occidentales') in HFD-fed mice. The powdered extract was administered using gelatins to C57BL/6 J mice randomly divided into four groups (n:8/group) for 13 weeks: standard diet (SD) group, HFD group, HFD+200 mg extract/kg body weight (BW), and HFD+400 mg extract/kg BW/day. Ellagic acid, chlorogenic acid, rutin, and kaempferol were the most abundant phenolics (2022.44-4028.43 µg/g). Among the HFD groups, the highest dose of the extracts promoted the lowest BW gain, and fasting triglycerides and cholesterol levels. Moreover, the HFD+400 mg/kg BW group showed the lowest epididymal and subcutaneous adipose tissue weight and adipocytes' diameter and area between the HFD-treated animals. The extract administration prevented hepatic lipid accumulation. Rutin demonstrated the highest in silico binding affinity with proteins from the AMPK pathway (ACACA, SIRT1, and SREBP1) (-6.70 to -8.70 kcal/mol). Results indicated beneficial effects in alleviating obesity-associated parameters in vivo due to bioactive compounds from native maize extracts.