Clinical applications and mechanism insights of natural flavonoids against type 2 diabetes mellitus.

Diabetes is a complex disease that affects a large percentage of the world's population, and it is associated with several risk factors. Self-management poses a significant challenge, but natural sources have shown great potential in providing effective glucose reducing solutions. Flavonoids, a class of bioactive substances found in different natural sources including medicinal plants, have emerged as promising candidates in this regard. Indeed, several flavonoids, including apigenin, arbutin, catechins, and cyanidin, have demonstrated remarkable anti-diabetic properties. The clinical effectiveness of these flavonoids is linked to their potential to decrease blood glucose concentration and increase insulin concentration. Thus, the regulation of certain metabolic pathways such as glycolysis and neoglycogenesis has also been demonstrated. In vitro and in vivo investigations revealed different mechanisms of action related to flavonoid compounds at subcellular, cellular, and molecular levels. The main actions reside in the activation of glycolytic signaling pathways and the inhibition of signaling that promotes glucose synthesis and storage. In this review, we highlight the clinical efficiency of natural flavonoids as well as the molecular mechanisms underlying this effectiveness.

Bioaccessibility of Phenolic Compounds, Resistant Starch, and Dietary Fibers from Australian Green Banana during In Vitro Digestion and Colonic Fermentation.

Green bananas contain a substantial amount of resistant starch (RS), dietary fiber (DF), and phytochemicals, which exhibit potent antioxidant capabilities, primarily attributable to the abundance of polyphenols. The objective of this study was to assess the variations in the contents and bioaccessibility of RS, DF, and phenolic compounds in three types of Australian green bananas (Cavendish "Musa acuminata", Ladyfinger "Musa paradisiaca L.", and Ducasse "Musa balbisiana"), along with their antioxidant capacities, and the production of short-chain fatty acids (SCFAs) following in vitro simulated gastrointestinal digestion and colonic fermentation. The studied cultivars exhibited significant levels of RS, with Ladyfinger showing the greatest (49%). However, Ducasse bananas had the greatest DF concentration (38.73%). Greater TPC levels for Ladyfinger (2.32 mg GAE/g), as well as TFC and TTC (0.06 mg QE/g and 3.2 mg CE/g, respectively) in Cavendish, together with strong antioxidant capacities (DPPH, 0.89 mg TE/g in Cavendish), have been detected after both intestinal phase and colonic fermentation at 12 and 24 h. The bioaccessibility of most phenolic compounds from bananas was high after gastric and small intestinal digestion. Nevertheless, a significant proportion of kaempferol (31% in Cavendish) remained detectable in the residue after colonic fermentation. The greatest production of SCFAs in all banana cultivars was observed after 24 h of fermentation, except valeric acid, which exhibited the greatest output after 12 h of fermentation. In conclusion, the consumption of whole green bananas may have an advantageous effect on bowel health and offer antioxidant characteristics.

Epidemiology and phylogeny of Haemonchus contortus through internal transcribed spacer 2 gene in small ruminants.

Introduction: Haemonchus contortus (H. contortus) is a blood-feeding nematode causing infectious disease haemonchosis in small ruminants of tropical and subtropical regions around the world. This study aimed to explore the prevalence and phylogeny of H. contortus in small ruminants using the internal transcribed spacer-2 (ITS-2) gene. In addition, a comprehensive review of the available literature on the status of H. contortus in Pakistan was conducted. Methods: Fecal samples were collected from sheep and goats (n = 180). Microscopically positive samples were subjected to DNA extraction followed by PCR using species-specific primers. Results: The overall prevalence of H. contortus was 25.55% in small ruminants. The prevalence of H. contortus was significantly associated with months and area. The highest occurrence of haemonchosis was documented in July (38.70%), whereas the lowest occurred in December (11.11%), with significant difference. The prevalence was highest in the Ghamkol camp (29.4%) and lowest in the arid zone of the Small Ruminant Research Institute (17.5%) (p = 0.01). The results of the systematic review revealed the highest prevalence of haemonchosis (34.4%) in Khyber Pakhtunkhwa (p = 0.001). Discussion: Phylogenetic analysis revealed a close relationship between H. contortus and isolates from Asia (China, India, Iran, Bangladesh, Malaysia, and Mongolia) and European countries (Italy and the United Kingdom). It has been concluded that H. contortus is prevalent in small ruminants of Kohat district and all over Pakistan, which could be a potential threat to food-producing animals, farmers, dairy, and the meat industry. Phylogenetic analysis indicates that H. contortus isolates share close phylogenetic relationships with species from Asia and Europe.

LC-ESI-QTOF-MS/MS characterization of phenolic compounds in Australian native passion fruits and their potential antioxidant activities.

Passion fruits, renowned globally for their polyphenolic content and associated health benefits, have enjoyed growing attention from consumers and producers alike. While global cultivar development progresses, Australia has pioneered several native cultivars tailored for its distinct planting conditions. Despite their cultivation, comprehensive studies on the phenolic profiles and antioxidant capacities of these Australian-native passion fruits are notably lacking. This study aims to investigate and compare the polyphenolic content present in the by-products, which are peel (L), and consumable portions, which are the pulp and seeds (P), of four indigenous cultivars: 'Misty Gem' (MG), 'Flamengo' (FG), 'Sweetheart' (SW), and 'Panama' (SH). Employing LC-ESI-QTOF-MS/MS for profiling, a comprehensive list of polyphenols was curated. Additionally, various antioxidant assays-DPPH, FRAP, ABTS, RPA, FICA, and •OH-RSA-were performed to evaluate their antioxidant potential. A total of 61 polyphenols were identified, categorized into phenolic acid (19), flavonoids (33), and other phenolic substances (9). In the antioxidant assays, the SHP sample exhibited the highest •OH--RSA activity at 98.64 ± 1.45 mg AAE/g, while the FGL sample demonstrated prominent DPPH, FRAP, and ABTS activities with values of 32.47 ± 1.92 mg TE/g, 62.50 ± 3.70 mg TE/g, and 57.84 ± 1.22 mg AAE/g, respectively. Additionally, TPC and several antioxidant assays had a significant positive correlation, including DPPH, FRAP, and ABTS. The Australian-native passion fruits revealed distinct polyphenolic profiles and diverse antioxidant capacities, establishing a foundation for deeper health benefit analyses. This study accentuates the significance of understanding region-specific cultivars and their potential nutraceutical applications.

Curcumin nanogel and its efficacy against oxidative stress and inflammation in rat models of ischemic stroke.

Aim: The study was designed to develop and analyze curcumin nanoparticles. Methods: Curcumin nanoparticles were formulated and evaluated. Their efficacy in protecting against brain damage was investigated in a rat model of ischemic stroke, considering motor function, muscle strength and antioxidant enzyme activity. Results: Curcumin nanoparticles displayed a zeta potential of -55 ± 13.5 mV and an average particle size of 51.40 ± 21.70 nm. In ischemic stroke rat models, curcumin nanoparticle treatment significantly improved motor functions, and muscle strength and increased the activities of antioxidant enzymes like glutathione peroxidase, glutathione, glutathione S-transferase, superoxide dismutase and catalase, reducing oxidative stress and inflammation. Conclusion: Curcumin nanoparticles showed significant neuroprotective effects in ischemic stroke models.

Optimization of Ultrasonic Extraction Parameters for the Recovery of Phenolic Compounds in Brown Seaweed: Comparison with Conventional Techniques.

Seaweed, in particular, brown seaweed, has gained research interest in the past few years due to its distinctive phenolic profile that has a multitude of bioactive properties. In order to obtain the maximum extraction efficiency of brown seaweed phenolic compounds, Response Surface Methodology was utilized to optimize the ultrasound-assisted extraction (UAE) conditions such as the amplitude, time, solvent:solid ratio, and NaOH concentration. Under optimal conditions, UAE had a higher extraction efficiency of free and bound phenolic compounds compared to conventional extraction (stirred 16 h at 4 °C). This led to higher antioxidant activity in the seaweed extract obtained under UAE conditions. The profiling of phenolic compounds using LC-ESI-QTOF-MS/MS identified a total of 25 phenolics with more phenolics extracted from the free phenolic extraction compared to the bound phenolic extracts. Among them, peonidin 3-O-diglucodise-5-O-glucoside and hesperidin 5,7-O-diglucuronide are unique compounds that were identified in P. comosa, E. radiata and D. potatorum, which are not reported in plants. Overall, our findings provided optimal phenolic extraction from brown seaweed for research into employing brown seaweed as a functional food.

A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality.

The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression.

Background: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) has been indicated in traditional medicine to treat depression. However, scientific rationalization is still lacking. Hence, this study aimed to investigate the antidepressant potential of A. laxiflora using network pharmacology and molecular docking analysis. Materials and methods: The active compounds and potential targets of A. laxiflora and depression-related targets were retrieved from public databases, such as PubMed, PubChem, DisGeNET, GeneCards, OMIM, SwissTargetprediction, BindingDB, STRING, and DAVID. Essential bioactive compounds, potential targets, and signaling pathways were predicted using in silico analysis, including BA-TAR, PPI, BA-TAR-PATH network construction, and GO and KEGG pathway enrichment analysis. Later on, with molecular docking analysis, the interaction of essential bioactive compounds of A. laxiflora and predicted core targets of depression were verified. Results: The network pharmacology approach identified 15 active compounds, a total of 219 compound-related targets, and 14,574 depression-related targets with 200 intersecting targets between them. SRC, EGFR, PIK3R1, AKT1, and MAPK1 were the core targets, whereas 3-acetyloleanolic acid and 3-acetylursolic acid were the most active compounds of A. laxiflora with anti-depressant potential. GO functional enrichment analysis revealed 129 GO terms, including 82 biological processes, 14 cellular components, and 34 molecular function terms. KEGG pathway enrichment analysis yielded significantly enriched 108 signaling pathways. Out of them, PI3K-Akt and MAPK signaling pathways might have a key role in treating depression. Molecular docking analysis results exhibited that core targets of depression, such as SRC, EGFR, PIK3R1, AKT1, and MAPK1, bind stably with the analyzed bioactive compounds of A. laxiflora. Conclusion: The present study elucidates the bioactive compounds, potential targets, and pertinent mechanism of action of A. laxiflora in treating depression. A. laxiflora might exert an antidepressant effect by regulating PI3K-Akt and MAPK signaling pathways. However, further investigations are required to validate.

Comparison of phenolic composition in Australian-grown date fruit (Phoenix dactylifera L.) seeds from different varieties and ripening stages.

In this research, different seeds of Australian-grown date palm (Phoenix dactylifera L.) were studied to evaluate the antioxidant potential and analyze their phenolic constituents. Phenolic compounds were extracted from seeds of various Australian-grown date varieties at different ripening stages. Eight varieties of date seeds (Zahidi, Medjool, Deglet nour, Thoory, Halawi, Barhee, Khadrawy, and Bau Strami) at three ripening stages (Kimri, Khalal, and Tamar) were investigated in this study. Date seeds at Khalal (9.87-16.93 mg GAE/g) and Tamar (9.20-27.87 mg GAE/g) stages showed higher total phenolic content than those at Kimri stage (1.81-5.99 mg GAE/g). For antioxidant assays like DPPH, FRAP, ABTS, RAP, FICA, and TAC, date seeds at Khalal and Tamar stages also showed higher antioxidant potential than Kimri stage. However, date seeds at Kimri stage (55.24-63.26 mg TE/g) expressed higher radical scavenging activity than Khalal (13.58-51.88 mg TE/g) and Tamar (11.06-50.92 mg TE/g) stages. Phenolic compounds were characterized using LC-ESI-QTOF-MS/MS, revealing the presence of 37 different phenolic compounds, including 8 phenolic acids, 18 flavonoids, and 11 other phenolic compounds. Further, phenolic compounds were quantified using LC-DAD, revealing that Zahidi variety of date seeds exhibited the highest content during the Kimri stage. In contrast, during the Khalal and Tamar stages, Deglet nour and Medjool date seeds displayed higher concentrations of phenolic compounds. The results indicated an increase in phenolic content in date seeds after the Kimri stage, with significant variations observed among different date varieties.

Evaluation of chalcones as new glycogen phosphorylase inhibitors - an in-vitro and in-silico approach.

Diabetes mellitus (DM) remains one of the pivotal diseases that have drawn the attention of researchers recently and during the last few decades. Due to its devastating symptoms, attempts to develop new drugs with mild side effects have resulted in a number of drugs that are functioning through various mechanisms. Among these, Glycogen phosphorylase (GP) inhibitors emerged as a new strategy for combating DM. GP is an enzyme that regulates blood glucose levels; it catalyses the breakdown of glycogen to glucose-1-phosphate in the liver and tissues with high and fluctuating energy demands. In the present research, we evaluate the possibility of type 2 diabetes therapy with the help of chalcones which are known to have antidiabetic activities. For this purpose, 29 chalcones were modelled, synthesised and investigated for their inhibitory activity against GP using in-vitro methods. Compounds 1, 2, and 3 were found to be the most potent compounds with IC50 values 26.6, 57.1 and 75.6 µM respectively. The observed results were further validated using in-silico methods. Molecular docking simulation revealed interaction patterns that explain the structure-activity relationships of the compounds with GP. Molecular dynamic (MD) simulation demonstrated a stable complex formation between compound 1 and GP through lower value and uniformity in root mean square deviation (RMSD) of the complex and root mean square fluctuation (RMSF) of the protein Cα.

Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: Mechanisms insights and efficiencies.

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs.

In vitro digestion and colonic fermentation of phenolic compounds and their antioxidant potential in Australian beach-cast seaweeds.

Beach-cast seaweed has recently garnered attention for its nutrient-rich composition, including proteins, carbohydrates, vitamins, minerals, and phytochemicals. This study focuses on the phenolic content and antioxidant potential of five Australian beach-cast seaweed species during in vitro digestion and colonic fermentation. The bioaccessibility of the selected phenolic compounds was estimated and short chain fatty acids (SCFAs) production was determined. Cystophora sp., showed a notable increase in phenolic content (23.1 mg GAE/g) and antioxidant capacity (0.42 mg CE/g) during the intestinal and gastric phases of in vitro digestion. Durvillaea sp. demonstrated a significant release of flavonoids (0.35 mg QE/g), while Phyllosphora comosa released high levels of tannins (0.72 mg CE/g) during the intestinal phase. During colonic fermentation, P. comosa released the highest levels of phenolic compounds (4.3 mg GAE/g) after 2 h, followed by an increase in flavonoids (0.15 mg QE/g), tannins (0.07 mg CE/g), and antioxidant activity (DPPH: 0.12 mg CE/g; FRAP: 0.61 mg CE/g) after 4 h. Moreover, P. comosa released a considerable amount of phenolic compounds during both in vitro digestion and colonic fermentation. All species consistently released phenolic compounds throughout the study. Phloroglucinol, gallic acid, and protocatechuic acid were identified as the most bioaccessible phenolic compounds in all five Australian beach-cast seaweeds in the in vitro digestion. Nevertheless, compound levels declined during the colonic fermentation phase due to decomposition and fermentation by gut microbiota. With regard to SCFAs, P. comosa displayed elevated levels of acetic (0.51 mmol/L) and propionic acid (0.36 mmol/L) at 2 h, while Durvillaea sp. showed increased butyric (0.42 mmol/L) and valeric (0.26 mmol/L) production acid after 8 h. These findings suggest that seaweed such as Cystophora sp., Durvillaea sp., and P. comosa are promising candidates for food fortification or nutraceutical applications, given their rich phenolic content and antioxidant properties that potentially offer gut health benefits.

Polymorphism of HLA and Susceptibility of Breast Cancer.

Breast cancer (BC) is the second most common malignancy in the world. Numerous studies have demonstrated the association between human leukocyte antigen (HLA) and cancer. The occurrence and development of BC are closely linked to genetic factors. Human leukocyte antigens G and E (HLA-G and HLA-E) are non-classical major histocompatibility complex (MHC) class I molecules. These molecules play an important role in immune surveillance by inhibiting the cytotoxic and natural killer T cells responsible for immune escape. The expression of HLA-G and HLA-E has been associated with several diseases, including tumors. The HLA system plays a key role in the escape of tumor cells from immune surveillance. This review aims to determine the correlation between BC susceptibility and HLA markers specific HLA alleles such as HLA-B07, HLA-DRB111, HLA-DRB113, and HLA-DRB115 are associated with an increased risk of developing BC. Furthermore, HLA-G mutations have been attributed to an elevated likelihood of metastasis in BC patients. Understanding the complex associations between the HLA system and BC development is critical for developing novel cancer prevention, detection, and treatment strategies. This review emphasizes the importance of analyzing HLA polymorphisms in the management of BC patients, as well as the urgent need for further research in this area.

Phytoimmunomodulators: A review of natural modulators for complex immune system.

In the past few decades, the medicinal properties of plants and their effects on the human immune system are being studied extensively. Plants are an incredible source of traditional medicines that help cure various diseases, including altered immune mechanisms and are economical and benign compared to allopathic medicines. Reported data in written documents such as Traditional Chinese medicine, Indian Ayurvedic medicine support the supplementation of botanicals for immune defense reactions in the body and can lead to safe and effective immunity responses. Additionally, some botanicals are well-identified as magical herbal remedies because they act upon the pathogen directly and help boost the immunity of the host. Chemical compounds, also known as phytochemicals, obtained from these botanicals looked promising due to their effects on the human immune system by modulating the lymphocytes which subsequently reduce the chances of getting infected. This paper summarises most documented phytochemicals and how they act on the immune system, their properties and possible mechanisms, screening conventions, formulation guidelines, comparison with synthetic immunity-enhancers, marketed immunity-boosting products, and immune-booster role in the ongoing ghastly corona virus wave. However, it focuses mainly on plant metabolites as immunomodulators. In addition, it also sheds light on the current advancements and future possibilities in this field. From this thorough study, it can be stated that the plant-based secondary metabolites contribute significantly to immunity building and could prove to be valuable medicaments for the design and development of novel immunomodulators even for a pandemic like COVID-19.

Evaluation of spontaneous fermentation impact on the physicochemical properties and sensory profile of green and roasted arabica coffee by digital technologies.

There is a growing demand for specialty coffee with more pleasant and uniform sensory perception. Wet fermentation could modulate and confer additional aroma notes to final roasted coffee brew. This study aimed to assess differences in volatile compounds and the intensities of sensory descriptors between unfermented and spontaneously fermented coffee using digital technologies. Fermented (F) and unfermented (UF) coffee samples, harvested from two Australia local farms Mountain Top Estate (T) and Kahawa Estate (K), with four roasting levels (green, light-, medium-, and dark-) were analysed using near-infrared spectrometry (NIR), and a low-cost electronic nose (e-nose) along with some ground truth measurements such as headspace/gas chromatography-mass spectrometry (HS-SPME-GC-MS), and quantitative descriptive analysis (QDA ®). Regression machine learning (ML) modelling based on artificial neural networks (ANN) was conducted to predict volatile aromatic compounds and intensity of sensory descriptors using NIR and e-nose data as inputs. Green fermented coffee had significant perception of hay aroma and flavor. Roasted fermented coffee had higher intensities of coffee liquid color, crema height and color, aftertaste, aroma and flavor of dark chocolate and roasted, and butter flavor (p < 0.05). According to GC-MS detection, volatile aromatic compounds, including methylpyrazine, 2-ethyl-5-methylpyrazine, and 2-ethyl-6-methylpyrazine, were observed to discriminate fermented and unfermented roasted coffee. The four ML models developed using the NIR absorbance values and e-nose measurements as inputs were highly accurate in predicting (i) the peak area of volatile aromatic compounds (Model 1, R = 0.98; Model 3, R = 0.87) and (ii) intensities of sensory descriptors (Model 2 and Model 4; R = 0.91), respectively. The proposed efficient, reliable, and affordable method may potentially be used in the coffee industry and smallholders in the differentiation and development of specialty coffee, as well as in process monitoring and sensory quality assurance.

Unraveling the versatility of human serum albumin - A comprehensive review of its biological significance and therapeutic potential.

Human serum albumin (HSA) is a multi-domain macromolecule with diverse ligand binding capability because of its ability to allow allosteric modulation despite being a monomeric protein. Physiologically, HSA act as the primary carrier for various exogenous and endogenous compounds and fatty acids, and alter the pharmacokinetic properties of several drugs. It has antioxidant properties and is utilized therapeutically to improve the drug delivery of pharmacological agents for the treatment of several disorders. The flexibility of albumin in holding various types of drugs coupled with a variety of modifications makes this protein a versatile drug carrier with incalculable potential in therapeutics. This review provides a brief outline of the different structural properties of HSA, and its various binding sites, moreover, an overview of the genetic, biomedical, and allosteric modulation of drugs and drug delivery aspects of HSA is also included, which may be helpful in guiding advanced clinical applications and further research on the therapeutic potential of this extraordinary protein.

Pharmacological Management for Pediatric Irritable Bowel Syndrome: A Review.

Irritable bowel syndrome is a multifactorial disease with chronic symptoms that interfere with the quality of life of patients. It represents one of the most common causes of functional abdominal pain in the pediatric population. Various theses with little evidence tried to explain the pathophysiology of the disease. Neurological origin was one of the theories explaining the disease, either by the disturbance of neurotransmitters like dopamine, noradrenaline, and serotonin, which have some evidence of their relation to GI tract functions. Other factors like bio-psycho-social factors that affect the pediatric population are represented in bullying, unrealistic academic expectations from the parents, continuous educational stress, and difficult relationships with peers. Other factors may be genetic abnormalities of the receptors or visceral hypersensitivity. Treatment strategies for the disease varied from physical activity like yoga to a diet like a low-FODMAP diet. Pharmacological treatment of the disease targets the presenting symptoms, represented by antispasmodic drugs treating abdominal pain/discomfort, antipsychotics that regulate the disturbance in the brain-gut axis, and other drugs targeting diarrhea or constipation that present with the patient according to the type of IBS and the condition of the patient.