Pentacyclic triterpenes modulate farnesoid X receptor expression in colonic epithelial cells: Implications for colonic secretory function.

The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells. T84 cells and murine enteroid-derived monolayers were employed to assess HG effects on FXR expression and activity in colonic epithelia. We measured mRNA levels by qRT-PCR and protein by ELISA and immunoblotting. Transepithelial Cl- secretion was assessed as changes in short circuit current in Ussing chambers. We determined HG treatment (5-10 µM) alone did not induce FXR activation but significantly increased expression of the receptor, both in T84 cells and murine enteroid-derived monolayers. This effect was accompanied by enhanced FXR activity, as assessed by FGF-15/19 induction in response to the synthetic, GW4064, or natural FXR agonist, chenodeoxycholic acid. Effects of HG on FXR expression and activity were mimicked by another PCT, oleanolic acid. Furthermore, we found FXR-induced downregulation of cystic fibrosis transmembrane conductance regulator Cl- channels and inhibition of transepithelial Cl- secretion were enhanced in HG-treated cells. These data demonstrate that dietary PCTs have the capacity to modulate FXR expression, activity, and antisecretory actions in colonic epithelial cells. Based on these data, we propose that plants rich in PCTs, or extracts thereof, have excellent potential for development as a new class of "FXR-targeted nutraceuticals".

Unravelling Novel Phytochemicals and Anticholinesterase Activity in Irish Cladonia portentosa.

Acetylcholinesterase inhibitors remain the mainstay of symptomatic treatment for Alzheimer's disease. The natural world is rich in acetylcholinesterase inhibitory molecules, and research efforts to identify novel leads is ongoing. Cladonia portentosa, commonly known as reindeer lichen, is an abundant lichen species found in Irish Boglands. The methanol extract of Irish C. portentosa was identified as an acetylcholinesterase inhibitory lead using qualitative TLC-bioautography in a screening program. To identify the active components, the extract was deconvoluted using a successive extraction process with hexane, ethyl acetate and methanol to isolate the active fraction. The hexane extract demonstrated the highest inhibitory activity and was selected for further phytochemical investigations. Olivetolic acid, 4-O-methylolivetolcarboxylic acid, perlatolic acid and usnic acid were isolated and characterized using ESI-MS and two-dimensional NMR techniques. LC-MS analysis also determined the presence of the additional usnic acid derivatives, placodiolic and pseudoplacodiolic acids. Assays of the isolated components confirmed that the observed anticholinesterase activity of C. portentosa can be attributed to usnic acid (25% inhibition at 125 µM) and perlatolic acid (20% inhibition at 250 µM), which were both reported inhibitors. This is the first report of isolation of olivetolic and 4-O-methylolivetolcarboxylic acids and the identification of placodiolic and pseudoplacodiolic acids from C. portentosa.

Effect of different botanically-diverse diets on the fatty acid profile, tocopherol content and oxidative stability of beef.

BACKGROUND: Beef from pasture-fed animals is viewed as a healthier and more welfare-friendly alternative to concentrate-fed beef. Botanically-diverse pastures consisting of numerous plant species may alter the fatty acid (FA) profile and the tocopherol content of beef, as well as the oxidative stability of the meat. In the present study, steers were assigned to one of three botanically-diverse diets: perennial ryegrass (PRG), perennial ryegrass + white clover (PRG + WC) or multi-species (MS), all with a finishing diet of the respective botanically-diverse silages plus a cereal-based concentrate, consistent with production systems in Ireland. The FA profile, tocopherol content, oxidative stability and colour of meat during storage were measured. RESULTS: Compared to the other diets, the MS diet resulted in higher proportions of linolenic acid (C18:3n-3c), linoleic acid (C18:2n-6c) and total polyunsaturated fatty acids (PUFA), with higher PUFA:saturated fatty acid and n-6:n-3 ratios in the meat. α-Tocopherol concentrations were lowest in the meat of animals from the MS diet. In uncooked meat, lipid oxidation and colour values were affected by storage time across all diets, whereas the MS diet led to higher hue values only on day 14 of storage. When cooked, meat from animals on PRG + WC and MS diets had higher lipid oxidation on days 1 and 2 of storage than meat from animals on the PRG diet. CONCLUSION: Feeding steers on a botanically-diverse diet consisting of six plant species can improve the n-3 FA and PUFA concentration of beef, affecting the susceptibility of cooked, but not uncooked, beef to oxidation. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Hesperetin's health potential: moving from preclinical to clinical evidence and bioavailability issues, to upcoming strategies to overcome current limitations.

Flavonoids are common in the plant kingdom and many of them have shown a wide spectrum of bioactive properties. Hesperetin (Hst), the aglycone form of hesperidin, is a great example, and is the most abundant flavonoid found in Citrus plants. This review aims to provide an overview on the in vitro, in vivo and clinical studies reporting the Hst pharmacological effects and to discuss the bioavailability-related issues. Preclinical studies have shown promising effects on cancer, cardiovascular diseases, carbohydrate dysregulation, bone health, and other pathologies. Clinical studies have supported the Hst promissory effects as cardioprotective and neuroprotective agent. However, further well-designed clinical trials are needed to address the other Hst effects observed in preclinical trials, as well as to a more in-depth understanding of its safety profile.

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent.

PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with S,S configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (R,R)-7, thus reducing the final yield significantly. Therefore, we have investigated potential alternatives to improve the efficiency of this synthesis. The first phase of the study has demonstrated proof of principle for a chiral alkylation of ketone 3 using phase-transfer catalysis, providing a key intermediate ketone (S)-4. The parent alkaloids required for the synthesis of PH46A, quinine or cinchonidine, have also been identified. Promising enantiomeric excesses of up to 50% have been achieved to date, and the use of an alternative substrate, unsaturated ketone 9, has also opened up further avenues for optimisation in future studies. The second part of the study involved preliminary screening the effects of a panel of hydrolase enzymes on (rac)-4 in order to identify a potential chemo-enzymatic route to optimise the introduction of chirality into PH46A at early stage of the synthesis. The hydrolase module has also yielded positive results; enzyme AH-46 with MtBE providing a selectivity factor of 8.4 with enantiomeric excess of 77%. Overall, positive results were obtained in this proof of concept study described herein. It is believed that conditions of both chiral PTC alkylation and biocatalytic hydrolysis could be optimised to further enhance the selectivity and improve the overall yield. This work is currently ongoing.

Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models.

Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. Fagonia cretica is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes. In the current study, the traditional medicine was prepared as a tea, and the profile of the main metabolites present in the traditional medicine was analysed via LC/MS/MS. The extract was shown to contain a number of phenolic glycosides including quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-glycoside, kaempferol-3(6'-malonylglucoside), isorhamnetin-3-O-rutinoside, and isorhamnetin 3-(6″-malonylglucoside) in addition to two unidentified sulphonated saponins. The traditional medicine inhibits α-glucosidase in vitro with an IC50 of 4.62 µg/mL. The hypoglycaemic effect of the traditional medicine was evaluated in normoglycaemic and streptozotocin-treated diabetic rats, using glibenclamide as an internal control. The preparation (250 or 500 mg/kg body weight) was administered once a day for 21 consecutive days. The dose of 500 mg/kg was effective in the management of the disease, causing a 45 % decrease in the plasma glucose level at the end of the experimental period. Histological analysis of pancreatic sections confirmed that streptozotocin/nictotinamide treatment caused destruction of pancreatic islet cells, while pancreatic sections from the treatment groups showed that both the extract and glibenclamide partially prevented this deterioration. The mechanism of this protective effect is unclear. However, such a finding suggests that ingestion of the tea could confer additional benefits and should be investigated further.

Molecular structure studies of (1S,2S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol.

The single enantiomer (1S,2S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol (2), has recently been synthesized and isolated from its corresponding diastereoisomer (1). The molecular and crystal structures of this novel compound have been fully analyzed. The relative and absolute configurations have been determined by using a combination of analytical tools including X-ray crystallography, X-ray Powder Diffraction (XRPD) analysis and Nuclear Magnetic Resonance (NMR) spectroscopy.

Vitamin K2 in Health and Disease: A Clinical Perspective.

Vitamins are essential organic compounds that vary widely in chemical structure and are vital in small quantities for numerous biochemical and biological functions. They are critical for metabolism, growth, development and maintaining overall health. Vitamins are categorised into two groups: hydrophilic and lipophilic. Vitamin K (VK), a lipophilic vitamin, occurs naturally in two primary forms: phylloquinone (VK1), found in green leafy vegetables and algae, and Menaquinones (VK2), present in certain fermented and animal foods and widely formulated in VK supplements. This review explores the possible factors contributing to VK deficiency, including dietary influences, and discusses the pharmacological and therapeutic potential of supplementary VK2, examining recent global clinical studies on its role in treating diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, diabetes, neurodegenerative disorders and cancers. The analysis includes a review of published articles from multiple databases, including Scopus, PubMed, Google Scholar, ISI Web of Science and CNKI, focusing on human studies. The findings indicate that VK2 is a versatile vitamin essential for human health and that a broadly positive correlation exists between VK2 supplementation and improved health outcomes. However, clinical data are somewhat inconsistent, highlighting the need for further detailed research into VK2's metabolic processes, biomarker validation, dose-response relationships, bioavailability and safety. Establishing a Recommended Daily Intake for VK2 could significantly enhance global health.

A new lanosyl guanidine from Vertebrata lanosa with anti-inflammatory activity.

N-Lanosyl guanidine (1), a new bromophenol containing a guanidine moiety was isolated from the red alga Vertebrata lanosa (L.) T.A. Christensen, which is frequently used for cosmetic purposes. Structure elucidation was performed by means of mass spectrometry as well as 1D and 2D NMR spectroscopy. Due to its structural features, 1 might share a common biosynthetic route with known bromophenolic ureido derivatives. Regarding potential bioactivities, 1 has shown clear anti-inflammatory properties, reducing cytokine release in lipopolysaccharide-stimulated phorbol 12-myristate 13-acetate-differentiated THP-1 macrophages. No signs of toxicity were observed, in either the cell line nor in the nematode Caenorhabditis elegans. However, 1 was inactive against the gram-negative bacterium Pseudomonas aeruginosa.

2-(Di-phenyl-methyl-idene)-2,3-di-hydro-1H-inden-1-one.

In the title mol-ecule, C22H16O, the indanone ring system is approximately planar with a dihedral angle between the fused rings of 5.13 (14)°. Two benzene rings are linked together at one side of a double bond, sitting on either side of the indanone ring system and making dihedral angles of 70.30 (12) and 44.74 (13)° with it. In the crystal, hydrogen bonding is not present, but weak C-H⋯π or π-π inter-actions occur and mol-ecules form a sheet-like structure in the bc plane.

Can botanically-diverse pastures positively impact the nutritional and antioxidant composition of ruminant meat? - Invited review.

A desire for more sustainable pasture-based ruminant feeding systems has led to growing interest in utilising botanically-diverse pastures (BDP) over monoculture pastures. Research suggests that, from a human consumption viewpoint, grass-based ruminant feeding leads to more nutritionally desirable fatty acid (FA) and antioxidant concentrations in meat compared with concentrate feeding, which can affect meat quality. The FA, antioxidant and secondary metabolite content of plants differ, depending on species, maturity and seasonality, offering the potential through targeted feeding of BDP to produce meat with superior nutritional and antioxidant profiles. This review explores the effect, if any, that grazing ruminants on BDP has on the FA profile, fat-soluble vitamin, and antioxidant content of meat. The input-output relationship between forage and red meat constituents is complex and is likely affected by species diversity, forage consumption patterns and modulation of rumen fermentation processes. Further investigation is required to fully understand the effect that BDP may have on the composition and quality of ruminant meat.

Design, synthesis and biological evaluation of a novel bioactive indane scaffold 2-(diphenylmethylene)c-2,3-dihydro-1H-inden-1-one with potential anticancer activity.

Over the past decades, designing of privileged structures has emerged as a useful approach to the discovery and optimisation of novel biologically active molecules, and many have been successfully exploited across and within different target families. Examples include indole, quinolone, isoquinoline, benzofuran and chromone, etc. In the current study, we focus on synthesising a novel hybrid scaffold constituting naturally occurring benzophenone (14) and indanone (22) ring systems, leading to a general structure of 2-(diphenylmethylene)-2,3-dihydro-1H-inden-1-one (23). It was hypothesised this new hybrid system would provide enhanced anti-cancer activity owing to the presence of the common features associated with the tubulin binding small molecule indanocine (10) and the estrogen receptor (ER) antagonist tamoxifen (24). Key hybrid molecules were successfully synthesised and characterised, and the in vitro cytotoxicity assays were performed against cancer cell lines: MCF7 (breast) and SKBR3 (breast), DU145 (prostate) and A549 (lung). The methyl-, chloro- and methoxy-, para-substituted benzophenone hybrids displayed the greatest degree of cytotoxicity and the E-configuration derivatives 45, 47 and 49 being significantly most potent. We further verified that the second benzyl moiety of this novel hybrid scaffold is fundamental to enhance the cytotoxicity, especially in the SKBR3 (HER2+) by the E-methyl lead molecule 47, MCF7 (ER+) by 45 and 49, and A549 (NSCLC) cell lines by 49. These hybrid molecules also showed a significant accumulation of SKBR3 cells at S-phase of the cell cycle after 72 hrs, which demonstrates besides of being cytotoxic in vitro against SKBR3 cells, 47 disturbs the replication and development of this type of cancer causing a dose-dependent cell cycle arrest at S-phase. Our results suggest that DNA damage might be involved in the induction of SKBR3 cell death caused by the hybrid molecules, and therefore, this novel system may be an effective suppressor of HER2+/Neu-driven cancer growth and progression. The present study points to potential structural optimisation of the series and encourages further focussed investigation of analogues of this scaffold series toward their applications in cancer chemoprevention or chemotherapy.

Pharmacogenomic Analysis of Combined Therapies against Glioblastoma Based on Cell Markers from Single-Cell Sequencing.

Glioblastoma is the most common and aggressive form of primary brain cancer and the lack of viable treatment options has created an urgency to develop novel treatments. Personalized or predictive medicine is still in its infancy stage at present. This research aimed to discover biomarkers to inform disease progression and to develop personalized prophylactic and therapeutic strategies by combining state-of-the-art technologies such as single-cell RNA sequencing, systems pharmacology, and a polypharmacological approach. As predicted in the pyroptosis-related gene (PRG) transcription factor (TF) microRNA (miRNA) regulatory network, TP53 was the hub gene in the pyroptosis process in glioblastoma (GBM). A LASSO Cox regression model of pyroptosis-related genes was built to accurately and conveniently predict the one-, two-, and three-year overall survival rates of GBM patients. The top-scoring five natural compounds were parthenolide, rutin, baeomycesic acid, luteolin, and kaempferol, which have NFKB inhibition, antioxidant, lipoxygenase inhibition, glucosidase inhibition, and estrogen receptor agonism properties, respectively. In contrast, the analysis of the cell-type-specific differential expression-related targets of natural compounds showed that the top five subtype cells targeted by natural compounds were endothelial cells, microglia/macrophages, oligodendrocytes, dendritic cells, and neutrophil cells. The current approach-using the pharmacogenomic analysis of combined therapies-serves as a model for novel personalized therapeutic strategies for GBM treatment.

The biological responses of vitamin K2: A comprehensive review.

Vitamin K1 (VitK1) and Vitamin K2 (VitK2), two important naturally occurring micronutrients in the VitK family, found, respectively, in green leafy plants and algae (VitK1) and animal and fermented foods (VitK2). The present review explores the multiple biological functions of VitK2 from recently published in vitro and in vivo studies, including promotion of osteogenesis, prevention of calcification, relief of menopausal symptoms, enhancement of mitochondrial energy release, hepato- and neuro-protective effects, and possible use in treatment of coronavirus disease. The mechanisms of action associated with these biological effects are also explored. Overall, the findings presented here suggest that VitK, especially VitK2, is an important nutrient family for the normal functioning of human health. It acts on almost all major body systems and directly or indirectly participates in and regulates hundreds of physiological or pathological processes. However, as biological and clinical data are still inconsistent and conflicting, more in-depth investigations are warranted to elucidate its potential as a therapeutic strategy to prevent and treat a range of disease conditions.

(1S)-1-Phenylethanaminium 4-{[(1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl]methyl}benzoate.

The title molecular salt, C(8)H(12)N(+)·C(26)H(21)O(3)(-), contains a dimeric indane pharmacophore that demonstrates potent anti-inflammatory activity. The indane group of the anion exhibits some disorder about the α-C atom, which appears common to many structures containing this group. A model to account for the slight disorder was attempted, but this was deemed unsuccessful because applying bond-length constraints to all the bonds about the α-C atom led to instability in the refinement. The absolute configuration was determined crystallographically as S,S,S by anomalous dispersion methods with reference to both the Flack parameter and Bayesian statistics on Bijvoet differences. The configuration was also determined by an a priori knowledge of the absolute configuration of the (1S)-1-phenylethanaminium counter-ion. The molecules pack in the crystal structure to form an infinite two-dimensional hydrogen-bond network in the (100) plane of the unit cell.

N-Cyclo-pentyl-N-(3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide.

The title mol-ecule, C(16)H(19)NO(2), consists of an indane moiety, which is connected through an N atom to an acetamide group and a cyclo-pentane ring. The N atom adopts planar triangular geometry. Inter-molecular inter-actions, such as π-π stacking or hydrogen bonding, were not observed.

ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer's disease process.

Alzheimer's disease (AD) accounts for approximately 60% of dementia cases worldwide. Advanced age is the most significant risk factor for AD and approximately two-thirds of cases relate to women. While the previous meta-analysis suggests that estrogen receptor (ESR) genetic polymorphisms are closely associated with dementia, the implications of this observation on a molecular level are not entirely understood. Our study explores this intricate molecular puzzle through the use of a variety of bioinformatics tools. Initially, we attempted to elucidate mechanisms underlying breast cancer development by identifying the high-throughput dataset of ESR1-knockdown breast cancer tissue samples. Surprisingly, KEGG pathway enrichment showed that the most frequently occurring proteins were related to axonal guidance and inflammation-related gene markers. These observations were supported by an external high throughput dataset of AD inflammatory samples in vivo. Our results suggest that ESR1 is modulated by apolipoprotein E (APOE) through CEBPB/ATF4, mir-155-5p, or mir-1-3p. Moreover, sea hare-hydrolysates (SHH), as one of the axonal guidance molecules, could regulate the STAT3/PRDM1/CEBPB pathway and consequently induce cell death through pyroptosis signaling pathways, trigger the secretion of IL1ß, leading to neuroinflammation and worsening AD pathogenesis. Molecular docking verification demonstrated that the predicted natural products scoulerine and genistein displayed strong binding affinities for BACE1 and ESR1, respectively. This strategy can be used to design novel, personalized therapeutic approaches to treatment and a first-in-class clinical lead for the personalised treatment of AD.

Network Pharmacology and Molecular Docking Elucidate the Underlying Pharmacological Mechanisms of the Herb Houttuynia cordata in Treating Pneumonia Caused by SARS-CoV-2.

Used in Asian countries, including China, Japan, and Thailand, Houttuynia cordata Thumb (H. cordata; Saururaceae, HC) is a traditional herbal medicine that possesses favorable antiviral properties. As a potent folk therapy used to treat pulmonary infections, further research is required to fully elucidate the mechanisms of its pharmacological activities and explore its therapeutic potential for treating pneumonia caused by SARS-CoV-2. This study explores the pharmacological mechanism of HC on pneumonia using a network pharmacological approach combined with reprocessing expression profiling by high-throughput sequencing to demonstrate the therapeutic mechanisms of HC for treating pneumonia at a systemic level. The integration of these analyses suggested that target factors are involved in four signaling pathways, including PI3K-Akt, Jak-STAT, MAPK, and NF-kB. Molecular docking and molecular dynamics simulation were applied to verify these results, indicating a stable combination between four metabolites (Afzelin, Apigenin, Kaempferol, Quercetin) and six targets (DPP4, ELANE, HSP90AA1, IL6, MAPK1, SERPINE1). These natural metabolites have also been reported to bind with ACE2 and 3CLpro of SARS-CoV-2, respectively. The data suggest that HC exerts collective therapeutic effects against pneumonia caused by SARS-CoV-2 and provides a theoretical basis for further study of the active drug-like ingredients and mechanism of HC in treating pneumonia.

The Traditional Chinese Medicine Houttuynia cordata Thunb decoction alters intestinal barrier function via an EGFR dependent MAPK (ERK1/2) signalling pathway.

BACKGROUND: A traditionally prepared aqueous extract (= decoction) of Houttuynia cordata Thunb (Yu xing cao) (HC) is widely used in Traditional Chinese Medicine (TCM) to treat inflammatory disease. Previous chemical and biological studies on HC have mainly focused on organic extracts rather than the aqueous decoction, which is the traditional formulation. PURPOSE: The study aimed to investigate whether the chemical composition of HC aqueous decoction (HCD) varies with geographical sourcing, to investigate the mechanism of action of HCD, and to determine if chemical variation impacts on HCDs anti-inflammatory activity. METHOD: Sixteen samples of HC were purchased from Sichuan, Hubei and Anhui provinces in the People's Republic of China (PRC) and were prepared by the traditional decoction method to yield their corresponding HCDs. A Quality Control (QC) sample was prepared by combining individual HCD extracts. HCDs were analysed by Nuclear Magnetic Resonance (NMR) and High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS). The anti-inflammatory activities associated with intestinal barrier function of HCD were studied by tumor necrosis factor-α (TNF-α) activated Caco-2 monolayers in vitro and in vivo using Dextran Sulfate Sodium (DSS)-induced murine colitis. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed. RESULTS: HCD samples exhibited different chemical fingerprints and three regional outliers were identified by Principal Component Analysis (PCA). Fifteen phytochemical metabolites were identified and quantified. HCD showed in vitro anti-inflammatory activity, enhancing zonula occludens-1 (ZO-1), occludin, interleukin (IL)-10 and decreasing IL-1ß, IL-6 and epidermal growth factor receptor (EGFR) via an EGFR-dependent mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 1/2 (ERK 1/2) signaling pathway. This beneficial effect on intestinal inflammation was also seen in the in vivo colitis model at a molecular level in colonic tissues. CONCLUSION: This study shows that the test HCDs were chemically different, resulting in different levels of activity on intestinal barrier function and inflammation. Moreover, a "Daodi" product showed the greatest biological activity in this study, thus validating the importance of the "Daodi" quality material in TCM and supporting the traditional used of HCD for the treatment of inflammation.