Accurate de novo design of membrane-traversing macrocycles.

We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10-6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.

Identification and characterization of a small-molecule metallophore involved in lanthanide metabolism.

Many bacteria secrete metallophores, low-molecular-weight organic compounds that bind ions with high selectivity and affinity, in order to access essential metals from the environment. Previous work has elucidated the structures and biosynthetic machinery of metallophores specific for iron, zinc, nickel, molybdenum, and copper. No physiologically relevant lanthanide-binding metallophore has been discovered despite the knowledge that lanthanide metals (Ln) have been revealed to be essential cofactors for certain alcohol dehydrogenases across a diverse range of phyla. Here, we report the biosynthetic machinery, the structure, and the physiological relevance of a lanthanophore, methylolanthanin. The structure of methylolanthanin exhibits a unique 4-hydroxybenzoate moiety which has not previously been described in other metallophores. We find that production of methylolanthanin is required for normal levels of Ln accumulation in the methylotrophic bacterium Methylobacterium extorquens AM1, while overexpression of the molecule greatly increases bioaccumulation and adsorption. Our results provide a clearer understanding of how Ln-utilizing bacteria sense, scavenge, and store Ln; essential processes in the environment where Ln are poorly bioavailable. More broadly, the identification of this lanthanophore opens doors for study of how biosynthetic gene clusters are repurposed for additional functions and the complex relationship between metal homeostasis and fitness.

Iron: Life's primeval transition metal.

Modern life requires many different metal ions, which enable diverse biochemical functions. It is commonly assumed that metal ions' environmental availabilities controlled the evolution of early life. We argue that evolution can only explore the chemistry that life encounters, and fortuitous chemical interactions between metal ions and biological compounds can only be selected for if they first occur sufficiently frequently. We calculated maximal transition metal ion concentrations in the ancient ocean, determining that the amounts of biologically important transition metal ions were orders of magnitude lower than ferrous iron. Under such conditions, primitive bioligands would predominantly interact with Fe(II). While interactions with other metals in certain environments may have provided evolutionary opportunities, the biochemical capacities of Fe(II), Fe-S clusters, or the plentiful magnesium and calcium could have satisfied all functions needed by early life. Primitive organisms could have used Fe(II) exclusively for their transition metal ion requirements.

Intestinal Lymphatic Biology, Drug Delivery and Therapeutics: Current status and Future directions.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focussed primarily on the drug physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs and lipid-conjugated materials that 'hitchhike' on lymphatic transport pathways. With the increasing development of novel biological therapeutics there has been interest in whether these novel therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarise the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies into the future. Significance Statement This comprehensive review details understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.

Implementing differentially pigmented skin models for predicting drug response variability across human ancestries.

Persistent racial disparities in health outcomes have catalyzed legislative reforms and heightened scientific focus recently. However, despite the well-documented properties of skin pigments in binding drug compounds, their impact on therapeutic efficacy and adverse drug responses remains insufficiently explored. This perspective examines the intricate relationships between variation in melanin-based skin pigmentation and pharmacokinetics and -dynamics, highlighting the need for considering diversity in skin pigmentation as a variable to advance the equitability of pharmacological interventions. The article provides guidelines on the selection of New Approach Methods (NAMs) to foster inclusive study designs in preclinical drug development pipelines, leading to an improved level of translatability to the clinic.

Progress in characterizing ABC multidrug transporters in zebrafish.

Zebrafish have proved to be invaluable for modeling complex physiological processes shared by all vertebrate animals. Resistance of cancers and other diseases to drug treatment can occur owing to expression of the ATP-dependent multidrug transporters ABCB1, ABCG2, and ABCC1, either because of expression of these transporters by the target cells to reduce intracellular concentrations of cytotoxic drugs at barrier sites such as the blood-brain barrier (BBB) to limit penetration of drugs into privileged compartments, or by affecting the absorption, distribution, and excretion of drugs administered orally, through the skin, or directly into the bloodstream. We describe the drug specificity, cellular localization, and function of zebrafish orthologs of multidrug resistance ABC transporters with the goal of developing zebrafish models to explore the physiological and pathophysiological functions of these transporters. Finally, we provide context demonstrating the utility of zebrafish in studying cancer drug resistance. Our ultimate goal is to improve treatment of cancer and other diseases which are affected by ABC multidrug resistance transporters.

Phytochemicals as Prebiotics and Biological Stress Inducers.

Phytochemicals in fruits and vegetables produce health benefits, but questions remain regarding their bioavailability, molecular targets, and mechanism of action. Here, we address these issues by considering the prebiotic and biological properties of phytochemicals. A fraction of phytochemicals consumed orally passes through the gut lumen, where it modulates the composition of the gut microbiota and maintains intestinal integrity. Phytochemicals and microbiota-derived metabolites that are absorbed by the organism comprise compounds that, at low doses, induce stress resistance mechanisms, including autophagy, DNA repair, and expression of detoxifying and antioxidant enzymes. We propose that these mechanisms improve cellular and organ function and can account for the promiscuous bioactivities of phytochemicals, despite their limited bioavailability and extremely varied chemical structures.

Renin-angiotensin system-mediated nitric oxide signaling in podocytes.

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1-7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes.NEW & NOTEWORTHY The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function.

Effects of Pterostilbene on Cardiovascular Health and Disease.

Pterostilbene is a phenolic compound commonly found in blueberries, peanuts, grapes, and other plants. It is a dimethoxy derivative of resveratrol. In recent years, it has gained significant attention due to its remarkable anti-inflammatory and antioxidant effects. In addition, its high bioavailability and low toxicity in many species has contributed to its promising research prospects. Cardiovascular disease is closely related to pathological processes such as inflammation and oxidative stress, which aligns well with the treatment applications of pterostilbene. As a result, numerous studies have investigated the effects of pterostilbene on cardiovascular health and disease. This paper summarizes the current research on pterostilbene, with a specific focus on its potential therapeutic role in treating cardiovascular disease.

Capsaicin: Emerging Pharmacological and Therapeutic Insights.

Capsaicin, the most prominent pungent compound of chilli peppers, has been used in traditional medicine systems for centuries; it already has a number of established clinical and industrial applications. Capsaicin is known to act through the TRPV1 receptor, which exists in various tissues; capsaicin is hepatically metabolised, having a half-life correlated with the method of application. Research on various applications of capsaicin in different formulations is still ongoing. Thus, local capsaicin applications have a pronounced anti-inflammatory effect, while systemic applications have a multitude of different effects because their increased lipophilic character ensures their augmented bioavailability. Furthermore, various teams have documented capsaicin's anti-cancer effects, proven both in vivo and in vitro designs. A notable constraint in the therapeutic effects of capsaicin is its increased toxicity, especially in sensitive tissues. Regarding the traditional applications of capsaicin, apart from all the effects recorded as medicinal effects, the application of capsaicin in acupuncture points has been demonstrated to be effective and the combination of acupuncture and capsaicin warrants further research. Finally, capsaicin has demonstrated antimicrobial effects, which can supplement its anti-inflammatory and anti-carcinogenic actions.

Methoxyfuranocoumarins of Natural Origin-Updating Biological Activity Research and Searching for New Directions-A Review.

Plant secondary metabolites, including furanocoumarins, have attracted attention for decades as active molecules with therapeutic potential, especially those occurring in a limited number of species as evolutionarily specific and chemotaxonomically important. The most famous methoxyfuranocoumarins (MFCs), bergapten, xanthotoxin, isopimpinellin, phellopterin, byakangelicol, byakangelicin, isobergapten, pimpinellin, sphondin, as well as rare ones such as peucedanin and 8-methoxypeucedanin, apaensin, cnidilin, moellendorffiline and dahuribiethrins, have recently been investigated for their various biological activities. The α-glucosidase inhibitory activity and antioxidant potential of moellendorffiline, the antiproliferative and proapoptotic properties of non-UV-activated bergapten and xanthotoxin, the effect of MFC on the activity of tyrosinase, acetyl- and butylcholinesterase, and the role of these compounds as adjuvants in anticancer and antibacterial tests have been confirmed. The anticonvulsant effects of halfordin, the antidepressant effects of xanthotoxin, and the antiadipogenic, neuroprotective, anti-amyloid-ß, and anti-inflammatory (via increasing SIRT 1 protein expression) properties of phellopterin, as well as the activity of sphondin against hepatitis B virus, have also attracted interest. It is worth paying attention to the agonistic effect of xanthotoxin on bitter taste receptors (TAS2Rs) on cardiomyocytes, which may be important in the future treatment of tachycardia, as well as the significant anti-inflammatory activity of dahuribiethrins. It should be emphasized that MFCs, although in many cases isolated for the first time many years ago, are still of great interest as bioactive molecules. The aim of this review is to highlight key recent developments in the study of the diverse biological activities of MFCs and attempt to highlight promising directions for their further research. Where possible, descriptions of the mechanisms of action of MFC are provided, which is related to the constantly discovered therapeutic potential of these molecules. The review covers the results of experiments from the last ten years (2014-2023) conducted on isolated natural cMFCs and includes the activity of molecules that have not been activated by UV rays.

Mechanochemical synthesis of novel metronidazole cocrystal: Structure characterization and pharmaceutical properties study.

A new cocrystalline form of metronidazole (MET) with propyl gallate (PRO), referred to as MET-PRO, has been successfully synthesized and characterized. Structural characterization reveals that MET and PRO are present in a 1:1 ratio within the cocrystal lattice, with one water molecule equivalent incorporated into the structure. This arrangement facilitates the formation of MET-PRO heterodimers and multiple stable units, collectively constructing a three-dimensional supramolecular network. The solubility and permeability of the current cocrystal, along with the parent drug MET, are evaluated under physiological pH conditions. Experimental findings reveal that MET within the cocrystal exhibits a 1.54-2.37 folds increase in solubility and approximately a threefold improvement in permeability compared to its standalone form. Intriguingly, these concurrent enhancements in the physicochemical properties of MET lead to augmented antibacterial activity in vitro, evidenced by a reduction in minimum inhibitory concentration. Even more intriguingly, the enhanced physicochemical properties observed in vitro for the current cocrystal translate into tangible pharmacokinetic benefits in vivo, characterized by prolonged half-life and enhanced bioavailability. Consequently, this research not only introduces a fresh crystal structure for antibacterial medication but also presents approach for optimizing drug properties across in vitro and in vivo settings, while concurrently bolstering the antibacterial effectiveness of MET through pharmaceutical cocrystallization techniques.

Nutraceutically-enhanced oral delivery of vitamin D3 via Bio-SNEDDS: Demonstrating in vivo superiority over pediatric formulations.

BACKGROUND: Vitamin D3 (VD3) deficiency among children in Saudi Arabia remains a pressing concern due to its poor bioavailability and the limitations of current pediatric formulations. To address this challenge, we developed a groundbreaking pediatric self-nanoemulsifying drug delivery system (Bio-SNEDDS) for VD3, fortified with black seed oil and moringa seed oil for dual therapeutic benefits. Through meticulous formulation optimization using ternary phase diagrams and comprehensive testing, our Bio-SNEDDS demonstrated exceptional performance. METHODS: Bio-SNEDDS were manufactured by incorporating Black seed oil and moringa seed oil as bioactive nutraceutical excipients along with various cosurfactant and surfactants. Bio-SNEDDS were systematically optimized through ternary phase diagrams, visual tests, droplet size analysis, drug solubilization studies, dispersion assessments, and pharmacokinetic testing in rats compared to Vi-De 3®. RESULTS: Pseudoternary phase diagrams identified oil blends producing large nanoemulsion regions optimal for SNEDDS formation. The optimized F1 Bio-SNEDDS showed a mean droplet diameter of 33.7 nm, solubilized 154.46 mg/g VD3 with no metabolite formation, and maintained >88% VD3 in solution during 24 h dispersion testing. Notably, in vivo pharmacokinetic evaluation at a high VD3 dose demonstrated an approximately two-fold greater relative bioavailability over Vi-De 3®, validating the superb oral delivery performance of Bio-SNEDDS even under challenging high-dose conditions. CONCLUSIONS: The Bio-SNEDDS provides an effective VD3 delivery strategy with established in vivo superiority over marketed products, along with offering additional health benefits from the natural oils.

Recent advances on cyanidin-3-O-glucoside in preventing obesity-related metabolic disorders: A comprehensive review.

Anthocyanins, found in various pigmented plants as secondary metabolites, represent a class of dietary polyphenols known for their bioactive properties, demonstrating health-promoting effects against several chronic diseases. Among these, cyanidin-3-O-glucoside (C3G) is one of the most prevalent types of anthocyanins. Upon consumption, C3G undergoes phases I and II metabolism by oral epithelial cells, absorption in the gastric epithelium, and gut transformation (phase II & microbial metabolism), with limited amounts reaching the bloodstream. Obesity, characterized by excessive body fat accumulation, is a global health concern associated with heightened risks of disability, illness, and mortality. This comprehensive review delves into the biodegradation and absorption dynamics of C3G within the gastrointestinal tract. It meticulously examines the latest research findings, drawn from in vitro and in vivo models, presenting evidence underlining C3G's bioactivity. Notably, C3G has demonstrated significant efficacy in combating obesity, by regulating lipid metabolism, specifically decreasing lipid synthesis, increasing fatty acid oxidation, and reducing lipid accumulation. Additionally, C3G enhances energy homeostasis by boosting energy expenditure, promoting the activity of brown adipose tissue, and stimulating mitochondrial biogenesis. Furthermore, C3G shows potential in managing various prevalent obesity-related conditions. These include cardiovascular diseases (CVD) and hypertension through the suppression of reactive oxygen species (ROS) production, enhancement of endogenous antioxidant enzyme levels, and inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway and by exercising its cardioprotective and vascular effects by decreasing pulmonary artery thickness and systolic pressure which enhances vascular relaxation and angiogenesis. Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are also managed by reducing gluconeogenesis via AMPK pathway activation, promoting autophagy, protecting pancreatic ß-cells from oxidative stress and enhancing glucose-stimulated insulin secretion. Additionally, C3G improves insulin sensitivity by upregulating GLUT-1 and GLUT-4 expression and regulating the PI3K/Akt pathway. C3G exhibits anti-inflammatory properties by inhibiting the NF-κB pathway, reducing pro-inflammatory cytokines, and shifting macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. C3G demonstrates antioxidative effects by enhancing the expression of antioxidant enzymes, reducing ROS production, and activating the Nrf2/AMPK signaling pathway. Moreover, these mechanisms also contribute to attenuating inflammatory bowel disease and regulating gut microbiota by decreasing Firmicutes and increasing Bacteroidetes abundance, restoring colon length, and reducing levels of inflammatory cytokines. The therapeutic potential of C3G extends beyond metabolic disorders; it has also been found effective in managing specific cancer types and neurodegenerative disorders. The findings of this research can provide an important reference for future investigations that seek to improve human health through the use of naturally occurring bioactive compounds.

Biotechnological approaches to reduce the phytic acid content in millets to improve nutritional quality.

MAIN CONCLUSION: The review article summarizes the approaches and potential targets to address the challenges of anti-nutrient like phytic acid in millet grains for nutritional improvement. Millets are a diverse group of minor cereal grains that are agriculturally important, nutritionally rich, and the oldest cereals in the human diet. The grains are important for protein, vitamins, macro and micronutrients, fibre, and energy sources. Despite a high amount of nutrients, millet grains also contain anti-nutrients that limit the proper utilization of nutrients and finally affect their dietary quality. Our study aims to outline the genomic information to identify the target areas of research for the exploration of candidate genes for nutritional importance and show the possibilities to address the presence of anti-nutrient (phytic acid) in millets. So, the physicochemical accessibility of micronutrients increases and the agronomic traits can do better. Several strategies have been adopted to minimize the phytic acid, a predominant anti-nutrient in cereal grains. In the present review, we highlight the potential of biotechnological tools and genome editing approaches to address phytic acid in millets. It also highlights the biosynthetic pathway of phytic acid and potential targets for knockout or silencing to achieve low phytic acid content in millets.

Human Enteroid Monolayers: A Novel, Functionally-Stable Model for Investigating Oral Drug Disposition.

To further the development of an in vitro model which faithfully recapitulates drug disposition of orally administered drugs, we investigated the utility of human enteroid monolayers to simultaneously assess intestinal drug absorption and first-pass metabolism processes. We cultured human enteroid monolayers from three donors, derived via biopsies containing duodenal stem cells that were propagated and then differentiated atop permeable Transwell® inserts, and confirmed transformation into a largely enterocyte population via RNA-seq analysis and immunocytochemical (ICC) assays. Proper cell morphology was assessed and confirmed via bright field microscopy and ICC imaging of tight junction proteins and other apically and basolaterally localized proteins. Enteroid monolayer barrier integrity was demonstrated by elevated transepithelial electrical resistance (TEER) that stabilized after 10 days in culture and persisted for 42 days. These results were corroborated by low paracellular transport probe permeability at 7 and 21 days in culture. The activity of a prominent drug metabolizing enzyme, CYP3A, was confirmed at 7, 21, and 42 days culture under basal, 1α,25(OH)2 vitamin D3-induced, and 6',7'-dihydroxybergamottin-inhibited conditions. The duration of these experiments is particularly noteworthy, as this is the first study assessing drug metabolizing enzymes and transporters (DMET) expression/function for enteroids cultured for greater than 12 days. The sum of these results suggests enteroid monolayers are a promising ex vivo model to investigate and quantitatively predict an orally administered drug's intestinal absorption and/or metabolism. Significance Statement This study presents a novel ex vivo model of the human intestine, human intestinal organoid (enteroid) monolayers, that maintain barrier function and metabolic functionality for up to 42-days in culture. The incorporation of both barrier integrity and metabolic function over an extended period within the same model is an advancement over historically used in vitro systems, which either lack one or both of these attributes or have limited viability.

An Algorithm to Assess Calcium Bioavailability from Foods.

BACKGROUND: The recommended calcium intakes to meet calcium requirements at various ages are based on average population absorption values. Absorption is altered by physiology, the calcium load, and type of food. The calcium intake necessary, therefore, to meet requirements depends upon diet composition, through bioavailability. OBJECTIVE: The objectives of this study was to improve predictions of calcium bioavailability on the basis of the food matrix. METHODS: We modeled calcium absorption data from individual foods, beverages, and fortified foods that were determined with calcium isotopic tracers and compared with milk as a referent to adjust for physiologic differences of the host. RESULTS: Data from 496 observations were modeled to develop a predictive algorithm for calcium bioavailability in adults on the basis of calcium load and oxalate and phytate loads, which represent the 2 main inhibitors of calcium absorption. CONCLUSIONS: This algorithm will be helpful in assessing calcium availability from the food supply, for developing diets for individuals and research cohorts, and for designing policies and interventions to address inadequate calcium intake for populations.

High-Moisture Extrusion of a Dietary Protein Blend Impairs In Vitro Digestion and Delays In Vivo Postprandial Plasma Amino Acid Availability in Humans.

BACKGROUND: Industrial processing can alter the structural complexity of dietary proteins and, potentially, their digestion and absorption upon ingestion. High-moisture extrusion (HME), a common processing method used to produce meat alternative products, affects in vitro digestion, but human data are lacking. We hypothesized that HME of a mycoprotein/pea protein blend would impair in vitro digestion and in vivo postprandial plasma amino acid availability. METHODS: In Study A, 9 healthy volunteers completed 2 experimental trials in a randomized, double-blind, crossover design. Participants consumed a beverage containing 25 g protein from a "dry" blend (CON) of mycoprotein/pea protein (39%/61%) or an HME content-matched blend (EXT). Arterialized venous blood samples were collected in the postabsorptive state and regularly over a 5-h postprandial period to assess plasma amino acid concentrations. In Study B, in vitro digestibility of the 2 beverages were assessed using bicinchoninic acid assay and optical fluorescence microscopy at baseline and during and following gastric and intestinal digestion using the INFOGEST model of digestion. RESULTS: Protein ingestion increased plasma total, essential (EAA), and branched-chain amino acid (BCAA) concentrations (time effect, P < 0.0001) but more rapidly and to a greater magnitude in the CON compared with the EXT condition (condition × time interaction, P < 0.0001). This resulted in greater plasma availability of EAA and BCAA concentrations during the early postprandial period (0-150 min). These data were corroborated by the in vitro approach, which showed greater protein availability in the CON (2150 ± 129 mg/mL) compared with the EXT (590 ± 41 mg/mL) condition during the gastric phase. Fluorescence microscopy revealed clear structural differences between the 2 conditions. CONCLUSIONS: These data demonstrate that HME delays in vivo plasma amino acid availability following ingestion of a mycoprotein/pea protein blend. This is likely due to impaired gastric phase digestion as a result of HME-induced aggregate formation in the pea protein. This trial was registered at clinicaltrials.gov as NCT05584358.

Association Between Dietary Intake of Phosphorus and Measures of Obesity in the Jackson Heart Study.

BACKGROUND: The relation between phosphorus (P) intake and obesity is equivocal, with hypotheses in both directions. OBJECTIVES: We investigated the relationship between P intake, assessed from a current database, and calculated bioavailable P intake and obesity among African-American adults. METHODS: We examined associations between original and bioavailable P (total, added, and natural) and BMI and waist circumference (WC) in a cross-sectional study of 5306 African-American adults (21-84 y) from the Jackson Heart Study. A total of 3300 participants had complete interviews, valid dietary data, and normal kidney function. Diet was assessed by food frequency questionnaire. A novel algorithm was used to estimate P bioavailability. BMI or WC was regressed on each P variable, adjusting for total energy intake and potential confounders. RESULTS: After adjusting for covariates, original P (total and added) and bioavailable P (total and added) intakes (expressed/100 mg) were associated with BMI (ß: 0.11, 0.67, 0.31, and 0.71, respectively; all P < 0.0001). Neither original nor bioavailable natural P was significantly associated (ß: -0.03 and 0.09, respectively; both P > 0.05). When added and natural P were included in the same model, added P (original and bioavailable) intakes remained strongly associated with BMI (0.70 and 0.73, respectively; both P < 0.0001). Similar results were seen for WC. Intake of original added P tended to be more strongly associated with BMI, in females (ß: 0.72; P < 0.0001) than in males (ß: 0.56; P = 0.003) (P-interaction = 0.06). CONCLUSIONS: We found that greater intake of added, not natural, which may be a proxy for intake of processed foods was associated with higher BMI and WC. These were somewhat stronger when bioavailability was considered and for women than for men. Further investigation is needed to fully understand the mechanisms driving these associations.

Quabodepistat (OPC-167832), a Novel Antituberculosis Drug Candidate: Enhancing Oral Bioavailability via Cocrystallization and Mechanistic Analysis of Bioavailability in Two Cocrystals.

Quabodepistat (code name OPC-167832) is a novel antituberculosis drug candidate. This study aimed to discover cocrystals that improve oral bioavailability and to elucidate the mechanistic differences underlying the bioavailability of different cocrystals. Screening yielded two cocrystals containing 2,5-dihydroxybenzoic acid (2,5DHBA) or 2-hydroxybenzoic acid (2HBA). In bioavailability studies in beagle dogs, both cocrystals exhibited better bioavailability than the free form; however, the extent of bioavailability of cocrystals with 2HBA (quabodepistat-2HBA) was 1.4-fold greater than that of cocrystals with 2,5DHBA (quabodepistat-2,5DHBA). Dissolution studies at pH 1.2 yielded similar profiles for both cocrystals, although the percent dissolution differed: quabodepistat-2HBA dissolved more slowly than quabodepistat-2,5DHBA. The poor solubility of quabodepistat-2HBA is likely the primary factor limiting dissolution at pH 1.2. To identify a dissolution method that maintains the bioavailability in beagle dogs, we performed pH-shift dissolution studies that mimic the dynamic pH change from the stomach to the small intestine. Quabodepistat-2HBA demonstrated supersaturation after the pH was increased to 6.8, while quabodepistat-2,5DHBA did not demonstrate supersaturation. This result was consistent with the results of bioavailability studies in beagle dogs. We conclude that a larger quantity of orally administered quabodepistat-2HBA remained in its cocrystal form while being transferred to the small intestine compared with quabodepistat-2,5DHBA.