Bioaccessibility of condensed tannins and their effect on the physico-chemical characteristics of lamb meat.

The bioaccessibility of tannins as antioxidants in meat is essential to maximise their effectiveness in protecting the product. This property determines the amount of tannins available to interact with meat components, inhibiting lipid and protein oxidation and, consequently, prolonging shelf life and preserving the sensory quality of the product. The objective of this study was to evaluate the bioaccessibility of condensed tannins (CT) from Acacia mearnsii extract (AME) and their effect on the physico-chemical characteristics of fattened lamb meat. Thirty-six Dorset × Hampshire lambs (3 months old and 20.8 ± 3.3 kg live weight) were used. The lambs were distributed equally (n = 9) into four treatments: T1, T2, T3 and T4, which included a basal diet plus 0%, 0.25%, 0.5% and 0.75% of CT from AME, respectively. At the end of the fattening period, bioaccessibility was evaluated, the animals were slaughtered and a sample of the longissimus dorsi (LD) muscle was collected to assess colour, lipid oxidation, cooking weight loss and shear force on days 1, 4, 7 and 14 of shelf-life, in samples preserved at -20 °C. In addition, the long chain fatty acid profile was analysed. A completely randomised design was used, and the means were compared with Tukey's test (P < 0.05). The mean lightness (L*), yellowness (b*) and hue (H*) values were higher for T3 and T4. The addition of CT did not affect (P > 0.05) redness (a*), cooking weight loss (CWL) or shear force (SF). T4 decreased (P < 0.05) stearic acid and increased cis-9 trans-12 conjugated linoleic acid (CLA). Bioaccessibility was higher in the supplemented groups (T1 < T2, T3 and T4). In conclusion, supplementing CT from AME in the diet of lambs did not reduce lipid oxidation, but T3 or T4 improved some aspects of meat colour and CLA deposition.

Formulation, Optimization and In-Vivo Characterization of Thermosensitive In-Situ Nasal Gel Loaded with Bacoside a for Treatment of Epilepsy.

The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 32-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.

Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

BACKGROUND: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. OBJECTIVES: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. METHODS: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. RESULTS: The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. CONCLUSIONS: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.

Sample Size Determination and Study Design Impact on Dose-Scale Pharmacodynamic Bioequivalence: a Case Study Using Orlistat.

Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.

Preparation and Evaluation of Berberine-Excipient Complexes in Enhancing the Dissolution Rate of Berberine Incorporated into Pellet Formulations.

Berberine is used in the treatment of metabolic syndrome and its low solubility and very poor oral bioavailability of berberine was one of the primary hurdles for its market approval. This study aimed to improve the solubility and bioavailability of berberine by preparing pellet formulations containing drug-excipient complex (obtained by solid dispersion). Berberine-excipient solid dispersion complexes were obtained with different ratios by the solvent evaporation method. The maximum saturation solubility test was performed as a key factor for choosing the optimal complex for the drug-excipient. The properties of these complexes were investigated by FTIR, DSC, XRD and dissolution tests. The obtained pellets were evaluated and compared in terms of pelletization efficiency, particle size, mechanical strength, sphericity and drug release profile in simulated media of gastric and intestine. Solid-state analysis showed complex formation between the drug and excipients used in solid dispersion. The optimal berberine-phospholipid complex showed a 2-fold increase and the optimal berberine-gelucire and berberine-citric acid complexes showed more than a 3-fold increase in the solubility of berberine compared to pure berberine powder. The evaluation of pellets from each of the optimal complexes showed that the rate and amount of drug released from all pellet formulations in the simulated gastric medium were significantly lower than in the intestine medium. The results of this study showed that the use of berberine-citric acid or berberine-gelucire complex could be considered a promising technique to increase the saturation solubility and improve the release characteristics of berberine from the pellet formulation.

Toward a more realistic estimate of exposure to chromium and nickel in soils of geogenic and/or anthropogenic origin: importance of oral bioaccessibility.

To enhance risk assessment for contaminated sites, incorporating bioavailability through bioaccessibility as a corrective factor to total concentration is essential to provide a more realistic estimate of exposure. While the main in vitro tests have been validated for As, Cd, and/or Pb, their potential for assessing the bioaccessibility of additional elements remains underexplored. In this study, the physicochemical parameters, pseudototal Cr and Ni concentrations, soil phase distribution, and oral bioaccessibility of twenty-seven soil samples were analysed using both the ISO 17924 standard and a simplified test based on hydrochloric acid. The results showed wide variability in terms of the concentrations (from 31 to 21,079 mg kg-1 for Cr, and from 26 to 11,663 mg kg-1 for Ni) and generally low bioaccessibility for Cr and Ni, with levels below 20% and 30%, respectively. Bioaccessibility variability was greater for anthropogenic soils, while geogenic enriched soils exhibited low bioaccessibility. The soil parameters had an influence on bioaccessibility, but the effects depended on the soils of interest. Sequential extractions provided the most comprehensive explanation for bioaccessibility. Cr and Ni were mostly associated with the residual fraction, indicating limited bioaccessibility. Ni was distributed in all phases, whereas Cr was absent from the most mobile phase, which may explain the lower bioaccessibility of Cr compared to that of Ni. The study showed promising results for the use of the simplified test to predict Cr and Ni bioaccessibility, and its importance for more accurate human exposure evaluation and effective soil management practices.

Genistein transfersome-embedded topical delivery system for skin melanoma treatment: in vitro and ex vivo evaluations.

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.

Spatial distribution, bioaccessibility, and human health implications of potentially toxic elements in mining-impacted topsoils in Obuasi Municipality of Ghana.

Potential toxic elements emanating from extracted ores during gold processing present occupational and unintentional health hazards in communities, the general populace, and the environment. This study investigated the concentrations and potential health effects of metal content in the topsoils of Obuasi municipality, which has been mined for gold over the past century. Surface topsoil samples, sieved to 250 µm, were initially scanned for metals using x-ray fluorescence techniques, followed by confirmation via ICP-MS. In vitro bioaccessibility assays were conducted using standard methods. The geoaccumulation indices (Igeo) indicate high enrichment of As (Igeo = 6.28) and Cd (Igeo = 3.80) in the soils, especially in the eastern part of the municipality where illegal artisanal mining is prevalent. Additionally, the southern corridor, situated near a gold mine, exhibited significant levels of As and Mn. Results obtained for the total metal concentrations and contamination indices confirmed the elevation of the studied potential toxic elements in the Obuasi community. A hazard index value of 4.42 and 3.30 among children and adults, respectively, indicates that indigens, especially children, are susceptible to non-cancer health effects.

Gut microbiota-mediated metabolism of green tea catechins and the biological consequences: An updated review.

Multiple beneficial effects have been attributed to green tea catechins (GTCs). However, the bioavailability of GTCs is generally low, with only a small portion directly absorbed in the small intestine. The majority of ingested GTCs reaches the large intestinal lumen, and are extensively degraded via biotransformation by gut microbiota, forming many low-molecular-weight metabolites such as phenyl-γ-valerolactones, phenolic acids, butyrate, and acetate. This process not only improves the overall bioavailability of GTC-derived metabolites but also enriches the biological activities of GTCs. Therefore, the intra- and inter-individual differences in human gut microbiota as well as the resulting biological contribution of microbial metabolites are crucial for the ultimate health benefits. In this review, the microbial degradation of major GTCs was characterized and an overview of the in vitro models used for GTC metabolism was summarized. The intra- and inter-individual differences of human gut microbiota composition and the resulting divergence in the metabolic patterns of GTCs were highlighted. Moreover, the potential beneficial effects of GTCs and their gut microbial metabolites were also discussed. Overall, the microbial metabolites of GTCs with higher bioavailability and bioactive potency are key factors for the observed beneficial effects of GTCs and green tea consumption.

Enhancing hepatoprotective action: oxyberberine amorphous solid dispersion system targeting TLR4.

Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and absorption thus resulting in low bioavailability. To overcome these drawbacks of OBB, amorphous spray-dried powders (ASDs) of OBB were formulated. The dissolution, characterizations, and pharmacokinetics of OBB-ASDs formulation were investigated, and its hepatoprotective action was disquisitive in the D-GalN/LPS-induced acute liver injury (ALI) mouse model. The characterizations of OBB-ASDs indicated that the crystalline form of OBB active pharmaceutical ingredients (API) was changed into an amorphous form in OBB-ASDs. More importantly, OBB-ASDs showed a higher bioavailability than OBB API. In addition, OBB-ASDs treatment restored abnormal histopathological changes, improved liver functions, and relieved hepatic inflammatory mediators and oxidative stress in ALI mice. The spray drying techniques produced an amorphous form of OBB, which could significantly enhance the bioavailability and exhibit excellent hepatoprotective effects, indicating that the OBB-ASDs can exhibit further potential in hepatoprotective drug delivery systems. Our results provide guidance for improving the bioavailability and pharmacological activities of other compounds, especially insoluble natural compounds. Meanwhile, the successful development of OBB-ASDs could shed new light on the research process of poorly soluble medicine.

Improvement of in vivo iron bioavailability using mung bean peptide-ferrous chelate.

There is an increasing amount of research into the development of a third generation of iron supplementation using peptide-iron chelates. Peptides isolated from mung bean were chelated with ferrous iron (MBP-Fe) and tested as a supplement in mice suffering from iron-deficiency anemia (IDA). Mice were randomly divided into seven groups: a group fed the normal diet, the IDA model group, and IDA groups treated with inorganic iron (FeSO4), organic iron (ferrous bisglycinate, Gly-Fe), low-dose MBP-Fe(L-MBP-Fe), high-dose MBP-Fe(H-MBP-Fe), and MBP mixed with FeSO4 (MBP/Fe). The different iron supplements were fed for 28 days via intragastric administration. The results showed that MBP-Fe and MBP/Fe had ameliorative effects, restoring hemoglobin (HGB), red blood cell (RBC), hematocrit (HCT), and serum iron (SI) levels as well as total iron binding capacity (TIBC) and body weight gain of the IDA mice to normal levels. Compared to the inorganic (FeSO4) and organic (Gly-Fe) iron treatments, the spleen coefficient and damage to liver and spleen tissues were significantly lower in the H-MBP-Fe and MBP/Fe mixture groups, with reparative effects on jejunal tissue. Gene expression analysis of the iron transporters Dmt 1 (Divalent metal transporter 1), Fpn 1 (Ferroportin 1), and Dcytb (Duodenal cytochrome b) indicated that MBP promoted iron uptake. These findings suggest that mung bean peptide-ferrous chelate has potential as a peptide-based dietary supplement for treating iron deficiency.

Assessment of protein and phospholipid bioaccessibility in ultrafiltered buttermilk cheese using TIM-1 in vitro gastrointestinal methods.

To meet the high consumer demand, butter production has increased over the last few years. As a result, the buttermilk (BM) co-produced volumes require new ways of adding value, such as in cheese manufacturing. However, BM use in cheese milk negatively influences the cheesemaking process (e.g., altered coagulation properties) and the product's final quality (e.g., high moisture content). The concentration of BM by ultrafiltration (UF) could potentially facilitate its use in cheese manufacturing through an increased protein content while maintaining the milk salt balance. Simultaneously, little is known about the digestion of UF BM cheese. Therefore, this study aimed to characterize the impact of UF BM on cheese manufacture, its structure, and its behavior during in vitro digestion. A 2-fold UF concentrated BM was used for cheese manufacture (skim milk [SM] - control). Compositional, textural, and microstructural analyses of cheeses were first conducted. In a second step, the cheeses were fed into an in vitro TNO gastrointestinal digestion model (TIM-1) of the stomach and small intestine and protein and phospholipid (PL) bioaccessibility was studied. The results showed that UF BM cheese significantly differed from SM cheese regarding its composition, hardness (p < 0.05) and microstructure. However, in TIM-1, UF BM and SM cheeses showed similar digestion behavior as a percentage of protein and PL intake. Despite relatively more non-digested and non-absorbed PL in the ileum efflux of UF BM cheese, the initially higher PL concentration contributes to an enhanced nutritional value compared to SM cheese. To our knowledge, this study is the first to compare the bioaccessibility of proteins and PL from UF BM and SM cheeses.

Digestion and absorption characteristics of iron-chelating silver carp scale collagen peptide and insights into their chelation mechanism.

Iron deficiency is widespread throughout the world, supplementing sufficient iron or improving the bioavailability of iron is the fundamental strategy to solve the problem of iron scarcity. Herein, we explored a new form of iron supplement, iron chelates of silver carp scales (SCSCP-Fe) were prepared from collagen peptide of silver carp scales (SCSCP) and FeCl2·4H2O, the effects of external environment and simulated gastrointestinal digestive environment on the stability of SCSCP-Fe and the structural changes of peptide iron chelates during digestion were investigated. The results of in vitro iron absorption promotion showed that the iron bioavailability of SCSCP-Fe was higher than that of FeSO4. Two potential high iron chelating peptides DTSGGYDEY (DY) and LQGSNEIEIR (LR) were screened and synthesized from the SCSCP sequence by molecular dynamics and LC-MS/MS techniques. The FTIR results displayed that the binding sites of DY and LR for Fe2+ were the carboxyl group, the amino group, and the nitrogen atom on the amide group on the peptide. ITC results indicated that the chelation reactions of DY and LR with Fe2+ were mainly dominated by electrostatic interactions, forming chelates in stoichiometric ratios of 1:2 and 1:1, respectively. Both DY and LR had a certain ability to promote iron absorption. The transport of DY-Fe chelate may be a combination of the three pathways: PepT1 vector pathway, cell bypass, and endocytosis, while LR-Fe chelate was dominated by bivalent metal ion transporters. This study is expected to provide theoretical reference and technical support for the high-value utilization of silver carp scales and the development of novel iron supplements.

Effect of fermentation on nutrient composition, antinutrients, and mineral bioaccessibility of finger millet based Injera: A traditional Ethiopian food.

Finger millet, like other cereals, contains high amounts of antinutrients that bind minerals, making them unavailable for absorption. This study explores the effect of traditional fermentation on nutritional, antinutritional, and subsequent mineral bioaccessibility (specifically iron, zinc, and calcium) of finger millet based Injera. Samples of fermented dough and Injera prepared from light brown and white finger millet varieties were analyzed for nutritional composition, antinutritional content, and mineral bioaccessibility following standard procedures. With some exceptions, the proximate composition of fermented dough was significantly affected by fermentation time. Compared to unfermented flour, the phytate and condensed tannin content significantly (p < 0.05) decreased for fermented dough and Injera samples. A strong decline in phytate and condensed tannin content was observed in white finger millet Injera as fermentation time increased, compared to light brown finger millet based Injera. The mineral bioaccessibility of Injera prepared from finger millet and maize composite flour increased with fermentation time, leading to a significant increase in bioaccessible iron, zinc, and calcium, ranging from 15.4-40.0 %, 26.8-50.8 %, and 60.9-88.5 %, respectively. The results suggest that traditional fermentation can be an effective method to reduce phytate and condensed tannin content, simultaneously increasing the bioaccessibility of minerals in the preparation of finger millet based Injera.

[Improvement of Intestinal and Transmucosal Absorption of Peptide and Protein Drugs].

It is well known that the oral bioavailability of hydrophilic and macromolecular drugs is generally very poor due to their poor membrane permeability characteristics. Among these poorly absorbed drugs, peptide and protein drugs are typical poorly absorbed drugs which have low stability and poor permeability in the gastrointestinal tract. Consequently, the clinical administration of peptide and protein drugs is presently limited to administration by injection. However, such frequent administration subjects the patients to considerable pain, and there is also the possibility of the manifestation of serious side effects. Therefore, various approaches have been examined to overcome the poor absorption characteristics of these drugs. These approaches include (1) to use additives including absorption enhancers and protease inhibitors, (2) to modify the chemical structure of peptide and protein drugs, and (3) to apply dosage forms to these drugs, (4) to develop a novel administration method for these drugs that can serve as an alternative to oral and injection administration. We demonstrated that intestinal and transmucosal absorption of peptide and protein drugs could be improved by using these approaches. These approaches may give us useful basic information to improve the intestinal and transmucosal absorption of peptide and protein drugs.

In vivo modification of the enamel pellicle and saliva resveratrol levels after use of resveratrol-containing orodispersible capsules.

OBJECTIVES: To evaluate in vivo 1) the bioavailability of trans-resveratrol when administered through sublingual capsules; 2) the effect of resveratrol on the protein composition of the acquired enamel pellicle (AEP). DESIGN: Ten volunteers received a sublingual capsule containing 50 mg of trans-resveratrol. Unstimulated saliva was then collected after 0, 30, 60, and 120 min and AEP was collected after 120 min following administration of the capsule. In the next week, the volunteers received a placebo sublingual capsule, and saliva and AEP were collected again. Saliva samples were analyzed for free trans-resveratrol using high-performance liquid chromatopgraphy (HPLC), and AEP samples were subjected to proteomic analysis (nLC-ESI-MS/MS). RESULTS: Trans-resveratrol was detected in saliva at all the time points evaluated, with the peak at 30 min. A total of 242 proteins were identified in both groups. Ninety-six proteins were increased and 23 proteins were decreased in the Resveratrol group. Among the up-regulated proteins, isoforms of cystatins, PRPs, Mucin-7, Histatin-1, Lactotrasnferrin and Lysozyme-C were increased and the isoforms of Protein S100, Neutrophil defensins, Albumin, PRPs, and, Statherin were decreased in Resveratrol group. CONCLUSION: The sublingual capsule is effective at increasing the bioavailability of trans-resveratrol in saliva. Several proteins involved in important processes to maintain systemic and oral health homeostasis were identified. These proteins differently expressed due to the presence of trans-resveratrol deserve attention for future studies, since they have important functions, mainly related to antimicrobial action.

Revolutionizing Cardiovascular Health with Nano Encapsulated Omega-3 Fatty Acids: A Nano-Solution Approach.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) offer diverse health benefits, such as supporting cardiovascular health, improving cognitive function, promoting joint and musculoskeletal health, and contributing to healthy aging. Despite their advantages, challenges like oxidation susceptibility, low bioavailability, and potential adverse effects at high doses persist. Nanoparticle encapsulation emerges as a promising avenue to address these limitations while preserving stability, enhanced bioavailability, and controlled release. This comprehensive review explores the therapeutic roles of omega-3 fatty acids, critically appraising their shortcomings and delving into modern encapsulation strategies. Furthermore, it explores the potential advantages of metal-organic framework nanoparticles (MOF NPs) compared to other commonly utilized nanoparticles in improving the therapeutic effectiveness of omega-3 fatty acids within drug delivery systems (DDSs). Additionally, it outlines future research directions to fully exploit the therapeutic benefits of these encapsulated omega-3 formulations for cardiovascular disease treatment.

Discovery of a Double-Stapled Short Peptide as a Long-Acting HIV-1 Inactivator with Potential for Oral Bioavailability.

Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 infection.

Efficacy of highly bioavailable oral curcumin in asymptomatic or mild COVID-19 patients: a double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Even after the peak of the COVID-19 pandemic, the number of mild cases remains high, requiring continuous control. Curcumin, owing to its anti-inflammatory properties, can suppress vital proliferation and cytokine secretion in animal models. We developed a highly absorbable curcumin, curcuRouge® (cR), which is approximately 100 times more orally bioavailable than conventional curcumin. We evaluated the effect of cR on the inhibition of disease progression in asymptomatic or mildly symptomatic COVID-19 patients. METHODS: This study evaluated the effect of 7-day oral intake of cR (360 mg twice daily). Patients within 5 days of COVID-19 diagnosis were randomly assigned to a placebo or cR group in a double-blind manner. RESULTS: Primary endpoint events [body temperature (BT) ≥ 37.5 °C and saturation of percutaneous oxygen (SpO2) < 96%] were fewer than expected, and the rate of these events was 2.8% in the cR group (2/71) and 6.0% in the placebo group (4/67); hazard ratio (HR) = 0.532, 95% confidence interval (CI) 0.097-2.902. Patients receiving cR tended to take fewer antipyretic medications than those receiving placebo (HR = 0.716, 95% CI 0.374-1.372). Among patients with a normal range of BT at baseline, the BT change rate was significantly (p = 0.014) lower in the cR group (- 0.34%) versus placebo (- 0.01%). CONCLUSION: The relative suppression of event rates and antipyretic medications taken, and significant decrease of subclinical BT support the anti-inflammatory effects of cR in asymptomatic or mildly symptomatic patients with COVID-19. TRIAL REGISTRATION: Japan Registry of Clinical Trials (CRB5200002).

Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation.

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.