Spray-dried Solid Lipid Nanoparticles for Enhancing Berberine Bioavailability via Oral Administration.

BACKGROUND: Berberine (BBR), an Eastern traditional medicine, has expressed novel therapeutic activities, especially for chronic diseases like diabetes, hyperlipemia, hypertension, and Alzheimer's disease. However, the low oral bioavailability of BBR has limited the applications of these treatments. Hence, BBRloaded solid lipid nanoparticles (BBR-SLNs) were prepared to improve BBR absorption into systemic circulations via this route. METHODS: BBR-loaded solid lipid nanoparticles (BBR-SLNs) were prepared by ultrasonication and then transformed into solid form via spray drying technique. The size morphology of BBR-SLNs was evaluated by dynamic light scattering (DLS) and scanning electron microscope (SEM). Crystallinity of BBR and interaction of BBR with other excipients were checked by spectroscopic methods. Entrapment efficiency of BBR-SLNs as well as BBR release in gastrointestinal conditions were also taken into account. Lastly, SLN's cytotoxicity for loading BBR was determined with human embryonic kidney cells (HEK293). RESULTS: Stearic acid (SA), glyceryl monostearate (GMS), and poloxamer 407 (P407) were selected for BBRSLNs fabrication. BBR-SLNs had homogenous particle sizes of less than 200 nm, high encapsulation efficiency of nearly 90% and loading capacity of above 12%. BBR-SLN powder could be redispersed without significant changes in physicochemical properties and was stable for 30 days. Spray-dried BBR-SLNs showed a better sustained in vitro release profile than BBR-SLNs suspension and BBR during the initial period, followed by complete dissolution of BBR over 24 hours. Notably, cell viability on HEK293 even increased up to 150% compared to the control sample at 100 µg/mL BBR-unloaded SLNs. CONCLUSION: Hence, SLNs may reveal a promising drug delivery system to broaden BBR treatment for oral administration.

Study on the effect of 40 Hz non-invasive light therapy system. A protocol for a randomized, double-blinded, placebo-controlled clinical trial.

Introduction: With no cure or effective treatment, the prevalence of patients with Alzheimer's disease (AD) is expected to intensify, thereby increasing the social and financial burden on society. Light-based 40 Hz brain stimulation is considered a novel treatment strategy for patients with AD that may alleviate some of this burden. The clinical trial ALZLIGHT will utilize a novel Light Therapy System (LTS). The LTS uses Invisible Spectral Flicker for non-invasive induction of 40 Hz neural activity. This protocol describes a trial evaluating the efficacy and safety of a light-based 40 Hz brain stimulation in patients with mild-to-moderate AD. Methods: 62 patients with mild-to-moderate AD will participate in a randomized, double-blinded, placebo-controlled, parallel-group, and single-center trial. The participants will partake in an enrollment period of 1 month, an intervention period of 6 months, and a 1.5-month post-interventional follow-up period. Prior to the baseline measurement (week 0), the patients will be randomized to either active or placebo intervention from baseline (week 0) to post-intervention follow-up (week 26). Discussion: This protocol describes a randomized, double-blinded, placebo-controlled clinical trial that may increase the understanding of the effect of gamma oscillations in the human brain and how it could be utilized as a novel and important tool for the treatment of AD. The effect is measured through a large, multidisciplinary assessment battery.Clinical trial registration:www.ClinicalTrials.gov, (NCT05260177). Registered on March 2, 2022.

Why do consumers choose private over public health services? Reflective accounts of health providers in Vietnam.

BACKGROUND: In Vietnam and many developing countries, private healthcare is increasingly being leveraged by governments to complement public services and increase health service access and utilisation. Extensive understanding of patterns of utilisation of private over public health services, and the rationale for such consumer decisions, is important to ensure and promote safe, affordable and patient-centred care in the two sectors. Few studies within the Southeast Asian Region have explored how private and public providers interact (via social networks, marketing, and direct contact) with consumers to affect their service choices. This study investigates providers' views on social factors associated with the use of private over public health services in Vietnam. METHOD: A thematic analysis was undertaken of 30 semi-structured interviews with experienced health system stakeholders from the Vietnam national assembly, government ministries, private health associations, health economic association, as well as public and private hospitals and clinics. RESULTS: Multiple social factors were found to influence the choice of private over public services, including word-of-mouth, the patient-doctor relationship and relationships between healthcare providers, healthcare staff attitudes and behaviour, and marketing. While private providers maximise their use of these social factors, most public providers seem to ignore or show only limited interest in using marketing and other forms of social interaction to improve services to meet patients' needs, especially those needs beyond strictly medical intervention. However, private providers faced their own particular challenges related to over-advertisement, over-servicing, excessive focus on patients' demands rather than medical needs, as well as the significant technical requirements for quality and safety. CONCLUSIONS: This study has important implications for policy and practice in Vietnam. First, public providers must embrace social interaction with consumers as an effective strategy to improve their service quality. Second, appropriate regulations of private providers are required to protect patients from unnecessary treatments, costs and potential harm. Finally, the insights from this study have direct relevance to many developing countries facing a similar challenge of appropriately managing the growth of the private health sector.

A new ß-carboline-type alkaloid from the flowers of Calotropis gigantea (L.) W.T.Aiton.

In our antioxidant screening of some Vietnamese plant extracts, the CHCl3-soluble fraction from Calotropis gigantea (L.) W.T.Aiton flowers showed moderate DPPH free radical scavenging activity with an IC50 value of 55.8 µg/mL. Thus, a further phytochemical study was carried out to obtain five alkaloids, including a new ß-carboline-type alkaloid, caloside H (1). These known compounds were identified as 5-hydroxy-(2-methoxymethyl)pyridine (2), nicotinic acid (3), p-(acetylamino)phenol (4), and thymine (5). These structures were determined based on the NMR spectroscopic analysis. In antioxidant assay, caloside H at concentration of 100 µM showed DPPH radical scavenging capacity with a percentage of inhibition of 40.2%. In addition, a plausible biosynthetic pathway for the formation of caloside H was proposed based on the Schiff base formation and Mannich-like reaction.

Stable Anode-Free All-Solid-State Lithium Battery through Tuned Metal Wetting on the Copper Current Collector.

A stable anode-free all-solid-state battery (AF-ASSB) with sulfide-based solid-electrolyte (SE) (argyrodite Li6 PS5 Cl) is achieved by tuning wetting of lithium metal on "empty" copper current-collector. Lithiophilic 1 µm Li2 Te is synthesized by exposing the collector to tellurium vapor, followed by in situ Li activation during the first charge. The Li2 Te significantly reduces the electrodeposition/electrodissolution overpotentials and improves Coulombic efficiency (CE). During continuous electrodeposition experiments using half-cells (1 mA cm-2 ), the accumulated thickness of electrodeposited Li on Li2 Te-Cu is more than 70 µm, which is the thickness of the Li foil counter-electrode. Full AF-ASSB with NMC811 cathode delivers an initial CE of 83% at 0.2C, with a cycling CE above 99%. Cryogenic focused ion beam (Cryo-FIB) sectioning demonstrates uniform electrodeposited metal microstructure, with no signs of voids or dendrites at the collector-SE interface. Electrodissolution is uniform and complete, with Li2 Te remaining structurally stable and adherent. By contrast, an unmodified Cu current-collector promotes inhomogeneous Li electrodeposition/electrodissolution, electrochemically inactive "dead metal," dendrites that extend into SE, and thick non-uniform solid electrolyte interphase (SEI) interspersed with pores. Density functional theory (DFT) and mesoscale calculations provide complementary insight regarding nucleation-growth behavior. Unlike conventional liquid-electrolyte metal batteries, the role of current collector/support lithiophilicity has not been explored for emerging AF-ASSBs.

Synthesis of heated aluminum oxide particles impregnated with Prussian blue for cesium and natural organic matter adsorption: Experimental and machine learning modeling.

Heated aluminum oxide particles impregnated with Prussian blue (HAOPs-PB) are synthesized for the first time using different molar ratios of aluminum sulfate and PB to improve the adsorption of cesium (133Cs+) and natural organic matter (NOM) from an aqueous solution. The Cs+ adsorption from various aqueous solutions, including surface, tap and deionized water by synthesized HAOPs-PB, is investigated. The influencing factors such as HAOPs-PB mixing ratio, pH and dosage are studied. In addition, pseudo 1st and 2nd order is tested for adsorption kinetics study. A machine learning model is developed using gene expression programming (GEP) to evaluate and optimize the adsorption process for Cs+ and NOM removal. Synthesized adsorbent showed maximum adsorption at a 1:1 M ratio of aluminum sulfate and PB in DI, tap, and surface water. The pseudo 2nd order kinetics model described the Cs + adsorption by HAOPs-PB more accurately that indicating physiochemical adsorption. Adsorption of Cs+ showed an increasing trend with higher HAOPs-PB concentration, while high pH also favored the adsorption. Maximum NOM adsorption is found at a higher HAOPs-PB dosage and a neutral pH value. Furthermore, the proposed GEP model shows outstanding performance for Cs+ adsorption modeling, whereas a modified-GEP model presents promising results for NOM adsorption prediction for testing dataset by learning the relationship between inputs and output with R2 values of 0.9348 and 0.889, respectively.

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens.

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women's Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.

A new 7',9-epoxylignan from the stems of Salacia chinensis.

Bioactivity-guided isolation of the CHCl3-soluble fraction of the stems of Salacia chinensis L. (Celastraceae) was carried out to obtain a new 7',9-epoxylignan (1) and three 7,9':7',9-diepoxylignans (2-4). The absolute configuration of 1 was elucidated based on NMR and ECD spectroscopic data interpretation. All isolated lignans showed intermediate α-glucosidase inhibitory activity with the IC50 values ranging from 28.5 to 85.6 µM.

A new 8,3'-neolignan from Solanum procumbens Lour.

The phytochemical investigation of the EtOAc-soluble fraction of the aerial parts of Solanum procumbens Lour. has been carried out to obtain seven compounds, including a new 8,3'-neolignan named solacanin A (1). Their chemical structures were elucidated based on the spectroscopic data interpretation. All isolated compounds were tested for their α-glucosidase inhibitory activity. Compounds 1 and 3-6 showed inhibitory activity with IC50 values of 221.5, 18.9, 6.0, 104.1, and 219.7 µM, respectively.[Formula: see text].

Two new derivatives of 8-prenyl-5,7-dihydroxycoumarin from the stems of Streblus ilicifolius (S.Vidal) Corn.

From the EtOAc-soluble extract of the stems of Streblus ilicifolius (Moraceae), two new secondary metabolites named strebluses A (1) and B (2) were isolated. Their chemical structures have been concluded based on the chemical derivatisation and the spectroscopic interpretation. All compounds have been tested for their tyrosinase inhibitory activity. They showed weaker inhibitory activity than that of kojic acid (IC50, 44.6 µM).[Formula: see text].

A new lignan from the stems of Buchanania lucida Blume (Anacardiaceae).

From the EtOAc-soluble extract of the stems of Buchanania lucida, one new lignan, (+)-(8S,8'S)-5'-methoxy-4,4'-di-O-methylsecoisolariciresinol (1), together with five known compounds (2-6) were isolated. Their structures were elucidated on the basis of NMR spectroscopic interpretation. The absolute configuration of 1 was determined based on the Cotton effects in the ECD spectrum. In the tyrosinase inhibitory activity test, p-hydroxybenzoic acid (6) showed the strong effect, with an IC50 value of 9.35 µM.

δ-Tocopherol derivatives from the leaves of Muntingia calabura L.

From an ethyl acetate-soluble fraction of the leaves of Muntingia calabura, one new trimeric δ-tocopherol derivative named as tocomuntin A (1), together with three known δ-tocopherol derivatives (2-4) were isolated. Their structures were elucidated based on the interpretation of NMR and MS spectroscopic data. In this work, δ-tocopherol (3) was found to have α-glucosidase inhibitory activity for the first time (IC50, 47.3 µM).

A new diphenylheptanoid from the rhizomes of Curcuma zedoaria.

A phytochemical investigation of the rhizomes of Curcuma zedoaria was carried out, leading to the isolation of a new diphenylheptanoid, zedoaroxane A (1), together with four known compounds (2-5). Their structures were elucidated based on NMR spectroscopic data. All isolated compounds possessed α-glucosidase inhibitory activity, with the IC50 values ranging from 35.2 to 89.0 µM, more potent than that of the positive control acarbose (IC50, 214.5 µM).

Tyrosinase Inhibitors from the Stems of Streblus Ilicifolius.

Two new stilbene derivatives, named strebluses C and D, were isolated from the EtOAc-soluble fraction of the stems of Streblus ilicifolius (Moraceae). Its absolute configuration was elucidated based on NMR spectroscopic data interpretation and optical rotation calculation. Streblus C possesses strong tyrosinase inhibitory activity with an IC50 value of 0.01 µM. Docking studies of 1 and 2 with oxy-tyrosinase were carried out to analyze their interactions. The analysis of the docked poses confirmed that 1 showed better binding affinity for oxy-tyrosinase than that of 2.

SARS-CoV-2 Papain-Like Protease Potential Inhibitors-In Silico Quantitative Assessment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

Diarylalkanoids as Potent Tyrosinase Inhibitors from the Stems of Semecarpus caudata.

From a CHCl3-soluble extract of the stems of Semecarpus caudata (Anacardiaceae), two new diarylalkanoids, semedienone (1) and semetrienone (2), were isolated. Their structures were elucidated based on NMR spectroscopic data interpretation. These compounds possess strong tyrosinase inhibitory activity with the IC50 values of 0.033 and 0.11 µM, respectively. Docking studies of 1 and 2 with oxy-tyrosinase were carried out to analyze their interactions. Accordingly, semedienone (1) showed good interactions with the peroxide group and amino acid residues. The biosynthesis of the isolated diarylalkanoids was proposed.

A new phenolic acid from the wood of Mangifera gedebe.

From the methanol extract of the wood of Mangifera gedebe (Anacardiaceae), we had isolated a new secondary metabolite named gedebic acid (1) and six known compounds (2-7). Their chemical structures were determined by spectroscopic methods as well as comparing with data in the literature. All compounds were tested for α-glucosidase inhibitory activity. Compounds 4-7 showed more potent inhibitory activity, with IC50 values ranging from 45.3 to 142.6 µM, than that of a positive control acarbose (IC50, 214.5 µM).

Management and outcomes of heart failure patients with CKD: experience from an inter-disciplinary clinic.

AIMS: CKD-HF patients suffer excess hospitalization and mortality, often under-treated with life-prolonging medications due to fear of worsening renal function and hyperkalaemia. Yet, role of inter-disciplinary working in improving therapy is unknown, which this study aims to investigate. METHODS AND RESULTS: Clinical, biochemical data, and medications at first and last clinic visit were obtained from patient records for 124 patients seen in kidney failure-heart failure clinic (23 March 2017 to 11 April 2019). Medication dose groups (none, low, and high dose), number of RAASi agents, and blood test results were compared between first and last visit in patients with at least two clinic visits (n = 97). Patient characteristics were age 78.5 years (IQR 68.1-84.4 years), male 67.7%, diabetes 51.6%, moderate (45.2%) vs. severe (39.5%) CKD, HF with reduced ejection fraction (HFrEF) (49.2%), follow-up 234 days (IQR 121-441 days). HFrEF was associated with increased risk of death (adjusted OR 4.49, 95% CI 1.43-14.05; P = 0.01). Distributions of patients according to number of RAASi agents they were on differed between first and last visit (P = 0.03). Dosage was increased in 25.9% for beta-blockers, 33.0% for ACEi/ARBs, and 17.5% for MRAs. Distributions of patients across MRA dosage groups was different (P = 0.03), with higher proportions on higher dosages at last visit, without significant changes in serum potassium or creatinine. Serum ferritin improved (131.0 vs. 267.5 µg/L; P < 0.001), and fewer patients had iron deficiency (56.7% vs. 26.8%; P = 0.002) at last visit compared to the first. CONCLUSIONS: This inter-disciplinary clinic improved guideline-recommended medication prescription, MRA dosages in CKD-HF patients without significant biochemical abnormality, and iron status. A prospectively designed study with medication titration protocol and defined patient-centred outcomes is needed to further assess effectiveness of such clinic.

Hopea odorata Extract Can Efficiently Kill Breast Cancer Cells and Cancer Stem-Like Cells in Three-Dimensional Culture More Than in Monolayer Cell Culture.

INTRODUCTION: The breast cancer cells with CD44+CD24- phenotype are known to play an important role in tumorigenesis, drug resistance, and cancer recurrence. Breast cancer cells with CD44+CD24- phenotype are cultured in three-dimensional (3D) stereotype showing the recapitulation of tumors in vivo such as cell differentiation, heterogeneity, and microenvironment. Using this 3D model in anti-cancer compound research results in a more accurate reflection than conventional monolayer cell culture. This study aimed to identify the antitumor activity of Hopea odorata methanol extract (HO-MeOH-E) on breast cancer cells and cancer stem-like cells in both models of three-dimensional culture (3D) and monolayer cell culture (2D). METHODS: HO-MeOH-E was produced from Hopea odorata plant. The VN9 breast cancer cells (VN9) were collected and expanded from the previous study. The breast cancer stem-like cells (VN9CSC) were sorted from the VN9 based on phenotype CD44+CD24-. Both VN9 and VN9CSC were used to culture in monolayer culture (2D) and organoids (3D) before they were used to treat with HO-MeOH-E. Two other anticancer drugs, doxorubicin and tirapazamine, were used as references. The antitumor activities of extracts and drugs were determined via two assays: antiproliferation using the Alamar blue assay and cell cycle assay. RESULTS: The results showed that HO-MeOH-E was sensitive to both VN9 and VN9CSC in 3D more than 2D culture (IC50 on 3D organoids 144.8 ± 2.172 µg/mL and on 2D 340.2 ± 17.01 µg/mL for VN9CSC (p < 0.001); IC50 on 3D organoids 2055 ± 82.2 µg/mL and on 2D 430.6 ± 8.612 µg/mL for VN9 (p < 0.0001), respectively). HO-MeOH-E inhibits VN9CSC proliferation by blocking S phase and increasing the populations of apoptotic cells; this is consensus to the effect of tirapazamine (TPZ) which is used in hypoxia-activated chemotherapy. CONCLUSION: Taken these results, HO-MeOH-E has the potential effect in hypoxia-activated chemotherapy specifically on breast cancer stem-like cells with CD44+CD24- phenotype.

4-Hydroxypanduratin A and Isopanduratin A Inhibit Tumor Necrosis Factor α-Stimulated Gene Expression and the Nuclear Factor κB-Dependent Signaling Pathway in Human Lung Adenocarcinoma A549 Cells.

Tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine, regulates inflammatory and immune responses by up-regulating gene expression in a manner that is dependent on the transcription factor nuclear factor κB (NF-κB). In the present study, we found that 4-hydroxypanduratin A and isopanduratin A, constituents of the rhizomes of Boesenbergia pandurata, inhibited the TNF-α-stimulated up-regulation of intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells. 4-Hydroxypanduratin A and isopanduratin A also reduced ICAM-1 mRNA expression and NF-κB-responsive luciferase activity in TNF-α-stimulated A549 cells. Moreover, 4-hydroxypanduratin A and isopanduratin A prevented the TNF-α-stimulated translocation of the NF-κB subunit p65 to the nucleus and the phosphorylation and proteasomal degradation of the inhibitor of the NF-κB α protein. The present results revealed that 4-hydroxypanduratin A and isopanduratin A inhibit TNF-α-stimulated gene expression and the NF-κB-dependent signaling pathway in A549 cells.