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Biomedicine & Pharmacotherapy =... Jun 2024Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only...
BACKGROUND AND AIMS
Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD.
APPROACH AND RESULTS
The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota.
CONCLUSIONS
Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD.
PubMed: 38943989
DOI: 10.1016/j.biopha.2024.117067 -
Virology Jun 2024The increasing prevalence of drug-resistant Escherichia coli (E. coli) resulting from the excessive utilization of antibiotics necessitates the immediate exploration of...
The increasing prevalence of drug-resistant Escherichia coli (E. coli) resulting from the excessive utilization of antibiotics necessitates the immediate exploration of alternative approaches to counteract pathogenic E. coli. Phages, with their unique antibacterial mechanisms, are considered promising candidates for treating bacterial infections. Herein, we isolated a lytic Escherichia phage Tequatrovirus YZ2 (phage YZ2), which belongs to the genus Tequatrovirus. The genome of phage YZ2 consists of 168,356 base pairs with a G + C content of 35.34% and 269 putative open reading frames (ORFs). Of these, 146 ORFs have been annotated as functional proteins associated with nucleotide metabolism, structure, transcription, DNA replication, translation, and lysis. In the mouse model of a skin wound infected by E. coli, phage YZ2 therapy significantly promoted the wound healing. Furthermore, histopathological analysis revealed reductions in IL-1β and TNF-α and increased VEGF levels, indicating the potential of phages as effective antimicrobial agents against E. coli infection.
PubMed: 38943783
DOI: 10.1016/j.virol.2024.110155 -
Cytokine Jun 2024Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations...
Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid β oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid β oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid β-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.
PubMed: 38943739
DOI: 10.1016/j.cyto.2024.156671 -
Drug and Alcohol Dependence Jun 2024Nails accumulate the alcohol metabolite, ethyl glucuronide (ETG), and the cannabis metabolite, carboxy- delta-9-THC over 3-6 months. Few studies have examined nail...
BACKGROUND
Nails accumulate the alcohol metabolite, ethyl glucuronide (ETG), and the cannabis metabolite, carboxy- delta-9-THC over 3-6 months. Few studies have examined nail toxicology testing's sensitivity and specificity and the agreement between nail testing and self-reported alcohol and marijuana use.
METHODS
In an ongoing clinical trial, 1101 veterans completed initial telephone questionnaires and were then asked to mail nail clippings for substance use analysis. We examined sensitivity and specificity of ETG and carboxy- delta-9-THC in nails compared to self-report of alcohol use patterns (the AUDIT-C) and substance-related harms (alcohol and THC subscales of the ASSIST). We then examined factors associated with discordance between nails and self-report.
RESULTS
Almost two-thirds (707/1101) of respondents mailed in nail clippings. Those with returned nails were disproportionately married, white race, older, and less depressed. At a threshold of 8pg/mg, sensitivity was only.50 to detect risky alcohol use and.49 to detect alcohol-related issues. Sensitivity for marijuana issues was only.61. Specificity was greater than.77 for all measures. Factors associated with positive nails/negative self-report (i.e. false positives) for risky alcohol use on the Audit-C included more pain and being unmarried; false positive nails for alcohol-related issues on the ASSIST were associated with being unmarried and non-Hispanic ethnicity. False positive nails for THC-related issues on the ASSIST were associated with being African American, Hispanic, and having had legal issues.
CONCLUSIONS
At standard cut-offs, nail measures had low sensitivity and higher specificity. The groups who disproportionately submit positive nails/negative self-report could have substance use patterns not adequately captured by self-report, inaccurate self-report due to social pressures, or distinct drug metabolism.
PubMed: 38943713
DOI: 10.1016/j.drugalcdep.2024.111358 -
Phytomedicine : International Journal... Jun 2024Papillary thyroid carcinoma (PTC) is an endocrine malignant tumor of the head and neck. Surgery and chemotherapy are PTC treatments, but have adverse effects....
BACKGROUND
Papillary thyroid carcinoma (PTC) is an endocrine malignant tumor of the head and neck. Surgery and chemotherapy are PTC treatments, but have adverse effects. Exploration of new non-toxic anti-PTC drugs for PTC treatment is an unmet need.
METHODS
We aimed to identify anti-PTC drugs that could inhibit PTC-cell proliferation through high-throughput screening of a library of well-characterized naturally occurring small-molecule compounds. Then, the anti-PTC function of rhodiolin was validated by in vitro cell models and xenograft tumor models RESULTS: We initially demonstrated that rhodiolin inhibited the growth and induced the apoptosis of PTC cells significantly in vitro and in vivo. At the metabolic level, rhodiolin blocked glycolysis through glucose 6-phosphate isomerase (GPI), which suggested that glycolytic inhibition may be involved in mediating the anti-PTC function of rhodiolin. Transcriptomics analysis combined with bioinformatics analysis identified rhodiolin treatment to inhibit phosphorylation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Collectively, our findings demonstrated that rhodiolin inhibited the proliferation and induced the apoptosis of PTC cells by blocking glycolysis through the glycolytic enzyme GPI, thereby inhibiting phosphorylation of the PI3K/Akt/mTOR signaling pathway.
CONCLUSION
Our study demonstrates the potential use of rhodiolin in inhibiting the proliferation and inducing the apoptosis of PTC cells. Inhibition of phosphorylation of the PI3K/Akt/mTOR signaling pathway mediated by GPI plays an extremely important part in the ant-PTC function of rhodiolin. These results suggest that rhodiolin is a promising drug in the treatment of PTC progression. Our results provide a novel target and cell signaling pathway for PTC therapy from the perspective of energy metabolism, which could provide new perspectives and new drug choices for PTC therapy. In addition to that, our study will help to make up for the lack of drug research for PTC.
PubMed: 38943696
DOI: 10.1016/j.phymed.2024.155804 -
Journal of the American Chemical Society Jun 2024Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and...
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel coli ( ) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
PubMed: 38943624
DOI: 10.1021/jacs.4c04840 -
The Veterinary Quarterly Dec 2024Mistletoe is an herb that grows on duku plants (Lancium demosticum) and is known as benalu duku (BD) in Indonesia. It is predicted to have benefits such as anticancer...
Mistletoe is an herb that grows on duku plants (Lancium demosticum) and is known as benalu duku (BD) in Indonesia. It is predicted to have benefits such as anticancer or antiviral properties, and it is also thought to have anti-diabetic pharmacological activity. Quercetin-like compounds (QLCs) are secondary metabolites with antidiabetic activity that are expected to lower blood sugar levels in animals after oral administration. This study aimed to analyze the ability of QLCs to reduce random blood sugar levels using experimental animals as clinical models. The research method used was exploratory, which used a before-after test model, and observations were made on the random blood sugar levels after treatment. Secondary metabolites were extracted from BD leaves, which were then screened. Diabetes was induced in 30 rats (Rattus norvegicus) by the administration of streptozotocin at 0.045 mg/g body weight daily for 2 days. The antidiabetic effects of the secondary metabolite at doses of 0.5 mg/kg body weight (twice a day) when administered orally for up to 5 days were tested in diabetic rats. The random sugar levels (mg/dL) were measured using a One Touch Ultra Plus medical device for observation of randomized blood sugar levels. Results and novelty: The results revealed that the secondary metabolite, as an analyte from the BD leaf extract, can significantly reduce random blood sugar levels. The secondary metabolite extracted from BD, could be used to treat diabetes in rats.
Topics: Animals; Diabetes Mellitus, Experimental; Rats; Hypoglycemic Agents; Quercetin; Blood Glucose; Male; Plant Extracts; Mistletoe; Administration, Oral; Plant Leaves
PubMed: 38943615
DOI: 10.1080/01652176.2024.2372090 -
Database : the Journal of Biological... Jun 2024Drug transporters, integral membrane proteins found throughout the human body, play critical roles in physiological and biochemical processes through interactions with...
Drug transporters, integral membrane proteins found throughout the human body, play critical roles in physiological and biochemical processes through interactions with ligands, such as substrates and inhibitors. The extensive and disparate data on drug transporters complicate understanding their complex relationships with ligands. To address this challenge, it is essential to gather and summarize information on drug transporters, inhibitors and substrates, and simultaneously develop a comprehensive and user-friendly database. Current online resources often provide fragmented information and have limited coverage of drug transporter substrates and inhibitors, highlighting the need for a specialized, comprehensive and openly accessible database. ISTransbase addresses this gap by amassing a substantial amount of data from literature, government documents and open databases. It includes 16 528 inhibitors and 4465 substrates of 163 drug transporters from 18 different species, resulting in a total of 93 841 inhibitor records and 51 053 substrate records. ISTransbase provides detailed insights into drug transporters and their inhibitors/substrates, encompassing transporter and molecule structure, transporter function and distribution, as well as experimental methods and results from transport or inhibition experiments. Furthermore, ISTransbase offers three search strategies that allow users to retrieve drugs and transporters based on multiple selectable constraints, as well as perform checks for drug-drug interactions. Users can also browse and download data. In summary, ISTransbase (https://istransbase.scbdd.com/) serves as a valuable resource for accurately and efficiently accessing information on drug transporter inhibitors and substrates, aiding researchers in exploring drug transporter mechanisms and assisting clinicians in mitigating adverse drug reactions Database URL: https://istransbase.scbdd.com/.
Topics: Humans; Membrane Transport Proteins; Internet; Databases, Protein; Databases, Factual; Animals; Databases, Pharmaceutical
PubMed: 38943608
DOI: 10.1093/database/baae053 -
Journal of Medicinal Chemistry Jun 2024Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by...
Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration and . Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their half-life with fatty side chains for albumin binding. The antitumor candidate displayed exceptional affinity ( = 1.72 × 10 M), internalization efficiency, anticancer potency (IC = 0.015 ± 0.002 μM), and pharmacokinetics ( = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.
PubMed: 38943600
DOI: 10.1021/acs.jmedchem.4c00511 -
Inorganic Chemistry Jun 2024Zwitterionic thiolate ligands have the potential to introduce novel assembly modes and functions for noble metal clusters. However, their utilization in the synthesis of...
Zwitterionic thiolate ligands have the potential to introduce novel assembly modes and functions for noble metal clusters. However, their utilization in the synthesis of silver clusters remains understudied, particularly for the clusters containing reductive Ag(0) species. In this article, we report the first synthesis of a mixed-valence silver(0/I) cluster protected by zwitterionic Tab as thiolate ligands (Tab = 4-(trimethylammonio)benzenethiolate), denoted as [Ag(Tab)](PF)·16CHOH·6EtO (·16CHOH·6EtO), alongside an Ag(I) cluster [Ag(Tab)(PhCOO)(MeCN)(HO)](PF)·11MeCN (·11MeCN). has a distinct hierarchical supratetrahedral structure with a central {Ag} kernel surrounded by four [Ag(Tab)] units. High-resolution electrospray ionization mass spectra demonstrate that has two free electrons, indicating a superatomic core. has a drum-like [Ag(Tab)(PhCOO)(HO)] inner core capped by two tetrahedral-like [Ag(Tab)(PhCOO)(MeCN)] units. can be transformed into after its reaction with NaBH in solution. Antibacterial measurements reveal that has a significantly lower minimum inhibitory concentration than that of the cluster. This work not only extends the stabilization of silver(0/I) clusters to neutral thiol ligands but also offers new materials for the development of novel antibacterial materials.
PubMed: 38943593
DOI: 10.1021/acs.inorgchem.4c01735