The oral dosage route still remains the most common and preferred route for drug administration due to convenient handling, high patient compliance, and cost-effectiveness. However, the oral absorption of drugs can be a complex process depending upon: (i) physicochemical properties of the drug (e.g., pK_a, lipophilicity, solubility), (ii) pharmaceutical factors (e.g., dosage form), and (iii) physiological factors (e.g., gastrointestinal pH values, gastric emptying rate, gastric and intestinal pH, metabolism). Oral administration of drugs sometimes leads to poor and/or variable oral bioavailability, possible leading to unstable clinical outcomes. To offer stable and improved pharmacokinetic behavior of drugs, a number of formulation approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of drugs. To provide new formulation platforms for better and safe medication, it is considered essential to understand the physicochemical, biochemical, metabolic, and biological barriers which limit overall drug bioavailability in more detail. The review article considers several crucial factors affecting oral absorption of drug substances. This article also describes the recent progress in formulation approaches to achieve stable and improved biopharmaceutical properties of orally-taken drugs.

Disulfiram (DSF), an irreversible aldehyde dehydrogenase 2 (ALDH2) inhibitor, is an U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism. Recent studies have reported an interesting antitumor activity of DSF against a wide range of human malignancies, while a growing number of ongoing and completed clinical trials have provided evidence supporting the repurposing of DSF as an anticancer treatment. Nevertheless, despite its current clinical indications and potential future therapeutic applications for treating various diseases, DSF is associated with serious side effects attributed to the inhibition of ALDH2. We have recently synthesized DSF analogs (2a–v) with limited inhibition of ALDH2. Here, we report the anticancer activity of these molecules by highlighting their effects on cell signaling in Jurkat cells. DSF and two DSF analogs, 2g and 2r, all stimulated apoptotic signaling pathways, although the 2g analog activated more apoptosis-related genes and induced higher levels of apoptosis in vitro. Differential gene expression data suggested that compounds 2g and 2r specifically reprogram target cells to downregulate pathways related to cell growth and division, while upregulating pathways related to apoptosis or differentiation. Interestingly, both compounds 2g and 2r had more differentially expressed genes related to DNA damage pathways (including those related to apoptosis) when compared to DSF, which may offer insights into their mechanisms of action.

Main protease (Mpro), also known as 3-chymotrypsin-like protease (3CLpro), is a nonstructural protein (NSP5) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the cleavage of virus polyproteins during viral replication at 11 sites, which generates 12 functional proteins. Mpro is a cysteine protease that presents specificity for the amino acid residue glutamine (Gln) at the P1 position of the substrate. Due to its essential role in processing the viral polyprotein for viral particle formation (assembly), Mpro inhibition has become an important tool to control coronavirus disease 2019 (COVID-19), since Mpro inhibitors act as antivirals. In this work, we proposed to identify specific inhibitors of the Mpro of SARS-CoV-2 using a monocyclic peptide (sunflower trypsin inhibitor (SFTI)) phage display library. Initially, we expressed, purified and activated recombinant Mpro. The screening of the mutant SFTI phage display library using recombinant Mpro as a receptor resulted in the five most frequent SFTI mutant sequences. Synthetized mutant SFTIs did not inhibit Mpro protease using the fluorogenic substrate. However, the mutant SFTI 4 efficiently decreased the cleavage of recombinant human prothrombin as a substrate by Mpro, as confirmed by sodium dodecyl sulfate (SDS)–polyacrylamide gel electrophoresis (PAGE). Additionally, SFTI 4 presented a dissociation constant (KD) of 21.66 ± 6.66 µM for Mpro by surface plasmon resonance. Finally, 0.1 µM SFTI 4 reduced VERO cell infection by SARS-CoV-2 wt after 24 and 48 h. In conclusion, we successfully screened a monocyclic peptide library using phage display for the Mpro of SARS-CoV-2, suggesting that this methodology can be useful in identifying new inhibitors of viral enzymes.

Host immunity and autophagy of cancer cells markedly impact the development of gastric cancer. Hua-Zhuo-Jie-Du decoction (TDP) has been used in gastritis clinically. This study aimed to evaluate the effects of TDP combined with cisplatin (DDP) on gastric cancer and explore the molecular mechanism. A total of 16 BALB/c nude mice were used to model the SGC7901 cells xenograft and treated with TDP and DDP or both, with the model group as the control. Hematoxylin–Eosin (H&E) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining were performed, and the expression levels of CD31 and Ki-67 were quantified by immunohistochemistry staining. Additionally, cyclooxygenase (COX)-2, matrix metalloproteinas (MMP)-2, and MMP-9 expression levels were quantified using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). WB was used to determine Cleaved-caspase3, Beclin-1, LC3B, and p-p62 levels. Lastly, flow cytometry was employed to evaluate immune responses in mice. TDP and DDP significantly decreased tumor weight and nuclear division, resulting in loosely distributed cells. Besides, TDP and DDP down-regulated the protein expression levels of Ki-67, CD31, COX-2, MMP-2, and MMP-9, as well as decreased the number of CD4+ IL-17+ cells. Conversely, TDP and DDP up-regulated Cleaved-caspase3 expression and the proportion of CD3+/CD4+ and CD8+/CD3+ cells. Notably, optimal effects were achieved using the combination of DDP and TDP. Furthermore, DDP increased the LCII/LCI ratio and the Beclin-1 levels while down-regulating p62 levels. However, TDP alleviated these effects. These results collectively indicated that the combination of TDP with DDP can inhibit the development of gastric cancer cells by mediating the immune and autophagy signaling pathways.

Lipid bilayer vesicles, liposomes are representative drug delivery carriers. High encapsulation efficiency and release control of drugs are essential for clinical application of liposomes. For efficient drug loading into liposomes, remote loading method using driving force like transmembrane gradients of pH and ions are utilized. Ions are called as “trapping agents,” which are also critical for the controlled release of drugs loaded into liposomes inside. It is difficult to apply ions as trapping agents to various drugs because of limited physicochemical compatibility between drugs and ions. Cyclodextrins (CDs) with hydrophobic cavity can make inclusion complexes with various hydrophobic compounds. Therefore, we aimed to evaluate the potential of CDs as a novel trapping agent using sulfobutylether-β-cyclodextrin (SBE-β-CD) and ibuprofen (IB), a weak acid hydrophobic drug. Encapsulation efficiency of IB in liposomes with pH gradient was approximately 27%, and it was enhanced by intraliposomal SBE-β-CD inclusion in addition to pH gradient, which was SBE-β-CD concentration-dependent. In liposomes with pH gradient, a large fraction of IB was released in a short time. This early-stage rapid IB release was significantly suppressed by the inclusion of SBE-β-CD inside liposomes. Thus, novel remote loading technology by intraliposomal SBE-β-CD enabled the efficient encapsulation of the hydrophobic drug into the aqueous phase of liposomes as well as their controlled release. This technology should be applied to various drugs that can be included into CDs in order to enhance their therapeutic benefits.

Depressed patients may exhibit glucocorticoid hypersecretion, suggesting that elevated levels of glucocorticoids may play an important role in the pathophysiology of depression. Some postmortem brain studies have shown decreased pH and increased lactate levels in psychiatric patients, implying involvement of these factors in the pathogenesis. To investigate the effects of glucocorticoids on brain pH and lactate levels, and their roles in depressive symptoms, brain pH and lactate were examined in mice treated with corticosterone (CORT), the major bioactive glucocorticoid in rodents. A single administration of CORT decreased hippocampal pH after 24 h. Three weeks of CORT treatment decreased pH in the prefrontal cortex (PFC), striatum, and hippocampus (HC), whereas intake of pH 9.0 drinking water increased pH in these brain regions. pH and lactate levels were correlated in the PFC and HC of mice treated with CORT for 3 weeks. The suppression of body weight gain and decrease in adrenal weight observed after 3 weeks of CORT treatment were not alleviated by pH 9.0 water. However, an increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus were alleviated. The decrease in brain pH and increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus induced by CORT treatment were abolished by co-treatment with the glucocorticoid receptor (GR) antagonist mifepristone. These findings indicate that decreased brain pH via GRs may be related to glucocorticoid-induced depression-like behavior and decreased hippocampal neurogenesis.

The extracellular matrix (ECM) in skeletal muscle is involved in a variety of physiological functions beyond the mechanical support of muscle tissue, nerves, and blood vessels; however, the role of the ECM in skeletal muscle remains unclear. There is little information regarding changes in the expression of factors comprising the ECM during cisplatin-induced muscle atrophy. In the present study, we examined the changes in gene expressions for skeletal muscle extracellular matrix components in skeletal muscle during cisplatin-induced muscle atrophy. Intraperitoneal administration of cisplatin caused muscle atrophy in mice and during this cisplatin-induced muscle atrophy, the expression of many procollagen genes (Col1a1, Col1a2, Col3a1, Col4a1, Col5a1, and Col5a2), elastin (Eln), fibronectin (Fn1), Laminin (Lama1, Lama2, and Lamb1) decorin (Dcn), heparan sulphate proteoglycans (Hspg2) and integrin (Itgb1) constituting the ECM was suppressed. Additional studies are needed to elucidate the pathological significance and mechanisms of reduced gene expression of ECM components associated with cisplatin-induced muscle atrophy.

Hyperuricemia is defined as high uric acid levels within the bloodstream and is commonly associated with gout, type 2 diabetes mellitus, and kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel drugs that prevent glucose reabsorption; additionally, this drug has shown promising results in patients at risk of developing cardiovascular or renal complications by lowering uric acid levels. This study aimed to investigate the association between SGLT2i and hyperuricemia. Here, a self-controlled sequence symmetry analysis using the JMDC administrative claims database (January 2005 to September 2022) consisting of 12396 patients, who were newly prescribed both SGLT2i and hypouricemic agents, was conducted. Trend-adjusted sequence ratios (SR) at intervals of 6, 12, 18, and 24 months were calculated. Significant inverse signals across all intervals were observed between SGLT2i and hypouricemic agents, with the strongest effect observed in the 24-month interval [adjusted SR 0.52 (95% CI 0.49–0.55)]. Significant inverse signals were observed for each of the six types of SGLT2i across all intervals. This indicates that SGLT2i initiation may be associated with a decreased risk of hyperuricemia. Further investigation of the efficacy of SGLT2i is needed in hypothesis-testing designs such as cohort studies.

Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in Alzheimer’s disease (AD). In this study, we investigated the temporal dynamics of BDNF expression in the hippocampus of 5xFAD mice, an AD model, focusing on sex and age differences and Bdnf mRNA splice variants. At 3 months of age, female wild-type (WT) mice exhibited significantly higher Bdnf mRNA levels compared to males. However, this difference was abolished in female 5xFAD mice. At 6 months of age, no sex differences in Bdnf mRNA levels were observed in WT mice, and the levels tended to be lower in female 5xFAD mice. Additionally, a significant decrease in the mRNA levels of full-length tropomyosin-related kinase B (TrkB), a BDNF receptor, was found in female 5xFAD mice at 6 months, while mRNA levels of the truncated TrkB were increased in both male and female 5xFAD mice. Specifically, among the Bdnf mRNA splice variants, the levels of Bdnf exon IIA–IX, exon IIB–IX, exon IIC–IX, and exon IXA mRNA were significantly higher in female WT mice compared to male WT mice at 3 months, but this difference was lost in female 5xFAD mice. These findings suggest that the expression of specific Bdnf splice variants would be maintained at higher levels in the hippocampus of young female mice than in males but may be disrupted in AD model mice. Our study may provide insights into the relationship between sex differences in AD onset and BDNF expression.

Intracellular ATP is released outside cells by various stimuli and is involved in cytoprotection by activating purinergic receptors. However, it remains unclear whether targeted radionuclide therapy induces extracellular ATP release. Here, we prepared ¹³¹I-labeled trastuzumab (¹³¹I-trastuzumab) and examined extracellular ATP release and its roles in ¹³¹I-trastuzumab’s growth inhibitory effects. ¹³¹I-trastuzumab was prepared by labeling with the chloramine-T method. The binding of ¹³¹I-trastuzumab to cells was investigated using the human epidermal growth factor receptor 2 (HER2)-positive cells (SKOV3) and the HER2-negative cell (MCF7). Extracellular ATP was determined by measuring chemiluminescence using a luciferin-luciferase reagent. The growth inhibitory effects of ¹³¹I-trastuzumab were investigated by colony formation assay. ¹³¹I-trastuzumab bound exclusively to SKOV3 cells. Treatment with ¹³¹I-trastuzumab at 4 MBq/mL and higher concentrations significantly increased extracellular ATP levels, whereas non-radioactive trastuzumab didn’t. This suggested that ATP release was specifically induced by radiation derived from ¹³¹I. The growth inhibitory effects of ¹³¹I-trastuzumab were significantly enhanced by pretreatment with apyrase (ecto-ATPase) or MRS2578 (a P2Y₆-selective antagonist), whereas they were significantly reduced by treatment with a P2Y₆-selective agonist. In conclusion, ¹³¹I-trastuzumab induced extracellular ATP release, and the released ATP was shown to be involved in mitigating radiation-induced reduction in cell viability through P2Y₆ receptor.

Hyperuricemia is caused by an imbalance of uric acid and is associated with many diseases. Although gout which is one of hyperuricemia-related diseases is curable with anti-hyperuricemic drugs some medications have side effects, such as hypersensitivity in patients with circulatory system disorders, flare reoccurrences, and increased cardiac risk. This study consisted of test tube (xanthine oxidase’s inhibition) and animal study. Animal study using with ICR mice was composed of control, potassium oxonate-induced hyperuricemia, allopurinol, and 3 Korean red ginseng water extract (KRGWE) treatment groups (62.5; 125, and 500 mg/kg). We orally administered KRGWE once a day for 7 d to induce hyperuricemia and injected PO 2 h before the final KRGWE administration. We measured serum uric acid, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen, and creatinine and analyzed the genes such as organic anion transport (OAT)-1, OAT-3, and urate transport (URAT)-1. KRGWE dose-dependently controlled xanthine oxidase activity in the serum and completely inhibited serum uric acid. KRGWE affected both uric acid excretion-related and uric acid reabsorption-related gene expression. KRGWE stimulated uric acid excretion-related gene expressions, such as OAT-1 and OAT-3, but inhibited uric acid reabsorption-related gene expression, such as URAT-1. KRGWE improved liver and kidney functioning. KRGWE improved liver/kidney functioning and is promising anti-hyperuricemic agent which can control serum uric acid via downregulating URAT1 and upregulating OAT1 and OAT3.

Therapeutic drug monitoring (TDM) is a routine clinical practice used to individualize drug dosing to maintain drug efficacy and minimize the consequences of overexposure. TDM is applied to many drug classes, including immunosuppressants, antineoplastic agents, and antibiotics. Considerable effort has been made to establish routine TDM practices for each drug. However, because TDM has been developed within the context of specific drugs, there is insufficient understanding of historical trends within the field of TDM research as a whole. In this study, we employed text-mining approaches to explore trends in the TDM research field. We first performed a PubMed search to determine which drugs and drug classes have been extensively studied in the context of TDM. This investigation revealed that the most commonly studied drugs are tacrolimus, followed by cyclosporine and vancomycin. With regard to drug classes, most studies focused on immunosuppressants, antibiotics, and antineoplastic agents. We also subjected PubMed records of TDM-related studies to a series of text-mining pipelines. Our analyses revealed how TDM research has evolved over the years, thereby serving as a cornerstone for forecasting future research trends.

The blood–brain barrier (BBB) is a dynamic interface controlling the compound translocation between the blood and the brain, thereby maintaining neural homeostasis. There is cumulative evidence that BBB impairment during diabetes mellitus (DM) takes part in the progression of cognitive dementia. As tight junction proteins and ATP-binding cassette (ABC) transporters regulate substance exchange between the circulating blood and brain, the expression and function of these molecules under DM should be fully clarified. To understand the alteration of ABC transporter function in the BBB under DM, in vitro multicellular rat BBB spheroids consisting of conditionally immortalized rat brain capillary endothelial cells, astrocytes, and pericytes were newly developed. Immunostaining and permeability analysis of paracellular transport markers suggested the construction of tight junctions on the surface of the BBB spheroids. Transport analyses using fluorescence substrates of P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4) indicate the functional expression of these transporters in the spheroids. After treatment with advanced glycation end-products (AGEs), involved in various signals during DM, the mRNA expression of tight junction molecules and ABC transporters in the BBB spheroids was upregulated. Furthermore, the functional changes in P-gp and BCRP in the BBB spheroids exposed to AGEs were canceled by the inhibitors of the receptor for AGEs (RAGE). These results suggest that AGE-RAGE interaction upregulates P-gp and BCRP function in the BBB.

Acute ischemic stroke is a cerebrovascular disease associated with high mortality and severe aftereffects which is caused by the blockage of cerebral blood vessels by a thrombus or embolus. Treatments for this condition are extremely limited. Herein, we aimed to explore the potential of 2,3,4-trihydroxybenzophenone (THB), a drug that suppresses oxidative stress and neuroinflammation, to promote functional recovery through neurite outgrowth, and to identify its protective effects in a mouse model of ischemic stroke. To determine the effects of THB on neurite outgrowth, neurite-bearing cells and neurite lengths were measured in Neuro2a cells. 1,1-Diphenyl-2-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging assays were further performed to determine the antioxidant activity of THB, while lipopolysaccharide-activated BV2 cells were used to determine the anti-inflammatory effects of THB. Transient middle cerebral artery occlusion (tMCAO) was further performed in a mouse model to determine the effects of THB on ischemic stroke. THB increased neurite outgrowth in mouse neuroblastoma cell lines and exhibits antioxidant and anti-neuroinflammatory properties. In addition, THB reduced infarct volume in a concentration-dependent manner in the tMCAO model, leading to an increase in survival rate. Moreover, THB significantly suppressed microglial activation in the cortex and striatum. These results suggest that THB has potential for treating transient cerebral ischemic stroke.

Although immune checkpoint inhibitors (ICIs) are an effective treatment for clear cell sarcoma (CCS), a rare melanocytic sarcoma with a poor prognosis, their efficacies are still limited. Therefore, a novel therapeutic strategy is required to improve the efficacy of ICIs. We previously reported that histone deacetylase (HDAC) inhibitors increased melanoma immunogenicity through the SOX10–IRF1 pathway and may improve the efficacy of ICIs for melanoma. We herein demonstrated that the inhibition of HDAC induced the expression of HLA class I molecules through IRF1 in CCS cells, similar to melanoma. The suppression of SOX10 by small interfering RNA (siRNA) induced the expression of HLA class I molecules. In addition, the isoform-specific inhibition of HDAC1/3 induced the expression of another IRF1 downstream molecule, PD-L1 in CCS cells in concert with the suppression of SOX10. Furthermore, the knockdown of IRF1 impaired the induction of PD-L1 expression in CCS cells. Therefore, the inhibition of HDAC1/3 has potential as a novel strategy to increase immunogenicity and as combination therapy with ICIs for CCS and melanoma.

Incidence of type I allergies, such as hay fever, is continuously increasing in developed countries, including Japan. Type I allergies are triggered by chemical mediators, such as histamine, which are released via immunoglobulin E (IgE)-mediated mast cell degranulation. Therefore, medications inhibiting the synthesis, release, and receptor binding of these mediators are commonly used to manage type I allergy symptoms. As self-care disease prevention practices are gaining attention worldwide, regular consumption of food and supplements containing safe components inhibiting mast cell degranulation is a potential strategy to prevent allergic attacks. Here, we aimed to assess the ability of phytochemicals derived from edible plants to inhibit mast cell degranulation using the β-hexosaminidase release assay and investigate their cytotoxicity and efficiency in alleviating allergic symptoms. We found that oridonin, a diterpenoid isolated from Isodon japonicus Hara, strongly inhibited β-hexosaminidase release from both the RBL-2H3 rat cell line and mouse bone marrow-derived mast cells stimulated with dinitrophenyl (DNP)-conjugated human serum albumin after sensitization with DNP-IgE. Oridonin also inhibited β-hexosaminidase release induced by the calcium ionophore, A23187, in both cell types. Notably, oridonin did not adversely affect cell survival at concentrations necessary to inhibit β-hexosaminidase release. In a mouse model of ovalbumin (OVA)-induced allergic rhinitis, intraperitoneal administration of oridonin significantly reduced the nasal rubbing caused by intranasal OVA administration without affecting the serum levels of OVA-specific IgE. Therefore, oridonin could be an effective daily intake component to alleviate allergic diseases by inhibiting mast cell degranulation.

Itch is an unpleasant sensation that induces a desire to scratch. Chronic itch is accompanied by inflammatory skin diseases and causes repetitive scratching leading to tissue damage. The thyrotropin-releasing hormone analog taltirelin exerts analgesic effects on acute and chronic pain by activating the descending inhibitory systems. However, little is known regarding its effects on acute and chronic itch. In this study, we examined the effects of taltirelin on acute and chronic itch. Subcutaneous injection of chloroquine increased the number of scratching bouts in 30 min, whereas intraperitoneal injection of taltirelin reduced these episodes in a dose-dependent manner. In addition, chronic itch induced by diphenylcyclopropenone treatment was alleviated by taltirelin injection. These findings indicate that taltirelin alleviates acute and chronic itch in mice, and can be a potent therapeutic antipruritic drug.

Escherichia coli O157:H7 and Salmonella spp. are common foodborne pathogens. Simple, rapid and accurate methods to detect and enumerate these pathogens are required to prevent outbreaks of foodborne illness. Here, a microfluidic system with on-chip staining and semi-automated counting functionality was combined with the use of immunomagnetic separation to collect E. coli O157:H7 and Salmonella Typhimurium without an enrichment step. The recovery of bacteria from lettuce at different spiking ratios of the two species was 61–83%. In the range 3.5 × 10² to 3.3 × 10⁵ cells/g of lettuce, there was a good linear relationship (R² = 0.9997–0.9998) between the average counts from the microfluidic quantification method and conventional immunofluorescence microscopy. Detection took <3 h. The limit of detection of the microfluidic device was 4 × 10¹ cells/g, comparable to that of plate culture and real-time PCR methods. Our microfluidic approach has potential for rapid on-site detection of multiple pathogenic bacteria in foods.

Nurr1 (NR4A2) is a member of nuclear receptor superfamily that regulates gene transcription in midbrain dopaminergic neurons and also inhibits nuclear factor-κB-mediated inflammatory responses in brain microglial cells. To date, various compounds have been reported to stimulate transcriptional activity of Nurr1 on neuronal genes, but their anti-inflammatory actions are poorly characterized. The present study examined the effects of three kinds of Nurr1 ligands, amodiaquine, 1,1-bis(3′-indolyl)-1-(p-chlorophenyl)-methane (C-DIM12) and 5-chloronaphthalen-1-amine (5-CNA), on inflammatory responses of microglial BV-2 cells. Lipopolysaccharide (LPS)-induced upregulation of interleukin-1β mRNA and tumor necrosis factor α mRNA was inhibited by all three compounds, whereas upregulation of interleukin-6 mRNA and inducible nitric oxide synthase (iNOS) mRNA was significantly inhibited only by 5-CNA. On the other hand, LPS-induced nuclear translocation of p65 subunit of nuclear factor-κB was prevented only by amodiaquine. C-DIM12 increased nuclear localization of Nurr1 and transiently upregulated Nurr1 protein expression, whereas amodiaquine and 5-CNA had no effect on these parameters. Notably, inhibitory effect of 5-CNA on iNOS mRNA upregulation was reversed by co-application of amodiaquine. Conversely, inhibitory effect of amodiaquine on p65 nuclear translocation was cancelled by 5-CNA. These results reveal distinct characteristics of anti-inflammatory actions of Nurr1 ligands.

Several machine learning models have been proposed to predict vancomycin (VCM)-associated nephrotoxicity; however, they have notable limitations. Specifically, they do not use the area under the concentration–time curve (AUC) as recommended in the latest guidelines and do not address imbalanced data. Thus, we aimed to develop a novel model for predicting VCM-associated nephrotoxicity while overcoming these limitations. We retrospectively analyzed the medical records of patients who received VCM intravenously at our hospital from August 2017 to July 2021. We developed machine learning models for predicting VCM-associated nephrotoxicity based on the AUC of VCM and other patient background factors by using the following machine learning algorithms: lasso regression, support vector machine, complement naïve Bayes classifier, decision tree, random forest, and AdaBoost. We utilized the synthetic minority oversampling technique (SMOTE) and class weighting technique for dealing with imbalanced data and compared the performance of our developed machine learning models with that of a conventional model (AUC-guided therapeutic drug monitoring (TDM); AUC at steady state ≤600 µg·h/mL). Data from 270 patients were analyzed. The random forest with SMOTE was the best-performing model, achieving an F1 score of 0.353 and a sensitivity of 0.632 on the test data, compared with the conventional model, with an F1 score of 0.286 and a sensitivity of 0.316. We developed the first machine learning model for predicting VCM-associated nephrotoxicity based on the AUC of VCM, reducing the number of overlooked cases of nephrotoxicity compared with AUC-guided TDM, which may benefit patients overlooked by AUC-guided TDM.

Cellular aging causes declining cell functionality, gradually disrupting cellular homeostasis. Mitochondria are crucial in numerous metabolic processes, including the electron transport chain and fatty acid β-oxidation. Mitochondrial dysfunction is closely linked to aging-related liver dysfunction because it impairs fatty acid metabolism, potentially leading to nonalcoholic fatty liver disease. We demonstrated that neferine-induced autophagy suppressed the aging phenotype in proliferative and replicative aging-induced cells and aging liver tissue by reactivating mitochondrial function. Pharmacological analyses revealed that neferine-induced autophagy via the death-associated protein kinase 1 (DAPK1) and c-Jun N-terminal kinase (JNK) signaling pathways despite the lack of AMP activated protein kinase (AMPK) signaling activation. Furthermore, neferine stimulated ATP production and β-oxidation activity in aging cells. Our in vivo experiments demonstrated that oral administration of neferine rejuvenated aging liver tissue, suppressed fatty acid accumulation in the liver, and reduced senescence-associated β-galactosidase activity. Thus, neferine rejuvenated aging cells and liver tissue by inducing autophagy to reactivate mitochondrial function.

Amyloid polypeptide aggregation is considered one of the factors involved in the pathogenesis of Alzheimer’s disease (AD) and type 2 diabetes (T2D), and the number of affected patients increases as the population ages. Amyloid β (Aβ) found in the brain of patients with AD and human islet amyloid polypeptide (hIAPP) found in the pancreas of patients with T2D are thought to be cytotoxic during the aggregation process, especially the low-molecular-weight oligomers that are aggregation intermediates. In this study, meroterpenoids isolated and structurally determined from the brown alga Sargassum macrocarpum were evaluated for their ability to inhibit hIAPP aggregation. The results showed that 16 compounds from S. macrocarpum exhibited hIAPP aggregation–inhibitory activity, mainly through the inhibition of fiber elongation. These compounds showed higher activity with a hydroquinone moiety than with a quinone moiety, similar to their aggregation–inhibitory activity against Aβ42. Furthermore, these peptides demonstrated the potential to inhibit oligomer formation at high concentration ratios of 1 : 4 or higher. Further, compounds lacking hydroxyl groups did not exhibit this aggregation–inhibitory activity, suggesting that the phenolic hydroxyl group is essential for this activity.

Nanaomycin K is a natural compound found in the culture broth of “Streptomyces rosa subsp. notoensis” OS-3966. Studies have shown that it inhibits epithelial–mesenchymal transition (EMT), a recognized mechanism of cancer cell migration. Here we investigated the EMT-inhibitory and antitumor effects of nanaomycin K in renal cell carcinoma (RCC). We treated the renal cancer cell line ACHN, Caki-1 and Renca with nanaomycin K and examined its effects on cell proliferation, apoptosis, and expression of EMT and apoptosis markers in vitro and in vivo. Wound healing assays were performed to assess cell migration in vitro, and the mice bearing ACHN tumors were treated intratumorally with nanaomycin K to observe tumor size over time. Nanaomycin K significantly inhibited ACHN, Caki-1 and Renca cell growth and cell migration and significantly induced apoptosis of ACHN in the presence of transforming growth factor (TGF)-β. At the gene level, nanaomycin K increased E-cadherin expression, decreased N-cadherin, Vimentin and Slug expressions, and promoted Caspase-3,8,9 expressions. Intratumor administration of nanaomycin K significantly inhibited tumor growth without apparent adverse events for mice. These results indicate that nanaomycin K inhibit cell growth and EMT in TGF-β-induced advanced RCC, and that nanaomycin K is a potential candidate for the treatment of RCC.