Probiotic and immunostimulating effects of live and heat-killed Pediococcus pentosaceus TAP041.

The selected strain, TAP041, showing an excellent ability to reduce the glyoxal and methylglyoxal levels, was identified by 16S rRNA gene-based phylogenetic analysis as Pediococcus pentosaceus. It demonstrated probiotic properties, including acid, bile salt, pancreatin, lysozyme tolerance, gut adhesion, and auto/coaggregation. In RAW264.7 macrophages, both live and heat-killed strains induced nitric oxide production and activated inducible nitric oxide synthase. RAW264.7 treated with P. pentosaceus TAP041 increased the expression level of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and cyclooxygenase-2, and regulated the expression of c-Jun amino-terminal kinase, p38, and extracellular signal-regulated kinase. These findings suggest that both live and heat-killed P. pentosaceus TAP041 can be used as potential immunostimulatory agents in functional food additives. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01530-2.

Metabolic Interaction Between Host and the Gut Microbiota During High-Fat Diet-Induced Colorectal Cancer.

Colorectal cancer (CRC) is the second-highest cause of cancer-associated mortality among both men and women worldwide. One of the risk factors for CRC is obesity, which is correlated with a high-fat diet prevalent in Western dietary habits. The association between an obesogenic high-fat diet and CRC has been established for several decades; however, the mechanisms by which a high-fat diet increases the risk of CRC remain unclear. Recent studies indicate that gut microbiota strongly influence the pathogenesis of both high-fat diet-induced obesity and CRC. The gut microbiota is composed of hundreds of bacterial species, some of which are implicated in CRC. In particular, the expansion of facultative anaerobic Enterobacteriaceae, which is considered a microbial signature of intestinal microbiota functional imbalance (dysbiosis), is associated with both high-fat diet-induced obesity and CRC. Here, we review the interaction between the gut microbiome and its metabolic byproducts in the context of colorectal cancer (CRC) during high-fat diet-induced obesity. In addition, we will cover how a high-fat diet can drive the expansion of genotoxin-producing Escherichia coli by altering intestinal epithelial cell metabolism during gut inflammation conditions.

Tonicity-induced cargo loading into extracellular vesicles.

The current challenge in using extracellular vesicles (EVs) as drug delivery vehicles is to precisely control their membrane permeability, specifically in the ability to switch between permeable and impermeable states without compromising their integrity and functionality. Here, we introduce a rapid, efficient, and gentle loading method for EVs based on tonicity control (TC) using a lab-on-a-disc platform. In this technique, a hypotonic solution was used for temporarily permeabilizing a membrane ("on" state), allowing the influx of molecules into EVs. The subsequent isotonic washing led to an impermeable membrane ("off" state). This loading cycle enables the loading of different cargos into EVs, such as doxorubicin hydrochloride (Dox), ssDNA, and miRNA. The TC approach was shown to be more effective than traditional methods such as sonication or extrusion, with loading yields that were 4.3-fold and 7.2-fold greater, respectively. Finally, the intracellular assessments of miRNA-497-loaded EVs and doxorubicin-loaded EVs confirmed the superior performance of TC-prepared formulations and demonstrated the impact of encapsulation heterogeneity on the therapeutic outcome, signifying potential opportunities for developing novel exosome-based therapeutic systems for clinical applications.

Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors.

Mixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibition of MLK3 in the enzymatic assay. In particular, compounds 9a, 9e, 9j, 9 k, 12b and 12d exhibited IC50 values of 6, 6, 8, 11, 14 and 14 nM, respectively. Furthermore, compounds 9a, 9e, 9 k and 12b exhibited favorable physicochemical properties among these compounds.

Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects.

AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

Circadian Regulation of Apolipoproteins in the Brain: Implications in Lipid Metabolism and Disease.

The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm disruption is an important risk factor for many diseases including neurodegenerative illnesses. The central and peripheral oscillators' circadian clock network controls the circadian rhythm in mammals. The clock genes govern the central clock in the suprachiasmatic nucleus (SCN) of the brain. One function of the circadian clock is regulating lipid metabolism. However, investigations of the circadian regulation of lipid metabolism-associated apolipoprotein genes in the brain are lacking. This review summarizes the rhythmic expression of clock genes and lipid metabolism-associated apolipoprotein genes within the SCN in Mus musculus. Nine of the twenty apolipoprotein genes identified from searching the published database (SCNseq and CircaDB) are highly expressed in the SCN. Most apolipoprotein genes (ApoE, ApoC1, apoA1, ApoH, ApoM, and Cln) show rhythmic expression in the brain in mice and thus might be regulated by the master clock. Therefore, this review summarizes studies on lipid-associated apolipoprotein genes in the SCN and other brain locations, to understand how apolipoproteins associated with perturbed cerebral lipid metabolism cause multiple brain diseases and disorders. This review describes recent advancements in research, explores current questions, and identifies directions for future research.