Biotin is a covalently attached enzyme cofactor required for intermediary metabolism in all three domains of life. Several important human pathogens (e.g. Mycobacterium tuberculosis) require biotin synthesis for pathogenesis. Humans lack a biotin synthetic pathway hence bacterial biotin synthesis is a prime target for new therapeutic agents. The biotin synthetic pathway is readily divided into early and late segments. Although pimelate, a 7-carbon α,ω-dicarboxylic acid that contributes 7 of the 10 biotin carbons atoms, was long known to be a biotin precursor, its biosynthetic pathway was a mystery until the Escherichia colipathway was discovered in 2010. Since then, diverse bacteria encode evolutionarily distinct enzymes that replace enzymes in the E. coli pathway. Two new bacterial pimelate synthesis pathways have been elucidated. In contrast to the early pathway, the late pathway, assembly of the fused rings of the cofactor, was long thought settled. However, a new enzyme that bypasses a canonical enzyme was recently discovered as well as homologs of another canonical enzyme that functions in synthesis of another protein-bound coenzyme, lipoic acid. Most bacteria tightly regulate transcription of the biotin synthetic genes in a biotin-responsive manner. The bifunctional biotin ligases which catalyze attachment of biotin to its cognate enzymes and repress biotin gene transcription are best understood regulatory system.

Stress profoundly impacts various aspects of both physical and psychological well-being. Our previous study demonstrated that venlafaxine (Vlx) and synbiotic (Syn) treatment attenuated learned fear-like behavior and recognition memory impairment in immobilized-stressed rats. In this study, we further investigated the physical, behavior, and cellular mechanisms underlying the effects of Syn and/or Vlx treatment on brain and intestinal functions in stressed rats. Adult male Wistar rats, aged 8 weeks old were subjected to 14 days of immobilization stress showed a decrease in body weight gain and food intake as well as an increase in water consumption, urinary corticosterone levels, and adrenal gland weight. Supplementation of Syn and/or Vlx in stressed rats resulted in mitigation of weight loss, restoration of normal food and fluid intake, and normalization of corticosterone levels. Behavioral analysis showed that treatment with Syn and/or Vlx enhanced depressive-like behaviors and improved spatial learning-memory impairment in stressed rats. Hippocampal dentate gyrus showed stress-induced neuronal cell death, which was attenuated by Syn and/or Vlx treatment. Stress-induced ileum inflammation and increased intestinal permeability were both effectively reduced by the supplementation of Syn. In addition, Syn and Vlx partly contributed to affecting the expression of the glial cell-derived neurotrophic factor in the hippocampus and intestines of stressed rats, suggesting particularly protective effects on both the gut barrier and the brain. This study highlights the intricate interplay between stress physiological responses in the brain and gut. Syn intervention alleviate stress-induced neuronal cell death and modulate depression- and memory impairment-like behaviors, and improve stress-induced gut barrier dysfunction which were similar to those of Vlx. These findings enhance our understanding of stress-related health conditions and suggest the synbiotic intervention may be a promising approach to ameliorate deleterious effects of stress on the gut-brain axis.

Aerobic organisms continuously generate internal superoxide and hydrogen peroxide, which can damage enzymes and impair growth. To avoid this problem cells maintain high levels of superoxide dismutases, catalases, and peroxidases. Surprisingly, we do not know the primary sources of these reactive oxygen species (ROS) in living cells. However, in vitro studies have shown that flavoenzymes can inadvertently transfer electrons to oxygen. Therefore, it seems plausible that substantial ROS may be generated when large metabolic fluxes flow through flavoproteins. Such a situation may arise during the catabolism of fatty acids. Acyl-CoA dehydrogenase (FadE) is a flavoprotein involved in each turn of the beta-oxidation cycle. In the present study the catabolism of dodecanoic acid specifically impaired the growth of strains that lack enzymes to scavenge hydrogen peroxide. The defect was absent from fadE mutants. Direct measurements confirmed that the beta-oxidation pathway amplified the rate of intracellular hydrogen peroxide formation. Scavenging-proficient cells did not display the FadE-dependent growth defect. Those cells also did not induce the peroxide stress response during dodecanoate catabolism, indicating that the basal defenses are sufficient to cope with moderately elevated peroxide formation. In vitro work still is needed to test whether the ROS evolve specifically from the FadE flavin site and to determine whether superoxide as well as peroxide is released. At present such experiments are challenging because the natural redox partner of FadE has not been identified. This study supports the hypothesis that the degree of internal ROS production can depend upon the type of active metabolism inside cells.

Inflammatory lung injury from a fever or sepsis can impair pulmonary function. While anti-inflammatory agents are commonly used, side effects could occur. Andrographolide (AGP) exhibits potent anti-inflammatory activity, making it a promising alternative treatment. Nevertheless, AGP has low solubility and absorption, and drug-delivery liposomes (Lip) improve site-specific targeting and controlled release. This study aimed to develop and evaluate the physicochemical properties, safety, and therapeutic efficacy of AGP-Lip through both in vitro and in vivo studies. The characteristics of AGP-Lip included an average size of 139.7 ± 2.00 nm, a polydispersity index of 0.16 ± 0.02, and a zeta potential of 34.5 ± 0.80 mV, with strong mucoadhesive properties. AGP-Lip exhibited no cytotoxicity in IMR-90 lung fibroblast cells while effectively reducing inflammation by decreasing nitric oxide production in RAW 264.7 murine macrophage cells exposed to lipopolysaccharide. In the animal study, adult male C57BL/6 mice received a single intraperitoneal dose of 100 μg/kg of tumor necrosis factor-α (TNF-α)-induced acute pulmonary systemic inflammation. Mice were randomly assigned to six groups (9 mice per group): control, PBS (negative control), Blank-Lip, AGP-Lip, dexamethasone (POS), and AGP-Lip+POS. All treatments (20 to 25 μL with AGP-Lip, AGP-Lip, and/or POS at 1 mg/kg) were administered via nasal delivery daily for 7 days. The vehicle-treated mice exhibited signs of sickness and systemic inflammation, including reduced body weight gain, hyperlocomotion, decreased exploratory activity, elevated total white blood cell counts, serum IL-6 and TNF-α, and upregulation of targeted mRNA expression of lung inflammatory markers. Histological analysis showed an increase in inflammatory scores, and secretory cells were also observed in the vehicle-treated group. AGP-Lip improved body weight and stress-related behaviors, restored mRNA expression levels of IFN-γ, IL-1α/β, IL-6, IL-10, NF-κBp65, and TNF-α, and alleviated mucus secretion in lung histological analysis. Notably, AGP-Lip effectively mitigated the detrimental effects compared to POS alone, showing significant differences in serum IL-6, lung inflammation-related gene expression (i.e., IFN-γ, IL-1α, NF-κBp50, and VEGF), and PAS staining relative to the combined treatment. These findings suggest that AGP-Lip could serve as a potential alternative treatment for acute respiratory infections, warranting further consideration for long-term administration and clinical trials.

Chronic stress induces mood disturbances, disrupts gut barrier function, and promotes low-grade systemic inflammation. This study assessed the therapeutic effects of atomoxetine (ATX), escitalopram (ESC), cannabidiol (CBD), and CBD-loaded lipid nanoparticles (CBD/LNP) in male rats exposed to repeated restraint stress. Stressed rats exhibited a 2.03-fold increase in interleukin-6 and a 1.89-fold increase in TNF-α, a 1.20-fold decrease in brain-derived neurotrophic factor, a 1.36-fold decrease in osteocalcin, accompanied by alterations in gut metabolites, particularly short-chain fatty acids (SCFAs; from 155.3 to 94.83 μmol/L), polyamines (from 273.6 to 192.4 μmol/L), and bile acids (BAs; from 21.19 to 14.53 μmol/L), compared with the control group. Protein analysis revealed gut barrier disruption and microglial/macrophage activation, accompanied by reduced synaptic plasticity. ATX improved gut permeability and reduced glial activation but did not restore osteocalcin. ESC provided neuroimmune benefits with limited and BA gut restoration and modulated the gut–brain axis and improved anxiety-like behaviors, partly by altering gut microbiota and metabolites. CBD and CBD/LNP treatment restored intestinal barrier function, as indicated by intestinal permeability in the range of 1.15–1.61-fold. These treatments also normalized bile acids (1.0–1.38-fold) and osteocalcin (1.0–1.28-fold) and significantly reduced glial activation (0.63–1.12-fold) as opposed to the non-treated stressed group. All treatments were found to be effective in correcting SCFA and polyamine levels. Histological analysis confirmed that CBD/LNP, ATX, and ESC ameliorated tissue alterations. These findings highlight CBD/LNP as a promising intervention for stress-induced gut–brain–bone axis disruption, supporting its potential as a therapeutic alternative through modulation of microbiota-driven gut–brain communication in stress-associated disorders.