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Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.Age-associated disease: Possible metabolic therapyBoosting levels of a byproduct of fatty acid breakdown may help alleviate the symptoms of age-associated health conditions. When the body is low on glucose, it breaks down fatty acids for energy, generating byproduct metabolites called ketones. The ketone β-hydroxybutyrate (β-HB) regulates cellular signaling and gene and protein expression. There are indications that ketogenic diets or ketone administration, which increase β-BH may prevent ageing-associated progression of illnesses like cardiovascular and neurodegenerative diseases and cancer. Young-min Han and co-workers at Georgia State University in Atlanta, USA, reviewed current understanding of β-BH and its molecular targets. β-BH is a potent metabolite small enough to filter through cell membranes and circulate throughout the body, including the brain, influencing signaling pathways. Further investigations into associated molecular mechanisms will verify the metabolite’s potential as a therapeutic agent.

Purpose of this study was to compare the complication rates between reverse-tapered and nontapered peripherally inserted central catheters (PICCs). In total, 407 patients who had an inpatient clinic-based PICC insertion between September 2019 and November 2019 were retrospectively analyzed. Seven PICC types were used (4 reverse tapered: 4-Fr single-lumen (n = 75), 5-Fr single-lumen (n = 78), 5-Fr double-lumen (n = 62), and 6-Fr triple-lumen (n = 61); 3 nontapered: 4-Fr single-lumen (n = 73), 5-Fr double-lumen (n = 30), and 6-Fr triple-lumen (n = 23)). Complications such as periprocedural bleeding, delayed bleeding, inadvertent removal, catheter obstruction by thrombosis, infection, and leakage were investigated. The overall complication rate was 27.1%. The complication rate was significantly higher for nontapered PICCs than reverse-tapered PICCs (50.0% vs 16.7%, P < 0.001). The overall periprocedural bleeding rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (27.0% vs 6.2%, P <0.001). The overall inadvertent removal rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (15.1% vs 3.3%, P < 0.001). There were no other significant differences in complication rates. Nontapered PICCs were associated with higher rates of periprocedural bleeding and inadvertent removal than reverse-tapered PICCs.

Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases.

In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 ( Stk11 ) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor ( Scf ) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1 T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11 -soluble-Scf axis as a potential cause of DC deficiency syndromes. In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.

Objectives: Based on the idea that the neovessels and nerves are a possible cause of pain, transcatheter arterial embolization (TAE) has been reported as a novel adjunctive treatment with good outcomes. Purpose of this was to examine the short-term outcomes of TAE including 1-day follow-up results in patients with chronic shoulder pain using patient-reported outcome measures.Study Design: Prospective study.Methods: TAE was performed with a suspension of imipenem/cilastatin sodium in contrast agent. Subjects were assessed before, 1 day after, and 1 month after the procedure using the visual analogue scale (VAS, 0–10), shoulder pain and disability index (SPADI, 0–100), and Constant–Murley score (CMS, 0–100).Results: A total of 10 patients were enrolled. All procedures were technically successful with the radial artery approach. Abnormal neovessels with angiographic blushes were identified in all cases, with a mean of 3.3 abnormal neovessels per patient (range, 2–4) and a total of 41 arteries embolized, averaging 4.1 vessels per patient (range, 3–5). Baseline VAS, SPADI, and CMS were 3.5, 50.0, and 47.4, respectively. The 1-day follow-up (VAS, 2.0; SPADI, 26.3; CMS, 68.1; p≤0.001 compared to baseline) and 1-month follow-up (VAS, 1.7; SPADI, 24.3; CMS, 72.8; p≤0.002 compared to baseline) demonstrated significant improvements. The 1-day and 1-month follow-up results were not significantly different.Conclusions: Substantial pain relief and functional scales improvement were observed both immediately and 1 month after TAE in chronic intractable shoulder pain. TAE may be an effective alternative treatment for patients with shoulder pain who do not respond to conservative or surgical treatment.Trial Registration: Korean Registry of Clinical Trials: KCT0004720

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of −18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.

We present the use of iOrganoAssay (images of Organoid Assay) to connect microscopy images with organoid assessment assays such as live–dead, immunocytochemistry, and drug treatment assays. The iOrganoAssay consists of an R script-based application (App) interface and datasets encompassing (1) microscopy images, (2) segmentation results, (3) morphometric data, (4) a metadata file, and (5) a validation dataset. The microscopy image collection includes 234 large-area images of intestinal organoids cultured in Matrigel dome region ( 3 mm), acquired using an automated stage-equipped microscopy system. Upon treatment with dextran sulfate sodium (DSS), microscopy images of morphological changes in intestinal organoids were captured and quantified. Image segmentation was performed to extract organoid morphological data, including area, perimeter, and circularity. These metrics were plotted to visualize daily variations, enabling systematic tracking of drug-induced morphological changes over time. Statistical comparisons were also provided using violin plots. To evaluate segmentation quality, we established a validation dataset of 28 manually annotated organoids (14 control, 14 DSS-treated) and calculated Dice scores, accuracy (Acc), segmentation error (SegErr), and centroid error (CenErr). This integrated dataset—covering organoid images, segmentation outputs, morphometric data, and validation metrics—provides a resource for organoid image-based studies in morphological monitoring and segmentation validation. Dataset: The dataset described is publicly available in Zenodo and GitHub. Dataset License: CC0

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Propolis, a natural resinous substance obtained from a variety of buds and plants, has been reported to possess various biological functions. Several recent studies have demonstrated the inhibitory effects of propolis on the growth of Helicobacter pylori (H. pylori) in vitro; however, current research efforts on Korean propolis (KP) remain insufficient especially in vivo. Our study aims to investigate the anti-inflammatory effect and molecular mechanism of KP on mouse gastric mucosa during H. pylori infection. We examined an in vivo H. pylori-induced gastric mucosal injury mice model. We found that KP inhibited the growth of H. pylori and attenuated the expression of H. pylori virulence factors such as cytotoxin-associated gene A, encoding urease A subunit, surface antigen gene and neutrophil-activating protein A. Moreover, KP reduced both gross lesions and pathological scores in H. pylori-challenged mice. In addition, KP markedly restrained the production of pro-inflammatory cytokines and nitric oxide levels compared with an untreated H. pylori-infected group. In particular, we found that KP repressed the phosphorylation of IκBα and NF-κB p65 subunit, and subsequently suppressed their downstream target genes. Taken together, these findings demonstrate the beneficial effects of KP on inflammation through the inhibition of NF-κB signaling as well as inhibition of H. pylori growth in a mouse model infected with H. pylori. This suggests the potential application of KP as a natural supplement for patient’s suffering from gastric mucosal injury caused by H. pylori infection.

Cinnamomum cassia (cassia) is a tropical aromatic evergreen tree of the Lauraceae family well known for its fragrance and spicy flavor and widely used in Asian traditional medicine. It has recently garnered attention for its diverse potential health benefits, including anti-inflammatory, anti-cancer, and anti-diabetic properties. However, the gastroprotective effect of C. cassia, particularly against ethanol-induced gastric damage, remains unclear. We investigated the potential gastroprotective property of C. cassia and the underlying mechanisms of action in a rat model of ethanol-induced gastric injury. To assess its effectiveness, rats were fed C. cassia for a 14-day period prior to inducing gastric damage by oral administration of ethanol. Our results indicated that pre-treatment with C. cassia mitigated ethanol-induced gastric mucosal lesions and bleeding. Reduced gastric acid secretion and expression of acid secretion-linked receptors were also observed. Additionally, pretreatment with C. cassia led to decreased levels of inflammatory factors, including TNF-α, p-p65, and IκBα. Notably, C. cassia upregulated the expressions of HO1 and HSP90, with particular emphasis on the enhanced expression of PAS and MUC, the crucial gastric mucosa defense molecules. These findings suggest that C. cassia has protective effects on the gastric mucosa and can effectively reduce oxidative stress and inflammation.