Inflammatory bowel disease (IBD) involves chronic inflammation, loss of epithelial integrity, and gastrointestinal microbiota dysbiosis, resulting in the development of a colon cancer known as colitis-associated colorectal cancer (CAC). In this study, we evaluated the effects of corylin in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The results showed corylin could improved the survival rate and colon length, maintained body weight, and ameliorated the inflammatory response in the colon. Then, we further identified the possible antitumor effects after 30-day treatment of corylin on an azoxymethane (AOM)/DSS-induced CAC mouse model. Biomarkers associated with inflammation, the colon tissue barrier, macrophage polarization (CD11c, CCR7, CD163, and CD206), and microbiota dysbiosis were monitored in the AOM/DSS group versus corylin groups. Corylin downregulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) mRNA expression and inflammatory signaling-associated markers (TLR4, MyD88, AP-1, CD11b, and F4/80). In addition, a colon barrier experiment revealed that epithelial cell proliferation of the mucus layer (Lgr5, Cyclin D1, and Olfm4) was downregulated and tight junction proteins (claudin-1 and ZO-1) were upregulated. Furthermore, the Firmicutes/Bacteroidetes ratio changed with corylin intervention, and the microbial diversity and community richness of the AOM/DSS mice were improved by corylin. The comparative analysis of gut microbiota revealed that Bacteroidetes, Patescibacteria, Candidatus Saccharimonas, Erysipelatoclostridium, and Enterorhabdus were significantly increased but Firmicutes, Turicibacter, Romboutsia, and Blautia decreased after corylin treatment. Altogether, corylin administration showed cancer-ameliorating effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Therefore, corylin could be a novel, potential health-protective, natural agent against CAC.

While psoriasis is known as a T cell- and dendritic cell-driven skin inflammation disease, macrophages are also reported to play some roles in its development. However, the signaling pathway of activated macrophages contributing to psoriasis is not entirely understood. Thus, we aimed to explore the possible mechanisms of how macrophages initiate and sustain psoriasis. The differentiated THP1 cells, stimulated by imiquimod (IMQ), were utilized as the activated macrophage model. IMQ was also employed to produce psoriasis-like lesions in mice. A transcriptomic assay of macrophages revealed that the expressions of pro-inflammatory mediators and GDAP1L1 were largely increased after an IMQ intervention. The depletion of GDAP1L1 by short hairpin (sh)RNA could inhibit cytokine release by macrophages. GDAP1L1 modulated cytokine production by activating the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways. Besides GDAP1L1, another mitochondrial fission factor, Drp1, translocated from the cytosol to mitochondria after IMQ stimulation, followed by the mitochondrial fragmentation according to the immunofluorescence imaging. Clodronate liposomes were injected into the mice to deplete native macrophages for examining the latter’s capacity on IMQ-induced inflammation. The THP1 cells, with or without GDAP1L1 silencing, were then transplanted into the mice to monitor the deposition of macrophages. We found a significant THP1 accumulation in the skin and lymph nodes. The silencing of GDAP1L1 in IMQ-treated animals reduced the psoriasiform severity score from 8 to 2. After depleting GDAP1L1, the THP1 recruitment in the lymph nodes was decreased by 3-fold. The skin histology showed that the GDAP1L1-mediated macrophage activation induced neutrophil chemotaxis and keratinocyte hyperproliferation. Thus, mitochondrial fission can be a target for fighting against psoriatic inflammation.

Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of ob/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in ob/ob mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.

Aging kidneys are characterized by an increased vulnerability to glomerulosclerosis and a measurable decline in renal function. Evidence suggests that renal and systemic klotho and sirtuin 1 (SIRT1) deficiencies worsen kidney damage induced by exogenous stresses. The aim of this study was to explore whether resveratrol would attenuate concanavalin A (Con A)-induced renal oxidative stress and advanced glomerulosclerosis in aged mice. Aged male C57BL/6 mice were treated orally with resveratrol (30 mg/kg) seven times (12 h intervals) prior to the administration of a single tail-vein injection of Con A (20 mg/kg). The plasma and urinary levels of kidney damage markers were evaluated. The kidney histopathology, renal parameters, and oxidative stress levels were measured. Furthermore, klotho was downregulated in mouse kidney mesangial cells that were pretreated with 25 µM resveratrol followed by 20 µg/mL Con A. The urinary albumin/creatinine ratio, blood urea nitrogen, kidney mesangial matrix expansion, tubulointerstitial fibrosis, and renal levels of α-smooth muscle actin, transforming growth factor beta, fibronectin, procollagen III propeptide, and collagen type I significantly increased in Con A-treated aged mice. Aged mice kidneys also showed markedly increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) and reactive oxygen species (ROS), with reduced superoxide dismutase activity and levels of glutathione, klotho, and SIRT1 after Con A challenge. Furthermore, in kidney mesangial cells, klotho silencing abolished the effects of resveratrol on the Con A-mediated elevation of the indices of oxidative stress and the expression of glomerulosclerosis-related factors. These findings suggest that resveratrol protects against Con A-induced advanced glomerulosclerosis in aged mice, ameliorating renal oxidative stress via the SIRT1-mediated klotho expression.

Obesity is associated with alterations in lipid metabolism and gut microbiota dysbiosis. This study investigated the effects of puerarin, a bioactive isoflavone, on lipid metabolism disorders and gut microbiota in high-fat diet (HFD)-induced obese mice. Supplementation with puerarin reduced plasma alanine aminotransferase, liver triglyceride, liver free fatty acid (FFA), and improved gut microbiota dysbiosis in obese mice. Puerarin’s beneficial metabolic effects were attenuated when farnesoid X receptor (FXR) was antagonized, suggesting FXR-mediated mechanisms. In hepatocytes, puerarin ameliorated high FFA-induced sterol regulatory element-binding protein (SREBP) 1 signaling, inflammation, and mitochondrial dysfunction in an FXR-dependent manner. In obese mice, puerarin reduced liver damage, regulated hepatic lipogenesis, decreased inflammation, improved mitochondrial function, and modulated mitophagy and ubiquitin-proteasome pathways, but was less effective in FXR knockout mice. Puerarin upregulated hepatic expression of FXR, bile salt export pump (BSEP), and downregulated cytochrome P450 7A1 (CYP7A1) and sodium taurocholate transporter (NTCP), indicating modulation of bile acid synthesis and transport. Puerarin also restored gut microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of Clostridium celatum and Akkermansia muciniphila. This study demonstrates that puerarin effectively ameliorates metabolic disturbances and gut microbiota dysbiosis in obese mice, predominantly through FXR-dependent pathways. These findings underscore puerarin’s potential as a therapeutic agent for managing obesity and enhancing gut health, highlighting its dual role in improving metabolic functions and modulating microbial communities.

Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium–aluminum–garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional ablative CO₂ and fully ablative erbium (Er):YAG lasers were also used for comparison. In the Franz diffusion cell study, pig or mouse skin was treated with a laser before exposure to palmitoyl tripeptide (PT)-1, PT-38, and copper tripeptide (CT)-1 at a concentration of 150 μM. Psoriasiform, atopic dermatitis (AD)-like, and photoaged skins were also developed as permeation barriers. The non-ablative laser elicited the ultrastructural disruption of the stratum corneum and epidermal vacuolation. All laser modalities significantly increased the skin permeation of peptides in vitro. The non-ablative laser chiefly enhanced peptide delivery to the receptor compartment, whereas the ablative laser mainly increased the intracutaneous peptide deposition. The picosecond- and nanosecond-domain Nd:YAG lasers elevated the amount of PT-1 in the receptor up to 40- and 22-fold compared with untreated skin, respectively. Laser treatment promoted peptide delivery in barrier-deficient and inflamed skins, although this enhancement effect was less than that observed in healthy skin. Fluorescence microscopy indicated the capability of the non-ablative laser to deliver peptides to deeper skin strata. The ablative laser confined the peptide distribution in the epidermis. Confocal microscopy showed that peptides penetrated the skin along the microdots created by the fractional Nd:YAG and CO₂ lasers. The skin barrier function determined by transepidermal water loss suggested quick recovery when using a nanosecond-domain laser (within 4 h). A longer period was needed for the skin treated with the fully ablative Er:YAG laser (76−84 h). Nanosecond non-ablative laser-facilitated peptide delivery may become an efficient and safe approach for cosmeceutical applications.