Search

Abstract Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single‐cell RNA sequencing (scRNA‐seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor‐associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF‐1α destabilization, leading to reduction in M2‐like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN‐response genes. Expression of these genes contributed to anti‐tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT‐initiated TAM‐specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway and plays a crucial role in the maintenance of the NAD+ pool during inflammation. Considering that macrophages are essential for tissue homeostasis and inflammation, we sought to examine the functional impact of NAMPT in inflammatory macrophages, particularly in the context of inflammatory bowel disease (IBD). In this study, we show that mice with NAMPT deletion within the myeloid compartment (Namptf/fLysMCre+/-, Nampt mKO) have more pronounced colitis with lower survival rates, as well as numerous uncleared apoptotic corpses within the mucosal layer. Nampt-deficient macrophages exhibit reduced phagocytic activity due to insufficient NAD+ abundance, which is required to produce NADPH for the oxidative burst. Nicotinamide mononucleotide (NMN) treatment rescues NADPH levels in Nampt mKO macrophages and sustains superoxide generation via NADPH oxidase. Consequently, Nampt mKO mice fail to clear dead cells during tissue repair, leading to substantially prolonged chronic colitis. Moreover, systemic administration of NMN, to supply NAD+, effectively suppresses the disease severity of DSS-induced colitis. Collectively, our findings suggest that activation of the NAMPT-dependent NAD+ biosynthetic pathway, via NMN administration, is a potential therapeutic strategy for managing inflammatory diseases.

Objective: We aimed to develop an optimal protocol for failed mechanical thrombectomy (MT) in cases of emergent large vessel occlusion (ELVO) with intracranial atherosclerosis (ICAS). Methods: A total of 117 patients without underlying heart disease who were not taking antiplatelet drugs had early reocclusion during MT for ELVO due to ICAS. They were divided into the following 3 groups according to rescue treatment methods: 1) Combined intravenous (IV) + intra-arterial (IA) tirofiban group (n = 48), emergent percutaneous transluminal angioplasty (PTA) and intracranial stenting (ICS) followed by IA injection of tirofiban and a continuous IV tirofiban infusion for 8 h; 2) IA tirofiban group (n = 33), only IA 0.5–1.0 mg tirofiban infusion for 5 min regardless of PTA or ICS; and 3) no tirofiban group (n = 36), no tirofiban injection regardless of PTA or ICS. Results: ICS was more frequently performed in the combined IV + IA tirofiban group than in the IA tirofiban group (100% vs 46%, p

Background: Ginseng is believed to have antitumor activity. Autophagy is largely a prosurvival cellular process that is activated in response to cellular stressors, including cytotoxic chemotherapy; therefore, agents that inhibit autophagy can be used as chemosensitizers in cancer treatment. We examined the ability of Korean Red Ginseng extract (RGE) to prevent autophagic flux and to make hepatocellular carcinoma (HCC) cells become more sensitive to doxorubicin. Methods: The cytotoxic effects of total RGE or its saponin fraction (RGS) on HCC cells were examined by the lactate dehydrogenase assay in a dose- or time-dependent manner. The effect of RGE or RGS on autophagy was measured by analyzing microtubule-associated protein 1A/1B-light chain (LC)3-II expression and LC3 puncta formation in HCC cells. Late-stage autophagy suppression was tested using tandem-labeled green fluorescent protein (GFP)–monomeric red fluorescent protein (mRFP)–LC3. Results: RGE markedly increased the amount of LC3-II, but green and red puncta in tandem-labeled GFP–mRFP–LC3 remained colocalized over time, indicating that RGE inhibited autophagy at a late stage. Suppression of autophagy through knockdown of key ATG genes increased doxorubicin-induced cell death, suggesting that autophagy induced by doxorubicin has a protective function in HCC. Finally, RGE and RGS markedly sensitized HCC cells, (but not normal liver cells), to doxorubicin-induced cell death. Conclusion: Our data suggest that inhibition of late-stage autophagic flux by RGE is important for its potentiation of doxorubicin-induced cancer cell death. Therapy combining RGE with doxorubicin could serve as an effective strategy in the treatment of HCC. Keywords: autophagic flux, cell death, ginseng extract

Abstract Sandwich panels comprising prefabricated ultra-high performance concrete (UHPC) composites can be used as eco-friendly and multi-functional structural elements. To improve the structural and thermal performance of composite sandwich panels, combinations of UHPC and expanded polystyrene (EPS) beads were investigated. High-performance expanded polystyrene concrete (HPEPC) was tested with various EPS bulk ratios to determine the suitability of the mechanical properties for use as a high-strength lightweight aggregate concrete. As a core material in composite sandwich panels, the mechanical properties of HPEPC were compared with those of EPS mortar. The compressive strength of HPEPC is approximately eight times greater than that of EPS mortar, and the thermal conductivity of approximately a quarter that of EPS mortar. The structural behavior of composite sandwich panels was empirically analyzed using different combinations of cores, face sheets, and adhesive materials. In the flatwise and edgewise compression tests, sandwich panels with HPEPC cores had high peak strengths, irrespective of the type of face sheets, as opposed to the specimens with EPS mortar cores. In the four-point bending tests, the sandwich panels with HPEPC cores, or reinforced UHPC face sheets combined with adhesive mortar, exhibited higher peak strengths than the other specimens, and failed in a stable manner, without delamination.

Objectives: Recently, necroptosis has attracted increasing attention in arthritis research; however, it remains unclear whether its regulation is involved in osteoarthritis (OA) pathogenesis. Since receptor-interacting protein kinase-3 (RIP3) plays a pivotal role in necroptosis and its dysregulation is involved in various pathological processes, we investigated the role of the RIP3 axis in OA pathogenesis.Methods: Experimental OA was induced in wild-type or Rip3 knockout mice by surgery to destabilise the medial meniscus (DMM) or the intra-articular injection of adenovirus carrying a target gene (Ad-Rip3 and Ad-Trim24 shRNA). RIP3 expression was examined in OA cartilage from human patients; Trim24, a negative regulator of RIP3, was identified by microarray and in silico analysis. Connectivity map (CMap) and in silico binding approaches were used to identify RIP3 inhibitors and to examine their direct regulation of RIP3 activation in OA pathogenesis.Results: RIP3 expression was markedly higher in damaged cartilage from patients with OA than in undamaged cartilage. In the mouse model, adenoviral RIP3 overexpression accelerated cartilage disruption, whereas Rip3 depletion reduced DMM-induced OA pathogenesis. Additionally, TRIM24 knockdown upregulated RIP3 expression; its downregulation promoted OA pathogenesis in knee joint tissues. The CMap approach and in silico binding assay identified AZ-628 as a potent RIP3 inhibitor and demonstrated that it abolished RIP3-mediated OA pathogenesis by inhibiting RIP3 kinase activity.Conclusions: TRIM24-RIP3 axis perturbation promotes OA chronicity by activating RIP3 kinase, suggesting that the therapeutic manipulation of this pathway could provide new avenues for treating OA. [ABSTRACT FROM AUTHOR]