Exploring the therapeutic potential of a nano micelle containing a carbon monoxide-releasing molecule for metabolic-associated fatty liver disease by modulating hypoxia-inducible factor-1α.

Metabolic-associated fatty liver disease (MAFLD) encompasses a spectrum of chronic liver diseases, including steatohepatitis, cirrhosis, and liver cancer. Despite the increasing prevalence and severity of MAFLD, no approved pharmacological interventions are currently available. Hypoxia-inducible factor-1α (HIF-1α) has emerged as a crucial early mediator in the pathogenesis of MAFLD. Previously, we demonstrated the potent anti-inflammatory properties of the nano-designed carbon monoxide (CO) donor, styrene maleic acid copolymer (SMA) encapsulating CO-releasing molecule (SMA/CORM2), which effectively suppressed HIF-1α in various inflammatory disorders. Here, we investigated the therapeutic potential of SMA/CORM2 in a mouse model of MAFLD induced by a high-fat methionine- and choline-deficient (HF-MCD) diet. Following 4 weeks of HF-MCD diet consumption, we observed pronounced hepatic lipid accumulation accompanied by disrupted lipid metabolism, polarization of macrophages towards the pro-inflammatory M1 phenotype, activation of the NLRP3 inflammasome, and upregulation of the TGF-ß fibrosis signaling pathway. Notably, the early and upstream event driving these pathological changes was the upregulation of HIF-1α. Treatment with SMA/CORM2 (10 mg/kg, three times per week) led to a significant increase in CO levels in both the circulation and liver, resulting in remarkable suppression of HIF-1α expression even before the onset of apparent pathological changes induced by the HF-MCD diet. Consequently, SMA/CORM2 administration exerted a significantly protective and therapeutic effect on MAFLD. In vitro studies using hepatocytes treated with high concentrations of fatty acids further supported these findings, as knockdown of HIF-1α using short hairpin RNA (shRNA) elicited similar effects to SMA/CORM2 treatment. Collectively, our results highlight the therapeutic potential of SMA/CORM2 in the management of MAFLD through suppression of HIF-1α. We anticipate that SMA/CORM2, with its ability to modulate HIF-1α expression, may hold promise for future applications in the treatment of MAFLD. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) is a crucial gaseous signaling molecule that plays a vital role in maintaining homeostasis and is a potential target for treating many inflammatory diseases. Developing drug delivery systems that can deliver CO stably and target specific tissues is of great interest. Our team previously developed a nano micellar CO donor, SMA/CORM2, which exhibits superior bioavailability to native CORM2 and shows therapeutic potential in many inflammatory disease models. In this study, we showed that SMA/CORM2, through controlled CO release, significantly ameliorated steatohepatitis and liver fibrosis induced by an HF-MCD diet by suppressing an HIF-1α mediated inflammatory cascade. These findings provide new insight into the anti-inflammatory function of CO and a promising approach for controlling metabolic-associated fatty liver disease.

Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner.

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.

Abatement of VOCs mixture of emerging concern by VUV-PCO process: From lab to pilot scale.

As a kind of emerging pollutant, volatile organic compounds (VOCs) are getting increasing attention due to their contribution to the formation of atmospheric haze and O3. Photocatalytic oxidation under vacuum ultraviolet photocatalytic oxidation (VUV-PCO) presents a promising method for VOCs degradation, but it is seldom studied for VOCs compound and the mechanism is still elusive. Herein, typical VOCs such as toluene and ethyl acetate were degraded separately or together in VUV system and in VUV-PCO system with the designed trifunctional catalyst Mn/TiO2/ZSM-5. Intermediates were recognized by PTR-TOF-MS. It is found that dual VOCs mixture outperformed single VOCs under both VUV process and VUV-PCO process. Possible degradation mechanisms were proposed. To explore the potential practicality of VUV-PCO technology, scale-up synthesis of Mn/TiO2/ZSM-5 on ceramic foams was successfully carried out and assembled into a homemade pilot-scale VUV-PCO equipment for the control of simulated VOCs complex (toluene, ethyl acetate, ethanol, and acetone). Pilot-scale catalytic testing with the monolithic catalysts achieved high removal efficiency (over 90 % efficiency after two cycles of regeneration) and confirmed the practical application possibility of VUV-PCO technology in multiple VOCs degradation. This work probes into the VUV-PCO technology applicability from lab scale to pilot scale and promotes the understanding of VUV and VUV-PCO in VOCs complex decomposition.

Role of vitamin D in ulcerative colitis: an update on basic research and therapeutic applications.

INTRODUCTION: Vitamin D deficiency is common in patients with ulcerative colitis (UC). Moreover, vitamin D supplementation seems to contribute to disease relief. Nevertheless, the exact etiological link between vitamin D deficiency and UC is far from clear, and an agreement has not been reached on the frequency and dosage of vitamin D supplementation required. AREAS COVERED: This review will outline the possible role of vitamin D in the pathogenesis of UC and summarize the current state of clinical research on vitamin D. Literature was searched on PUBMED, with 'Vitamin D,' 'Ulcerative colitis,' 'Vitamin D receptor,' and 'disease activity' as MeSH Terms. Relevant information is presented in figures or tables. EXPERT OPINION: The etiological relationship between vitamin D and the onset of UC is still being researched. More high-quality double-blind randomized clinical studies are needed to determine the efficacy of vitamin D supplementation in the treatment of UC, whether as the main treatment or as an adjuvant treatment. Importantly, determining the dosage and frequency of vitamin D supplementation should be the main research direction in the future, and regional factors should also be fully considered in this respect.

Evaluation of the antimicrobial effect of silver ion tubing on dental unit waterlines.

PURPOSE: To assess the antimicrobial effects of silver ion tubing (ST) on dental unit waterlines (DUWLs) and their sustainability over time. METHODS: Six dental chair units (DCUs) equipped with ST and four with common tubing (CT) were included in the study. Repeated flushing with phosphate-buffered saline (PBS) was conducted to dislodge biofilms. Then, genetic analysis of the PBS was performed. The tubing was also detached and scanned under a scanning electron microscope (SEM) to observe the adherent biofilm on the lumen walls. RESULTS: Low bacterial levels were noted in both the CT and ST groups, but biofilm attachment was only observed in the CT group. CLINICAL SIGNIFICANCE: Silver ion tubing exhibited high antibacterial activity by reducing the colonization of pathogens in the dental unit water inhibiting biofilm formation, and showing promise as an efficient infection control method for dental unit waterlines.

Vitamin D deficiency exacerbates hepatic oxidative stress and inflammation during acetaminophen-induced acute liver injury in mice.

Several experiments confirmed that vitamin D3 protected against acetaminophen (APAP)-induced acute liver injury (ALI). This research aimed to evaluate the influence of vitamin D deficiency (VDD) on APAP-induced ALI. In VDD and VDD + APAP groups, mice were fed with VDD diet. In APAP and VDD + APAP groups, mice were intraperitoneally injected with a sublethal dose of APAP (150 mg/kg). A sublethal dose of APAP caused a slight elevation of ALT and AST. Interestingly, APAP-induced elevation of ALT and AST was aggravated in VDD-fed mice. APAP-induced hepatic necrosis was exacerbated in VDD-fed mice. In addition, APAP-induced hepatocyte death, measured using TUNEL assay, was exacerbated in VDD-fed mice. Additional experiment showed that APAP-induced hepatic GSH depletion and lipid peroxidation were exacerbated in VDD-fed mice. Moreover, APAP-induced upregulation of antioxidant genes, such as hepatic heme oxygenase-1 (Ho-1), glutathione peroxidase (Gshpx), superoxide dismutase 1 (Sod1) and catalase enzymes (Cat), was aggravated in VDD-fed mice. Although a sublethal dose of APAP did not cause hepatic inflammation, hepatic proinflammatory cytokines and chemokines, such as Tnf-α, Kc, Mcp-1 and Mip2, were upregulated in VDD-fed mice treated with APAP. These results provide experimental data that VDD exacerbates hepatic oxidative stress and inflammation during APAP-induced ALI.

Comparative analysis of the diagnostic value of several methods for the diagnosis of patent foramen ovale.

The aim of this research was to compare the sensitivity and positive predictive value of contrast transcranial Doppler (c-TCD), contrast transthoracic echocardiography (c-TTE), and contrast transesophageal echocardiography (c-TEE), to determine the best method for diagnosing patent foramen ovale (PFO) and to provide a reference for the further improvement of clinical practice. We investigated 161 patients who suffered from migraines, cryptogenic stroke, TIA, and cerebral infarction of unknown cause. All patients underwent transcatheter examination, and the results of the right heart catheterization (RHC) were considered the gold standard for PFO diagnosis. The present study revealed that c-TTE with the Valsalva maneuver had a higher sensitivity in detecting PFO related right-to-left shunt (PFO-RLS), c-TCD performed similarly to c-TEE but maybe produce more false positives. Moreover, when we observed color shunt from the slit-like channel between the septum primum and the septum secundum on TEE, the positive predictive value was the highest. Patients with suspected PFO should be examined with c-TTE and c-TEE for confirmation. When there were a large number of bubbles in the left heart, especially in the presence of color shunt, the positive predictive value was the highest. The positive results of c-TCD only point out the presence of right-to-left shunt and cannot exclude extracardiac shunt, so c-TCD should not be used as a screen for PFO, additional measures such as c-TTE and c-TEE should be used.

Mechanistic insights into toluene degradation under VUV irradiation coupled with photocatalytic oxidation.

Volatile organic compounds (VOCs) exists ubiquitously in chemical industries and were regarded as major contributors to air pollution, which should be strictly regulated. Vacuum ultraviolet irradiation coupled with photocatalytic oxidation (VUV-PCO) has been considered as an efficient approach to VOCs removal due to high-energy photons which could break down VOCs directly and be absorbed by photocatalysts to generate free radicals for further oxidation. However, the photochemical transformation mechanisms of VOCs have not been fully revealed. Herein, we systematically analyzed the intermediates using proton-transfer-reaction mass spectrometer (PTR-MS) to explore the transformation mechanisms of toluene degradation in VUV and VUV-PCO processes. VUV-PCO process displayed superior toluene degradation efficiency (50 %) and mineralization efficiency (65 %) compared with single VUV photolysis (35 %) and UV photocatalysis (5 %). TiO2 was deeply involved into CO2 generalization by amplifying the advantages of VUV system and further mineralizing the intermediates. In VUV and VUV-PCO processes, O2 participation changed the intermediates distribution by increasing multiple oxygenated products, while the introduction of water contributed to the formation and degradation of most intermediates. A possible degradation mechanism of toluene under VUV irradiation combined with TiO2 was proposed. This study provides a deep mechanistic insight into VOCs degradation by VUV-PCO process.

Wet scrubber coupled with heterogeneous UV/Fenton for enhanced VOCs oxidation over Fe/ZSM-5 catalyst.

The traditional treatment processes for volatile organic compounds (VOCs) removal generally suffered several disadvantages, such as secondary air-pollutants. To overcome these issues, wet scrubber coupled with heterogeneous UV/Fenton was developed for gaseous VOCs (i.e. toluene) removal. ZSM-5 supported iron oxide (Fe/ZSM-5) was prepared as a multifunctional catalyst for activation of H2O2 and enhancement of gas-liquid mass transfer. Toluene was removed efficiently by this coupled process with the removal efficiency of 85% during 120 min. Many intermediates were detected in the solution by GC-MS while no intermediates were observed in the outlet gas, suggesting that wet scrubber coupled with heterogeneous UV/Fenton could significantly reduce secondary air pollutants. The possible mechanism of toluene oxidation was proposed including the physical adsorption by Fe/ZSM-5 and OH oxidation. This study provides an environmentally benign and highly efficient chemical scrubbing process for gaseous VOCs removal.

Catalytic oxidation of VOCs over Mn/TiO2/activated carbon under 185 nm VUV irradiation.

Volatile organic compounds (VOCs) are regarded as the major contributors to air pollution, and should be strictly regulated. Photocatalytic oxidation (PCO) is of great interest for the removal of VOCs owing to its strong oxidation capability. However, its application is greatly limited by catalytic deactivation. Vacuum Ultraviolet (VUV) irradiation provides a novel way to improve the photocatalytic activity while much O3 will be generated which may cause secondary pollution. In this study, a multi-functional catalyst of Mn/TiO2/activated carbon (AC) was developed to eliminate and utilize O3, as well as enhance catalytic oxidation of VOC degradation via ozone-assisted catalytic oxidation (OZCO). The results indicate that Mn modified TiO2/AC (i.e. 0.1%Mn/20%TiO2/AC) achieved a toluene removal efficiency of nearly 86% with 100% elimination rate of O3. With the help of Mn/TiO2/AC catalyst, O3 was catalytically decomposed and transformed into active species of O (1D) and OH, thus enhancing toluene removal. The combination of VUV irradiation with multi-functional catalyst provides a novel and efficient way for the degradation of VOCs.

Safflower extract inhibiting apoptosis by inducing autophagy in myocardium derived H9C2 cell.

The Heart failure (HF) is considered as the end-stage of various heart disease and associated with high mortality globally. Progressive loss of cardiac myocytes via apoptosis is considered as the most important factor for HF pathology. In this study, we demonstrated that Safflower extract was able to inhibitthe apoptosis inducted by Angiotensin II (AngII) in a ratmyocardium derived cell line H9C2. Further examination of LC-3II conversion and autophagosome formation suggested Safflower extract induced autophagy in treated cell. Inhibition of Safflower extract induced autophagy by 3-methyladenine (3MA) abolished anti-apoptotic function of Safflower extract, while application of autophagy stimulator Rapamycin in H9C2 inhibited apoptosis as well. Moreover, treatment of H9C2 cell with Safflower extract also inhibited expression of pro-apoptotic genes BAD and Bax. In conclusion, our data indicated that Safflower extract inhibit apoptosis via inducing autophagy in myocardium cell and demonstrated the potential as novel therapeutic drug for Heart failure.

[Gene deletion and functional analysis of the EAL domain protein vieAxoo in Xanthomonas oryzae pv. oryzae].

OBJECTIVE: To better reveal the functions of key members involved in cyclic di-GMP signal metabolism pathways in the bacterial blight pathogen of rice Xanthomonas oryzae pv. oryzae (Xoo). METHODS: vieAxoo (PXO 04753), a gene putatively encoding the EAL domain proteins was investigated by gene deletion mutation using the marker exchange, complementation and phenotypic analysis. RESULT: The sequence of vieAxoo cloned from genomic DNA of the wild-type strain PXO99(A) was found to be highly conserved in plant-pathogenic Xanthomonas spp. VieAxoo was structurally featured with EAL and REC domains. No significant changes in virulence to rice, EPS production and flagellar motility were found in deltavieAxoo compared to PXO99(A), whereas remarkable changes in induction of hypersensitive responses (HR) in tobacco and biofilm formation were observed. CONCLUSION: VieAxoo might function as an important reponse regulator in cyclic di-GMP signaling and regulation of bacterial induction of HR and biofilm formation of Xoo.

PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.

MAVS is critical in innate antiviral immunity as the sole adaptor for RIG-I-like helicases. MAVS regulation is essential for the prevention of excessive harmful immune responses. Here we identify PCBP2 as a negative regulator in MAVS-mediated signaling. Overexpression of PCBP2 abrogated cellular responses to viral infection, whereas knockdown of PCBP2 exerted the opposite effect. PCBP2 was induced after viral infection, and its interaction with MAVS led to proteasomal degradation of MAVS. PCBP2 recruited the HECT domain-containing E3 ligase AIP4 to polyubiquitinate and degrade MAVS. MAVS was degraded after viral infection in wild-type mouse embryonic fibroblasts but remained stable in AIP4-deficient (Itch(-/-)) mouse embryonic fibroblasts, coupled with greatly exaggerated and prolonged antiviral responses. The PCBP2-AIP4 axis defines a new signaling cascade for MAVS degradation and 'fine tuning' of antiviral innate immunity.