IGF2BP3 modified GLI2 transcriptionally regulates SYVN1 and facilitates sepsis liver injury through autophagy.

Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-activated receptor α (PPARα) was downregulated. Suppressing GLI2 or synovialapoptosis inhibitor 1 (SYVN1) in LPS-exposed cells increased PPARα levels, enhanced cell viability and autophagy, while inhibiting apoptosis. LPS enhanced the GLI2-SYVN1 promoter binding. SYVN1 fostered ubiquitin-mediated degradation of PPARα. IGF2BP3 stabilized GLI2 mRNA by targeting its m6A site. Silencing IGF2BP3 led to decreased GLI2 and SYVN1 but increased PPARα levels, promoting cell survival and autophagy, while repressing apoptosis. This was counteracted by SYVN1 overexpression. In cecal ligation and puncture mice, IGF2BP3, SYVN1, or GLI2 knockdown ameliorated liver damage and augmented autophagy. In summary, IGF2BP3 enhanced GLI2 stability, overexpressed GLI2 subsequent promoted SYVN1 levels by interacting with its promoter, leading to ubiquitinated degradation of PPARα, thereby inhibiting PPARα-mediated autophagy and then exacerbating liver injury in sepsis.

Synthesis and in vitro antitumor activity of galactosamine-docetaxel conjugates.

Docetaxel (DTX) is a semi-synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX-(suc-Gal)2, DTX-(DTDPA-Gal)2, and DTX-(DSeDPA-Gal)2. These three conjugates were characterized by 1H NMR, FT-IR and HRMS. The in vitro drug release study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit glutathione (GSH)-responsive drug release and DTX-(DSeDPA-Gal)2 displays higher GSH-responsiveness. The in vitro antitumor activity study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX-(suc-Gal)2, DTX-(DSeDPA-Gal)2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX-(DSeDPA-Gal)2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX-(DSeDPA-Gal)2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells.

Occurrence of metals, phthalate esters, and perfluoroalkyl substances in cellar water and their relationship with bacterial community in rural areas of China.

Water cellars are traditional rainwater harvesting facilities that have been widely used in rural areas of northwest China. However, there are few reports about the water quality and health risk caused by the cellar water, especially phthalate esters (PAEs) and perfluoroalkyl substances (PFASs). This study investigated and assessed the health risks caused by the metals, PAEs, PFASs and bacterial communities in cellar water. The results showed that the turbidity and total number of bacterial colonies ranged from 4.7 to 58.5 NTU and 5-557 CFU/mL, respectively. The turbidity and total number of bacterial colonies were the main water quality problems. Due to high concentration of Tl (0.005-0.171 µg/L), the samples reached a high level of metal pollution. PAEs showed no non-carcinogenic and carcinogenic risk. The perfluorobutanoic acid (PFBA), perfluorobutanesulfonic acid (PFBS), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) were the main components of PFASs. PFOA and PFOS reached a moderate risk level in many cellar water samples. Moreover, Tl, Pb, As, PFBA and PFBS could change the bacterial community composition and induce the enrichment of bacterial functions related to human diseases. Besides these parameters, dissolved oxygen (DO) also affected the bacterial functions related to human diseases. Therefore, more attention should be paid to turbidity, DO, Tl, Pb, As, PFOA, PFOS, PFBA and PFBS in the cellar water. These results are meaningful for the water quality guarantee and health protection in rural areas of China.

Co-occurrence of phthalate esters and perfluoroalkyl substances affected bacterial community and pathogenic bacteria growth in rural drinking water distribution systems.

The adverse health effects of phthalate esters (PAEs) and perfluoroalkyl substances (PFAS) in drinking water have attracted considerable attention. Our study investigated the effects of PAEs and PFAS on the bacterial community and the growth of potential human pathogenic bacteria in rural drinking water distribution systems. Our results showed that the total concentration of PAEs and PFAS ranged from 1.02 × 102 to 1.65 × 104 ng/L, from 4.40 to 1.84 × 102 ng/L in rural drinking water of China, respectively. PAEs concentration gradually increased and PFAS slowly decreased along the pipeline distribution, compared to concentrations in the effluents of rural drinking water treatment plants. The co-occurrence of higher concentrations of PAEs and PFAS changed the structure and function of the bacterial communities found within these environments. The bacterial community enhanced their ability to respond to fluctuating environmental conditions through up-regulation of functional genes related to extracellular signaling and interaction, as well as genes related to replication and repair. Under these conditions, co-occurrence of PAEs and PFAS promoted the growth of potential human pathogenic bacteria (HPB), therefore increasing the risk of the development of associated diseases among exposed persons. The main HPB observed in this study included Burkholderia mallei, Mycobacterium tuberculosis, Klebsiella pneumoniae, Acinetobacter calcoaceticus, Escherichia coli, and Pseudomonas aeruginosa. Contaminants including particles, microorganisms, PAEs and PFAS were found to be released from corrosion scales and deposits of pipes and taps, resulting in the increase of the cytotoxicity and microbial risk of rural tap water. These results are important to efforts to improve the safety of rural drinking water.

Metoprolol attenuates intracerebral hemorrhage-induced cardiac damage by suppression of sympathetic overactivity in mice.

The high rates of mortality and disability resulting from intracerebral hemorrhage (ICH) are closely related to subsequent cardiac complications. The mechanisms underlying ICH-induced cardiac dysfunction are not fully understood. In this study, we investigated the role of sympathetic overactivity in mediating cardiac dysfunction post ICH in mice. Collagenase-injection ICH model was established in adult male C57BL/6J mice. Neurological function was subsequently evaluated at multiple time points after ICH and cardiac function was measured by echocardiography on 3 and 14 days after ICH. Plasma adrenaline, noradrenaline, cortisol and heart ß1 adrenergic receptor (ß1-AR) levels were assessed to evaluate sympathetic activity. Picro Sirius Red (PSR) staining was performed to evaluate cardiomyocyte hypertrophy and interstitial fibrosis. Monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6(IL-6), nuclear factor kappa-B(NF-κB), NADPH oxidase-2 (NOX2), matrix metalloprotein (MMP-9) and transforming growth factor-beta (TGF-ß) levels were assessed to evaluate inflammation, fibrosis and oxidative stress levels in heart after ICH. Macrophages and neutrophils were assessed to evaluate inflammatory cell infiltration in heart after ICH. ICH induced sympathetic excitability, as identified by increased circulating adrenaline, noradrenaline, cortisol levels and ß1-AR expression in heart tissue. Metoprolol-treated ICH mice had improved cardiac and neurological function. The suppression of sympathetic overactivity by metoprolol attenuates cardiac inflammation, fibrosis and oxidative stress after ICH. In conclusion, ICH-induced secondary sympathetic overactivity which mediated inflammatory response may play an important role in post-ICH cardiac dysfunction.

Human umbilical cord blood cells rescued traumatic brain injury-induced cardiac and neurological deficits.

BACKGROUND: Traumatic brain injury (TBI) evokes neurological deficits and induces cardiac dysfunction. Treatment with human umbilical cord blood cells (HUCBCs) represents a potential therapeutic strategy for TBI-induced neurological deficits. The present study aimed to determine whether HUCBCs could ameliorate the cardiac dysfunction and neurological deficits induced by TBI. METHODS: Adult male C57BL/6J mice were subjected to controlled cortical impact (CCI)-induced TBI and were treated with either HUCBCs (1×106) or phosphate-buffered saline (PBS), via tail vein injections, 3 days after TBI. Neurological and cognitive functions were subsequently evaluated at multiple time points after TBI and cardiac function was assessed by echocardiography 3 and 30 days after TBI. Brain and heart tissues were paraffin-embedded 30 days after TBI. Hematoxylin and eosin (H&E) staining was performed on brain tissue sections to calculate the brain damage volume, and Picro Sirius Red (PSR) staining was performed on heart tissue sections to evaluate myocardial fibrosis. Terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL) staining was employed to assess cell apoptosis 30 days after TBI. Transforming growth factor-beta (TGF-ß) and NADPH oxidase-2 (NOX2) levels were assessed to evaluate inflammation and oxidative stress levels 30 days after TBI. RESULTS: TBI elicited acute and chronic cardiac deficits, identified by decreased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) values 3 and 30 days after TBI, in addition to neurological and cognitive deficits. TBI mice treated with HUCBCs exhibited enhanced LVEF and FS values 30 days after TBI compared with untreated TBI controls. HUCBC treatment significantly improved neurological and cognitive functions and reduced cardiomyocyte apoptosis, inflammatory response, oxidative stress, and cardiac fibrosis in heart tissues 30 days after TBI. CONCLUSIONS: TBI induced both neurological deficits and cardiac dysfunction in mice, which were ameliorated by HUCBC treatment. The anti-inflammatory activities of HUCBCs may contribute to these observed therapeutic effects.

Long noncoding RNA HAS2-AS1 promotes tumor progression in glioblastoma via functioning as a competing endogenous RNA.

Glioblastoma multiforme (GBM) is a refractory tumor with poor prognosis and requires more effective treatment regimens. It has been confirmed that long noncoding RNAs (lncRNAs) substantially regulate various human disease including GBM. However, the biological roles and its underlying molecular mechanisms still need to be further investigated. In this study, the biological function and potential molecular mechanism of lncHAS2-AS1 in GBM were explored. It was discovered that HAS2-AS1 was elevated in glioma tissues and correlated with the prognosis of patients with glioma. Reduction of HAS2-AS1 suppressed the migration and invasion in vitro and in vivo. The transcription factor STAT1 could raise HAS2-AS1 by binding to its promoter region. Besides, HAS2-AS1 could adjust PRPS1 via sponging miR-608 in a direct manner. On the whole, the results of this study evidence that HAS2-AS1 is an oncogene and a potential therapeutic target for GBM.

Design, synthesis, and antifungal activity of novel cinnamon-pyrazole carboxamide derivatives.

Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon-pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 µM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.