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[Display omitted] • Design, synthesis and antitumor evaluation of biotin-PEG4‑diarylidenyl piperidone prodrugs. • In vitro and In vivo antitumor activity screening for prodrugs 3a and 3b. • 3a and 3b released their original drugs DAP-F and DAP-NO 2 in nude mice. • DAP-F , DAP-NO 2 , 3a and 3b targeted STAT3 inhibition. • 3a and 3b interacted with SH2-binding domain, while DAP-F and DAP-NO 2 interacted with DNA-binding domain. Two biotin-polyethylene glycol (PEG)4‑diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b , were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives (DAP-F and DAP-NO 2) through a PEG4 linker, respectively. The results of the MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay and a SW480 xenograft model identified compounds 3a and 3b as candidate antitumor agents with good efficacy, limited toxicity, and low resistance, as compared to the original drugs (DAP-F and DAP-NO 2), cisplatin, and doxorubicin (dox). The results of a preliminary pharmacokinetic study showed that compounds 3a and 3b slowly released their original drug DAP-F and DAP-NO 2 within 12 h after intraperitoneal injection, respectively. Western blot analysis and computer docking simulations indicated that DAP-F , DAP-NO 2 , and compounds 3a and 3b were indeed inhibitors of signal transducer and activator of transcription 3 (STAT3) and the antitumor effects of compounds 3a and 3b were exerted by sequentially interacting with the SH2-binding domain followed by the DNA-binding domain after releasing the original drugs DAP-F and DAP-NO 2 , respectively. These results suggest that the targeted prodrug model led to good antitumor efficacy with reduced toxicity, while a dual STAT3-binding model may promote antitumor efficacy and resistance. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the tissue distributions of antibiotics in the fish, the bioaccumulation and trophic transfer in freshwater food web in Taihu Lake, a large shallow freshwater lake. Twenty four out of 41 antibiotics were detected in the biotas of the food web; and antibiotic concentrations followed the orders: fish plasma ~ fish muscle < fish liver ~ fish bile and fish < invertebrates ~ plankton. Antibiotic concentrations in the liver of piscivores were higher than those in omnivores and planktivores. Most bioaccumulation factors (BAFs) of sulfonamides (SAs), macrolides (MLs), ionophores (IPs) and lincomycin (LIN) were less than 2000 L/kg, indicating low bioaccumulation ability of these compounds in fish. Fluoroquinolones (FQs) were frequently detected in fish liver, invertebrates and plankton with much of BAFs great than 5000 L/kg, indicating that FQs have the potential of bioaccumulation in fish. Relationship analysis between BAFs and physicochemical properties of antibiotics showed that the bioaccumulation of antibiotics in the biota was related with their adsorption ability. Generally, the antibiotics in the food web of Lake Taihu including plankton, invertebrates and fish showed trophic dilution. The normalized estimated daily intake (EDI) values are less than the acceptable daily intake (ADI) values, and then hazard quotients were much less than 1. This result suggests the consumption of fish, crab and shrimp in Lake Taihu would probably not pose direct detrimental effects on humans. Image 1 • 24 antibiotics were detected in the biotas of the freshwater food web in Lake Taihu. • Antibiotics in the biotas showed the order: fish < invertebrates ~ plankton. • BAFs of FQs in biotas greater than 5000 L/kg, suggesting potential bioaccumulation. • The bioaccumulation of antibiotics was positively related with their K oc. • Antibiotics in the edible fish, shrimp and crab may not pose risks on human health. [ABSTRACT FROM AUTHOR]

Background The choice between volar locking plates (VLP) and external fixation (EF) for unstable distal radius fractures have not reached a consensus. The meta-analysis of randomized controlled trials was performed to compare VLP with EF to determine the dominant strategy. Materials and methods Meta-analysis was performed with a systematic search of studies conducted by using the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases. The randomized controlled trials that compared VLP with EF was identified. Characteristics, functional outcomes, radiological results, and complications were manually extracted from all the selected studies. Results Six studies encompassing 445 patients met the inclusion criteria. There was significant difference between two procedures in disabilities of the arm shoulder and hand scores at 3,6, and 12 mo, visual analogue scale at 6 mo, grip strength at 3 mo, supination at 3 and 6 mo, extension at 3 mo, ulnar variance at 12 mo, and reoperation rate at 12 mo, postoperatively. However, there was no significant difference between flexion, pronation, radial deviation, and ulnar deviation at all follow-up points postoperatively and overall complications at 12 mo, postoperatively. Conclusions EF had less reoperative rate due to complications, however, VLP had advantages in functional recovery in the early period after surgery, but two methods had similar functional recovery at 12 mo, postoperatively. Clinician should make the treatment decision with great caution for the patients who sustained unstable distal radial fractures. [ABSTRACT FROM AUTHOR]

To explore the effect of double-stranded RNA-dependent kinase (PKR) in acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS). A mouse model of lipopolysaccharide (LPS)-induced ALI was used to evaluate the levels of phosphorylated (p)-PKR and NLRP3 in lung tissue, and the protective effects of a PKR inhibitor on lung injury. And in vitro, macrophages were incubated with LPS, with or without PKR inhibitor pre-treatment. It was observed that the levels of p-PKR protein and NLRP3 protein were significantly increased compared with those in control tissues after LPS administration. Meanwhile, treatment with PKR inhibitor decreased inflammation, injury score, wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein levels, neutrophil count in BALF, myeloperoxidase activity and expression of high-mobility group box1(HMGB1) and interleukin(IL)-1β in the lungs of LPS-challenged mice. In vitro, we demonstrated that the levels of p-PKR and NLRP3, and cell mortality rate were increased in macrophages which were incubated with LPS compared with those without LPS administration, and PKR inhibitor significantly suppressed the level of NLRP3, caspase-1, HMGB1 and IL-1β. These results indicate that PKR plays a key role in ALI through NLRP3-pyrotosis pathway and pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS. • The role of PKR in the pathogenesis of ALI/ARDS was explored. • Inhibition of PKR protects against LPS-induced ALI by suppressing NLRP3-pyrotosis pathway. • Pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections, including bacterial pneumonia. The hLF(1-11) peptide comprising the first 11 N-terminal residues of human lactoferrin exerts antimicrobial activity in vivo and was highly effective against multidrug-resistant A. baumannii strains in vitro and in vivo. Pyroptosis is a caspase-1-dependent inflammatory cell death process and is induced by various microbial infections. In the present study, we investigated the molecular mechanisms that regulate pyroptosis induced by A. baumannii in macrophages. Our results revealed that A. baumannii induced pyroptosis through caspase-1 activation and IL-1β production. We also found that caspase-1 activation and IL-1β maturation in A. baumannii -triggered pyroptotic cell death were reduced by hLF(1-11) treatment. Moreover, hLF(1-11) inhibited the A. baumannii -induced caspase-1 activation and pyroptosis of pulmonary alveolar macrophages in vivo. [ABSTRACT FROM AUTHOR]

Sepsis-induced encephalopathy (SAE) is a detrimental complication in patients with severe sepsis, while there is still no effective treatment. Previous studies have elucidated the neuroprotective effects of glucagon-like peptide-1 receptor (GLP-1R) agonists. However, the role of GLP-1R agonists in the pathological process of SAE is unclear. Here, we found that GLP-1R was up-regulated in the microglia of septic mice. The activation of GLP-1R with Liraglutide could inhibit endoplasmic reticulum stress (ER stress) and associated inflammatory response as well as apoptosis triggered by LPS or tunicamycin (TM) in BV2 cells. In vivo experiments confirmed the benefits of Liraglutide in the regulation of microglial activation, ER stress, inflammation, and apoptosis in the hippocampus of septic mice. Additionally, the survival rate and cognitive dysfunction of septic mice were also improved after Liraglutide administration. Mechanically, cAMP/PKA/CREB signaling is involved in the protection of ER stress-induced inflammation and apoptosis in cultured microglial cells under LPS or TM stimulations. In conclusion, we speculated that GLP-1/GLP-1R activation in microglia might be a potential therapeutic target for the treatment of SAE. Graphic abstract illustrating the mechanism of GLP-1R activation in microglia in the protection against SAE-induced ER stress and associated signaling. Sepsis triggers ER stress and associated inflammation as well as apoptosis in microglial cells. GLP-1R activated by GLP-1R agonist could reverse ER stress and related downstream processes through cAMP/PKA/CREB pathway. [Display omitted] • GLP-1R is mainly expressed in microglia of septic mice. • Activation of GLP-1R on microglia alleviates ER stress and associated apoptosis and inflammation via cAMP/PKA/CREB pathway. • Activation of GLP-1R on microglia improves survival rate and cognitive impairment of septic mice. [ABSTRACT FROM AUTHOR]

Neutrophils activated during acute lung injury (ALI) form neutrophil extracellular traps (NETs) to capture pathogens. However, excessive NETs can cause severe inflammatory reactions. Macrophages are classified as M1 macrophages with proinflammatory effects or M2 macrophages with anti-inflammatory effects. During ALI, alveolar macrophages (AMs) polarize to the M1 phenotype. This study tested the hypothesis that NETs may aggravate ALI or acute respiratory distress syndrome (ARDS) inflammation by promoting alveolar macrophage polarization to the M1 type. Our research was carried out in three aspects: clinical research, animal experiments and in vitro experiments. We determined that NET levels in ARDS patients were positively correlated with M1-like macrophage polarization. NET formation was detected in murine ALI tissue and associated with increased M1 markers and decreased M2 markers in BALF and lung tissue. Treatment with NET inhibitors significantly inhibitor NETs generation, downregulated M1 markers and upregulated M2 markers. Regardless of LPS pre-stimulation, significant secretion of proinflammatory cytokines and upregulated M1 markers were detected from bone marrow-derived macrophages (M0 and M2) cocultured with high concentrations of NETs; conversely, M2 markers were downregulated. In conclusion, NETs promote ARDS inflammation during the acute phase by promoting macrophage polarization to the M1 phenotype. We propose that NETs play an important role in the interaction between neutrophils and macrophages during the early acute phase of ALI. [ABSTRACT FROM AUTHOR]