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With flue-cured tobacco (Nicotiana tabacum) cultivar K326 as test material, a field experiment was conducted at Nanxiong area of Guangdong Province in 2008 to study the effects of four planting patterns, i.e., single-row ridge + film mulching at early stage, single-row ridge + film mulching at early and late stages, double-row concave ridge + film mulching at early stage, and double-row concave ridge + film mulching at early and late stages, on the senescence characteristics of its roots and leaves, and the economic traits of its leaves. Comparing with other three planting patterns, double-row concave ridge + film Aulching at early and late stages promoted the root growth of test cultivar during its whole growth period, with the root vigor increased significantly. Meanwhile, the leaf chlorophyll content and protective enzymes (SOD and POD) activities were higher, and the MDA content was lower. The leaf yield, output value, average price, and the proportion of superior leaves were also higher. Double-row concave ridge + film mulching at early and late stages alleviated the senescence characteristics of roots and leaves, and improved the economic traits of flue-cured tobacco leaves, being the efficient planting pattern to product high-quality flue-cured tobacco leaves in Nanxiong tobacco-growing area of Guangdong Province. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) was the third gasotransmitter to be recognized as a cytoprotectant. A recent study demonstrated that exogenous supplementation of H2S ameliorates functional insufficiency in chronic kidney disease (CKD). However, how the H2S system is impaired by CKD has not been elucidated. The uremic toxin indoxyl sulfate (IS) is known to accumulate in CKD patients and harm the renal tubular cells. This study therefore treated the proximal tubular cells, LLC-PK1, with IS to see how IS affects H2S formation. Our results showed that H2S release from LLC-PK1 cells was markedly attenuated by IS when compared with control cells. The H2S donors NaHS and GYY-4137 significantly attenuated IS-induced tubular damage, indicating that IS impairs H2S formation. Interestingly, IS downregulated the H2S-producing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), and these effects could be reversed by inhibition of the IS receptor, aryl hydrocarbon receptor (AhR). As transcription factor specificity protein 1 (Sp1) regulates the gene expression of H2S-producing enzymes, we further showed that IS significantly decreased the DNA binding activity of Sp1 but not its protein expression. Blockade of AhR reversed low Sp1 activity caused by IS. Moreover, exogenous H2S supplementation attenuated IS-mediated superoxide formation and depletion of the cellular glutathione content. These results clearly indicate that IS activates AhR, which then attenuates Sp1 function through the regulation of H2S-producing enzyme expression. The attenuation of H2S formation contributes to the low antioxidant defense of glutathione in uremic toxin-mediated oxidative stress, causing tubular cell damage. [ABSTRACT FROM AUTHOR]

Triflamp, a 28 kDa snake venom metalloproteinase purified from the venom of Trimeresurus flavoviridis, possesses the proteolytic activities toward P-selectin glycoprotein ligand-1 (PSGL-1), glycoprotein Ib (GPIb) and fibrinogen. In human whole blood preparation, however, triflamp (6 μg/ml) failed to cleave neutrophil PSGL-1 and platelet GPIb. Human α2-macroglobulin (α2M) was mainly responsible for the neutralization of the proteolytic effects of triflamp on PSGL-1, GPIb and fibrinogen. Human α2M neutralized triflamp at a stoichiometry about 1.1:1 (molar basis) determined by azocaseinolysis. SDS-PAGE analysis revealed that triflamp cleaved the bait-region of α2M. Western blot demonstrated that triflamp interacted with the C-terminal half-subunits of truncated α2M resulting in the formation of high-molecular-weight species of α2M-triflamp complexes. In the presence of competing nucleophile, 0.2 M methylamine, the proteolytic activity of triflamp was conserved. In vivo we found that mice neutrophils were resistant to the cleavage of PSGL-1 by triflamp. However, mouse PSGL-1 and GPIb were susceptible to be cleaved by triflamp in washed mouse neutrophil and platelet preparation, respectively. Similarly, mouse serum was also responsible for the inactivation of the proteolytic activity of triflamp. This study provides direct evidences for the reasonable explanation regarding the reduced proteolytic activity of triflamp toward its substrates in whole blood preparation and in vivo model. [Copyright &y& Elsevier]

Studies the P2 receptor subtype on canine tracheal epithelial cells (TEC) responsible for stimulating inositol phosphate accumulation and calcium mobilization. Effects of nucleotides on accumulation and mobilization; Characteristics of inositol phosphate formation; Agonist specificity for the calcium transient in TEC.

Serum vascular endothelial growth factor (VEGF) is involved in follicular vascularization, oxygenation, and consequently in oocyte maturation and embryo development. Unanswered questions remain regarding the relationship of intrafollicular VEGF level in preovulatory leading follicles to oocyte maturation and ovarian reserve during ovarian stimulation. We conducted this study to investigate the relationship of intrafollicular VEGF level in the fluid of single preovulatory leading follicles to ovarian reserve and oocyte maturation in patients receiving GnRH antagonist in vitro fertilization (IVF) protocol treatment. One hundred and eighty-five patients receiving IVF treatment were recruited and assigned to low-, normal-, and high-ovarian-reserve groups according to their serum anti-Müllerian hormone (AMH) level. Follicular fluid (FF) in preovulatory leading follicles, serum profiles, and clinical variables were collected for analysis. The result disclosed a significant among-group difference in FF VEGF concentration. Moreover, the serum AMH level was also negatively correlated with FF VEGF level. The oocyte maturation rate tended to be increased at higher AMH levels. FF VEGF concentration was significantly positively correlated with basal FSH level. In conclusion, FF VEGF concentration has a negative association with ovarian reserve level and oocyte maturation rate in patients undergoing GnRH antagonist IVF protocols. [ABSTRACT FROM AUTHOR]

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor‐specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects. [ABSTRACT FROM AUTHOR]

Previous studies have shown that CCL2 may cause chronic pain, but the exact mechanism of central sensitization is unclear. In this article, we further explore the presynaptic role of CCL2. Behavioral experiments show that intervertebral foramen injection CCR2 antagonists into dorsal root ganglion (DRG) can inhibit the inflammatory pain caused by CCL2 in spinal cord. We raised the question of the role of presynaptic CCR2 in the spinal dorsal horn. Subsequent electron microscopy experiments showed that CCR2 was expressed in the presynaptic CGRP terminal in the spinal dorsal horn. CCL2 can enhance presynaptic calcium signal. Whole-cell patch-clamp recordings showed that CCL2 can enhance NMDAR-eEPSCs through presynaptic effects, and further application of glutamate sensor method proved that CCL2 can act on presynaptic CCR2 to increase the release of presynaptic glutamate. In conclusion, we suggest that CCL2 can directly act on the CCR2 on presynaptic terminals of sensory neurons in the spinal dorsal horn, leading to an increase in the release of presynaptic glutamate and participate in the formation of central sensitization. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue repair/remodeling and the subepithelial stroma region in whose nasal mucosa has been reported by us to have thromboxane A2 (TXA2) prostanoid (TP) receptor and overexpress connective tissue growth factor (CTGF). Therefore, this study aimed to investigate the relationship between TP receptor activation and CTGF production/function in human CRSsNP nasal mucosa stromal fibroblasts. We found that TP agonists including U46619 and IBOP ([1S‐[1α,2α(Z),3β(1E,3 S*),4α]]‐7‐[3‐[3‐hydroxy‐4‐(4‐iodophenoxy)‐1‐butenyl]‐7‐oxabicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoic acid) could promote CTGF protein/messenger RNA expression and secretion. The pharmacological intervention and TP activation assay with U46619 identified the possible participation of PKCμ, PKCδ, nuclear factor‐κB (NF‐κB), and cyclic AMP response element‐binding protein (CREB) phosphorylation/activation in the CTGF induction. Moreover, a phorbol ester—phorbol‐12‐myristate 13‐acetate (PMA) exhibited a similar cellular signaling and CTGF production profile to that elicited by TP activation. However, further small interfering RNA interference analysis revealed that only NF‐κB and PKCδ‐CREB pathways were necessarily required for TP‐mediated CTGF production, which could not be completely supported by those findings from PMA. Finally, in a functional assay, although CTGF did not affect fibroblast proliferation, TP‐mediated CTGF could drive novel self‐migration in fibroblasts both in the scratch/wound healing and transwell apparatus assays. Meanwhile, the overall staining for stress fibers and formation of the lamellipodia and filopodia‐like structures was concomitantly increased in the treated migrating cells. Collectively, we provided here that novel TP mediates CTGF production and self‐migration in human nasal fibroblasts through NF‐κB and PKCδ‐CREB signaling pathways. More importantly, we also demonstrated that thromboxane, TP receptor, CTGF, and stromal fibroblasts may act in concert in the tissue remodeling/repair process during CRSsNP development and progression. [ABSTRACT FROM AUTHOR]

Ovarian follicular fluid (FF) has a direct impact on oocyte quality, playing key roles in fertilization, implantation, and early embryo development. In our recent study, we found FF thromboxane (TX) to be a novel factor inversely correlated with oocyte maturation and identified thrombin, transforming growth factor β (TGFβ), TNF-α, and follicular granulosa cells (GCs) as possible contributors to FF TX production. Therefore, this study sought to investigate the role of TGFβ3 in regulating TX generation in human ovarian follicular GCs. TGFβ3 was differentially and significantly present in the FF of large and small follicles obtained from IVF patients with average concentrations of 68.58 ± 12.38 and 112.55 ± 14.82 pg/mL, respectively, and its levels were correlated with oocyte maturity. In an in vitro study, TGFβ3 induced TX generation/secretion and the converting enzyme-COX-2 protein/mRNA expression both in human HO23 and primary cultured ovarian follicular GCs. While TGFβRI and Smad2/3 signaling was mainly required for COX-2 induction, ERK1/2 appeared to regulate TX secretion. The participation of Smad2/3 and COX-2 in TGFβ3-induced TX generation/secretion could be further supported by the observations that Smad2/3 phosphorylation and nuclear translocation and siRNA knockdown of COX-2 expression compromised TX secretion in GCs challenged with TGFβ3. Taken together, the results presented here first demonstrated that FF TGFβ3 levels differ significantly in IVF patients' large preovulatory and small mid-antral follicles and are positively associated with oocyte maturation. TGFβ3 can provoke TX generation by induction of COX-2 mRNA/protein via a TGFβR-related canonical Smad2/3 signaling pathway, and TX secretion possibly by ERK1/2. These imply that TGFβ3 is one of the inducers for yielding FF TX in vivo, which may play a role in folliculogenesis and oocyte maturation. [ABSTRACT FROM AUTHOR]

In this study, we consider a technological approach to obtain a high perpendicular magnetic anisotropy of the Co/Pd multilayers deposited on nanoporous TiO2 templates of different types of surface morphology. It is found that the use of templates with homogeneous and smoothed surface relief, formed on silicon wafers, ensures conservation of perpendicular anisotropy of the deposited films inherent in the continuous multilayers. Also, their magnetic hardening with doubling of the coercive field is observed. However, inhomogeneous magnetic ordering is revealed in the porous films due to the occurrence of magnetically soft regions near the pore edges and/or inside the pores. Modeling of the field dependences of magnetization and electrical resistance indicates that coherent rotation is the dominant mechanism of magnetization reversal in the porous system instead of the domain-wall motion typical of the continuous multilayers, while their magnetoresistance is determined by electron-magnon scattering, similarly to the continuous counterpart. The preservation of spin waves in the porous films indicates a high uniformity of the magnetic ordering in the fabricated porous systems due to a sufficiently regular pores array introduced into the films, despite the existence of soft-magnetic regions. The results are promising for the design and fabrication of future spintronic devices. [ABSTRACT FROM AUTHOR]

Heme oxygenase 1 (HO-1) is mainly regulated by the redox-sensitive transcription factor, namely nuclear factor erythroid 2-related factor 2 (Nrf2). We previously found a physically-made gold nanoparticle (GNP) can affect migration, adhesion, and proliferation of rat aortic vascular smooth muscle cells (VSMCs). This study was sought to investigate whether the GNP can affect HO-1 expression level in VSMCs. Cellular fractionation, Western blotting, and immunofluorescence microscopy were used to determine Nrf2 translocation and phosphorylation. SiRNA interference was used to examine role of Nrf2 in GNP-induced HO-1 expression. The GNP concentration- and time-dependently enhanced HO-1 protein and mRNA expression; however, the mRNA induction was declined after 16 h treatment. The GNP treatment caused Nrf2 expression level and phosphorylation. In addition, it induced cytosolic Nrf2 translocation into nucleus. The HO-1 induction was inhibited by a ROS scavenger N-acetylcysteine (NAC), thiol-containing antioxidants (glutathione [GSH] and dithiothreitol [DTT]), JNK and p38 MAPK inhibitors, and nuclear transport inhibitor leptomycin. Meanwhile, the GNP-induced Nrf2 translocation (activation) was also reduced by NAC, JNK and p38 MAPK inhibitors, and nuclear transport inhibitor. Intriguingly, the GNP only enhanced activation of p38 MAPK but not JNK1/2. Finally, introduction of Nrf2 siRNA to cells to knockdown Nrf2 expression significantly inhibited GNP-induced HO-1 protein expression. This study elucidates the action mechanism that the naked physically-made GNP can enhance HO-1 expression in rat aortic VSMCs by inducing Nrf2 expression and phosphorylation and translocation into nucleus. The Nrf2 activation is mediated through a redox-related reaction and p38 MAPK activation. [ABSTRACT FROM AUTHOR]

In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE2 in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE2 production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE2 release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE2 generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation. [ABSTRACT FROM AUTHOR]

Significance: Pyroptosis is a discovered programmed cell death that is mainly executed by the gasdermin protein family. Cell swelling and membrane perforation are observed when pyroptosis occurs, and is accompanied by the liberation of cell contents. Recent Advances: As the study of pyroptosis continues to progress, there is increasing evidence that pyroptosis influences the development of tumors. In addition, the relationship between pyroptosis and tumor is diverse for different tissues and cells. Critical Issues: In this review, we first introduce the research history and molecular mechanisms of pyroptosis. Then we specifically discuss the link between pyroptosis and metabolic and oxidation in tumorigenesis. In the subsequent sections, we focus on the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy, and discuss the implications of pyroptosis in tumor treatment. In addition, we further summarize the therapeutic value of pyroptosis in tumor treatment. Future Directions: A detailed understanding of the role played by pyroptosis in tumors will help us to further explore tumor formation and progression and provide ideas for the development of new pyroptosis-based therapeutic approaches for patients. Antioxid. Redox Signal. 39, 512–530. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a strictly aerobic, nonmotile, nonfermenting, gram-negative bacillus. It is a highly infectious and invasive pathogen with high mortality and morbidity rates among immunodeficient patients. Due to increasing levels of drug resistance and the inefficiency of existing antimicrobial treatments, it is crucial to develop novel agents to control this pathogen. Several recent studies have investigated virulence factors that are associated with the pathogenesis of A. baumannii , and could thus serve as novel therapeutic targets. The present review comprehensively summarizes the current understanding of these virulence factors and their mechanisms in A. baumannii. We also highlight factors that could be potential therapeutic targets, as well as list candidate virulence factors for future researchers and clinical practitioners. [ABSTRACT FROM AUTHOR]

Chemokines were known to participate in inflammation and angiogenesis but have been recently recognized to be involved in embryonic implantation and endometrium-related pathologies. Among these chemokines, the CXC chemokines, such as CXCL1, have potential roles to work as biomarkers to identify patients with uterine adenomyosis. In this study, human endometrial epithelial cells (HEECs) were derived from patients’ endometrium with adenomyosis. The inductive effects of CXCL1 production by various mediators/growth factors were investigated in the HEECs. Of the tested mediators, VEGF was found to be the most effective. The immunohistochemistry and RT-PCR analysis revealed a positive staining for VEGF and CXCL1 at the epithelium and the presence of CXCL1 in the human endometrium specimens, respectively. The CXCL1 induction by VEGF could be reduced by the antagonist for VEGF receptor (VEGFR), and by the inhibitors for NADPH oxidase and NF-κB signaling pathway. However, it was not affected by sex hormones and the inhibitors for MAPKs, PI-3K, protein kinase A and C. In parallel, VEGF induced p47 phox NADPH oxidase activation, IκBα phosphorylation, NF-κB translocation and NF-κB-DNA complex formation in the HEECs. Moreover, the CXCL1 released by the HEECs with VEGF stimulation attracted vascular endothelial cell migration. Taken together, we show that VEGF and CXCL1 are expressed in epithelium of the endometrium with adenomyosis and demonstrate here for the first time that VEGF is capable of inducing CXCL1 expression in HEECs through VEGFR, p47 phox NADPH oxidase and NF-κB signaling pathway, which is functionally required for attracting vascular endothelial cell migration. [ABSTRACT FROM AUTHOR]

In humans, successful implantation requires a finely tuned synchrony between an appropriately developing embryo and the receptive endometrium, involving apposition, adhesion, and invasion. Therefore, this study was sought to establish a coculture cell model to investigate trophoblast-mediated blastocyst apposition and adhesion to endometrial epithelium events during embryo implantation. The direct contact and indirect noncontact coculture models were successfully established by using human BeWo trophoblasts and HEC-1A endometrial epithelial cells. Interestingly, a significant increase of ICAM-1 protein and mRNA expression was observed in both coculture systems when challenged with follicle-stimulating factor (FSH). In accordance with these observations, trophoblast-conditioned medium (CM) could also enhance epithelial ICAM-1 production, suggesting involvement of trophoblast-secreting factor(s) in crosstalk between two cells. Indeed, FSH stimulation enhanced TNF-α expression in the trophoblasts and epithelial ICAM-1 induction were abolished by a TNF-α blocking/neutralizing antibody (TNF-α B/N Ab). Meanwhile, the intracellular calcium, PKA/CREB, and transcription/translation signaling pathways in epithelial cells participated in the ICAM-1 induction. Finally, the trophoblast cells were more susceptible to adhesion to CM-primed epithelial cell monolayer, where the adhesion could be abolished by TNF-α B/N Ab. Therefore, we present here novel findings that coculture of trophoblast with endometrial epithelial cells in the presence of FSH leads to an increase in epithelial ICAM-1 expression and trophoblast adhesion to epithelial monolayer through stimulating trophoblast's TNF-α cytokine production. This study also addresses an important issue that a possible role of microenvironmental and exogenously-added FSH in enhancing blastocyst interaction with endometrium during embryo implantation of natural or in-vitro fertilization cycle. [Display omitted] • The epithelial ICAM-1 is upregulated in trophoblast-endometrial epithelial cell cocultures by FSH stimulation. • The trophoblast-released TNF-α and intraepithelial calcium and PKA/CREB signaling mediate epithelial ICAM-1 induction. • The novel epithelial ICAM-1 induction is functionally involved in trophoblast-endometrial epithelial cell interaction. [ABSTRACT FROM AUTHOR]

Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy. [Display omitted] • Elevated HIF-2 α expression, insulin resistance, and disorder lipid metabolism in liver of HFD-induced mice. • BBR decreases HIF-2 α expression and the ceramides related to insulin resistance. • BBR promotes glycogen synthesis via the PP2A-AKT-GSK3 β signaling pathway. • BBR alleviates glucose and lipid metabolism by inhibiting HIF-2 α. [ABSTRACT FROM AUTHOR]

Background: The optimal sequence of pulmonary vessel interruption during lung cancer resection remains controversial. This review aimed to elucidate the association of vein-first versus artery-first ligation and survival of the patients.Methods: We searched PubMed, Web of Science, Scopus, Embase, Cochrane Library and Google Scholar from their inception to September 2021 for published articles that compared vein-first (the pulmonary vein was interrupted first) and artery-first procedure (the pulmonary artery was ligated first) during lung cancer surgery.Results: Finally, a total of 13 full articles were obtained. First, 7 studies with survival information were included for meta-analyses. As compared with the artery-first ligation, vein-first approach did not decrease the risk of local recurrence (risk ratio [RR] 0.92 in favour of vein-first; 95% confidence interval [CI] 0.61-1.39, p = 0.68) or distant metastasis (RR 0.92; 95% CI 0.30-2.85, p = 0.89); but it was associated with better disease-free survival (RR 0.52; 95% CI 0.37-0.73, p < 0.01) as well as 5-year overall survival (RR 0.60; 95% CI 0.41-0.86, p < 0.01). In addition, the operative time, intraoperative blood loss, total complications, and length of postoperative stay were mainly comparable between the two groups. Second, 7 studies provided the data of tumor cells indicated by different biomarkers and detection methods; and 3 of these reports showed that vein-first ligation decreased the extent of intraoperative tumor dissemination. However, a quantitative meta-analysis was not possible due to the significant heterogeneity.Conclusion: Vein-first ligation in lung cancer surgery may be associated with improved survival of the patients, which might be ascribed to potentially lower risk of tumor cell dissemination. Well-designed, large-scale trials are warranted to clarify these occasional findings. [ABSTRACT FROM AUTHOR]

[Display omitted] • TGFβ1 is found in IVF patients' follicular fluid (FF) and its level is sufficient to be physiologically active. • TGFβ1 causes angiogenesis via follicular granulosa cells (GCs)-mediated VEGF induction and secretion. • The cellular signaling pathways for VEGF production in GCs are TGFβR, Smad2/3, PI3 K/Akt, and JNK1/2. • The FF TGFβ1, GCs, and VEGF act in concert to cause follicular angiogenesis in human IVF cycle. A growing body of evidence indicates that angiogenesis in folliculogenesis contributes to oocyte developmental competence in natural and in-vitro fertilization (IVF) cycle of animals. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has an important role involved in angiogenesis. However, its expression level and regulatory mechanism in ovarian follicular fluid (FF) in patients undergoing IVF with controlled ovarian stimulation (COS) remains to be explored. In this study, the primary cultured human ovarian follicular granulosa cells (GCs) were prepared from FF and their identity was characterized by the presence of the GC specific markers. The transforming growth factor β1 (TGFβ1) was found to induce a significant increase in VEGF mRNA level and protein expression/secretion in GCs. In line with these observations, TGFβ1 could be detected in the ovarian FF, ranging from about 400 to 2000 pg/mL among three IVF patient groups with different patient's serum Anti-Müllerian hormone level. The cellular signaling analysis revealed that TGFβ1 induced VEGF production through TGFβ receptor (TGFβR), Smad2/3, PI3 K/AKT, and JNK1/2-related signaling pathways. Finally, in a functional study, the TGFβ1-primed GC VEGF secretion promoted in-vitro angiogenesis in vascular endothelial cells and ex-vivo vessel sprouting in aortic ring. Taken together, we demonstrated here that TGFβ1 expressed in ovarian FF is an inducer for promoting VEGF production in follicular GCs through TGFβR-mediated signaling pathways and the released VEGF subsequently leads to angiogenesis. This possibly contributes to oocyte developmental competence in folliculogenesis of IVF patients with a COS protocol. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that microbiomes play an important role in the pathogenesis of chronic rhinosinusitis (CRS). In addition to a known short pentraxin, C-reactive protein, long pentraxin 3 (PTX3) belongs to pentraxin family which detects conserved microbial pentraxin motifs and mobilizes early defense against foreign invaders, but its participation in CRS remains unclear. In the present study, through an intensive screening, peptidoglycan (PGN) was selected as a main material to investigate the action mechanism of a cell wall component on CRS without nasal polyps (CRSsNP) nasal mucosa-derived fibroblasts and the PTX3 expression in human nasal mucosa tissue and discharge. The PGN not only enhanced PTX3 mRNA and protein production in cells but also caused marked PTX3 secretion into extracellular space. The pharmacological interventions indicated that the PTX3 induction was mediated mainly through toll-like receptor 2 (TLR2), phosphoinositide-phospholipase C (PI-PLC), protein kinase C (PKC), NF-κB, and cAMP response element binding protein (CREB), which was further confirmed by the observations that a direct PKC activator (phorbol ester) had a similar inductory effect on PTX3 expression/production and the siRNA interference knockdown of PKCμ/δ, NF-κB, and CREB compromised PTX3 production. Meanwhile, PTX3 was found to be overexpressed/produced in nasal mucosa and discharge/secretion of the CRSsNP patients. Collectively, we first demonstrated here that PGN enhances PTX3 expression and release in nasal fibroblasts through TLR2, PI-PLC, PKCμ/δ, NF-κB, and CREB signaling pathways. The PTX3 is overexpressed in nasal mucosa and discharge/secretion of CRSsNP patients, revealing its possible importance in CRSsNP development and progression. Key messages: Long pentraxin 3 (PTX3) is highly expressed in nasal mucosa and discharge/secretion of patients of chronic rhinosinusitis without nasal polyps (CRSsNP). The bacteria cell wall component-peptidoglycan (PGN) causes PTX3 expression in CRSsNP nasal mucosa-derived fibroblasts, contributing to the PTX3 increase in tissues. PGN induces PTX3 expression through a previously known IκB/NF-κB and a novel PKCμ/δ and CREB signaling pathway. The PTX3 may be used as a biomarker for CRS. [ABSTRACT FROM AUTHOR]

Due to the limitations of current extraction methods, extracellular DNA (eDNA) is rarely discerned from intracellular DNA (iDNA) despite having unique contributions to antibiotic resistance genes (ARGs) propagation. Furthermore, eDNA may be free (f-eDNA) or adsorbed to or suspended solids, including cells (a-eDNA), which affects ARG persistence and transmissivity. We developed a novel method using magnetic beads to separate iDNA, a-eDNA, and f-eDNA to assess how these physical states of ARGs change across a wastewater treatment plant. This method efficiently extracted eDNA (>85.3%) with higher recovery than current methods such as alcohol precipitation, CTAB-based extraction, and DNA extraction kits (<10%). Biological treatment and UV disinfection decreased the concentration of intracellular ARGs (iARGs) and adsorbed extracellular ARGs (a-eARGs), causing an increase of released free extracellular ARGs (f-eARGs). More ARGs were discharged through the wasted biosolids than in the effluent; iARGs and a-eARGs are prevalent in wasted biosolids ((73.9 ± 22.5) % and (23.4 ± 15.3) % of total ARGs respectively), while f-eARGs were prevalent in the effluent ((90.3 ± 16.5) %). Bacterial community analysis showed significant correlations between specific genera and ARGs (e.g., Aeromonas , Pseudomonas and Acinetobacter were strongly correlated with multidrug-resistance gene bla TEM). This treatment system decreased the discharge of iARGs to receiving environments, however, increased eARG concentrations were present in the effluent, which may contribute to the environmental resistome. Unlabelled Image • Magnetic beads efficiently extract extracellular DNA from wastewater & sludge. • Wastewater treatment redistributes ARGs among iDNA, a-eDNA and f-eDNA. • Overall, iARGs and a-eARGs are removed while f-eARGs increase. • More ARGs were discharged through the wasted biosolids than in the effluent. • iARGs prevailed in biosolids while f-eARGs were dominant in the effluent. [ABSTRACT FROM AUTHOR]

Abstract The super antibiotic resistance genes (SARGs) demonstrate more severe threats than other antibiotic resistance genes while have not received enough attention in the environment. The study explored the prevalence and the antibiotic tolerance profiles of two typical SARGs, MCR -1 and NDM -1, and their hosting bacteria in the downstream of the Yangtze River and the nearby wastewater treatment plant (WWTP) and drinking water treatment plant (DWTP). Results indicated that MCR -1 and NDM -1 were prevalent in the influent and biological units of the WWTP. Their hosting bacteria were effectively removed, but 2.49 × 108 copies/L MCR -1 and 7.00 × 106 copies/L NDM -1 were still persistent in the effluent. In the Yangtze River, MCR -1 and NDM -1 were detected with higher abundance and antibiotic tolerance than the WWTP effluent and were significantly affected by nearby water contamination and human activities. In the DWTP, MCR -1 and NDM -1 were detected with average values 5.56 × 107 copies/L and 2.14 × 105 copies/L in the influent. Their hosting bacteria were undetectable in the effluent, but the two SARGs were still persistent with 1.39 × 107 copies/L and 6.29 × 104 copies/L, and were greatly enriched in the sludge. Molecular ecological networks demonstrated wide hosting relationships between MCR -1/ NDM -1 and bacteria community in the DWTP. Redundancy analysis found that MCR -1 positively correlated with COD and NH 3 -N, while negatively correlated with turbidity. Additionally, MCR -1 hosting bacteria positively correlated with NO 3 −-N and negatively correlated with COD and NH 3 -N. NDM -1 positively correlated with turbidity and NDM -1 hosting bacteria positively correlated with COD and NO 2 −-N. The study demonstrated that the WWTP could not effectively remove SARGs with high amount of them being discharged into the Yangtze River. Then they were transported into the DWTP and the persistent SARGs in the effluent would probably be transferred into human, thus imposing great threats on public health. Graphical abstract Unlabelled Image Highlights • MCR-1 and NDM-1 are prevalent in the WWTP, DWTP and the Yangtze River samples. • WWTP and DWTP treatment processes cannot effectively remove MCR-1 and NDM-1. • Drinking water is a direct source of SARGs pollution threating public health. • The two SARGs abundance and tolerance are affected greatly by human activities. • Hosting relationships drive the correlation between ARGs and influencing factors. [ABSTRACT FROM AUTHOR]

Co@CoMoO x -α-CrOOH on nickel foam was developed as outstanding bifunctional electrocatalysts for alkaline water splitting, requires a low overpotential of only 36 mV and 278 mV to achieve current density of 10 mA cm−2 for HER and OER. [Display omitted] • Co@CoMoO x -α-CrOOH/NF as efficient electrocatalyst for overall water splitting. • Hybridization of α-CrOOH with Co-Mo oxides provide faster charge transfer kinetics. • α-CrOOH can modulate the local coordination environment and electronic structure. • Achieved overall efficiency that comparable to benchmark Pt/C/NF||IrO 2 /NF device. Rational design of highly active, durable and cost-efficient bifunctional catalysts for electrochemical water splitting is critical for aggressive reform of energy technologies. Herein, earth-abundant transition-metal (TM) oxide-(oxy)hydroxide (Co@CoMoO x -α-CrOOH) is synthesized as overall water splitting catalyst via a facile electrodeposition approach. Detailed X-ray absorption spectra (XAS) reveal that incorporation of α-CrOOH can implicitly modulate the local coordination environment and the electronic structure of Co/Mo/Cr cations, as well as their synergistic interaction that contributes to more rapid charge-transfer kinetics and enhanced catalytic activity. The precisely designed Co@CoMoO x -α-CrOOH/NF electrode displays prominent overall water-splitting efficiency that require a cell voltage only 1.57 V to achieve 10 mA cm−2 along with remarkable stability over 24 h in alkaline solution, which is comparable to a Pt/C/ NF || IrO 2 /NF water-splitting device at the state of the art. This work provides a sustainable strategy to design efficient and cost-effective TM oxide-based catalysts for water-splitting application. [ABSTRACT FROM AUTHOR]

A static analytic method was employed to measure the solubility of azithromycin in the binary water + 1,2-propanediol systems at T = (289.35 to 319.15) K. The modified Apelblat equation, the General Single Model and the Hybrid model were used to correlate the solubility data. The mole fraction solubility of azithromycin increased with increasing temperature and the mole fraction composition of 1,2-propanediol. Compared with the experimental data, the back-calculated values of the three models showed good correlation in all cases. The overall root mean square deviations ( ORMSD ) of the three models are 2.0788, 2.0451 and 5.9461, respectively. However, the modified Apelblat equation and the General Single model led to more reliable and accurate results than the Hybrid model. The fundamental solubility data and the three models in this work could be applied for related process design of azithromycin. Finally, the dissolution Gibbs energy and enthalpy for azithromycin in various binary mixtures were derived from the Van't Hoff and Krug analysis, which indicated that the process was endothermic and nonspontaneous, and the result well agreed with the analysis of their molecular and intermolecular forces. [ABSTRACT FROM AUTHOR]

In this paper, by combining the boundary element method (BEM) and peridynamics (PD), a bubble-ice interaction model is established, which can investigate the dynamic interactions between a high-pressure bubble and an ice plate with particular focus on the mechanical behaviors of ice breaking. The bubble dynamics are solved by BEM based on the potential flow theory. Ice cracks initiation and propagation are simulated by the bond-based peridynamics which is validated by a three-point bending test. The fluid–structure interaction (FSI) is achieved by matching the normal velocity and hydrodynamic loads at the fluid–structure interface. To validate the proposed FSI model, an experiment is carried out in which an oscillating bubble is generated under an ice plate by underwater discharge system. The whole interaction process is captured by a Phantom V711 high-speed camera. Qualitative agreements are achieved between the numerical and experimental results. The underlying mechanism of cracks initiation, propagation, branching, and coalescence of the ice plate is found to highly depend on three parameters, i.e., bubble–ice distance, ice thickness and bubble size. The present study is expected to provide further assists in the understanding of ice breaking problems. [ABSTRACT FROM AUTHOR]

Objective We sought to evaluate 5-year outcomes between microendoscopy-assisted minimally invasive (MIS) and open transforaminal lumbar interbody fusion (TLIF). Methods Sixty single-level MIS and open surgeries were performed (30 patients in either group). Perioperative parameters including operative duration, intraoperative estimated blood loss, fluoroscopy time, postoperative analgesic usage, ambulatory time, and complications were recorded. Visual analog scale (back and leg), Japanese Orthopaedics Association score, and Oswestry Disability Index were obtained. Finally, self-evaluation of surgical outcomes (modified MacNab criteria), interbody fusion rate (Bridwell grade 1), and prevalence of adjacent segment degeneration were assessed. Results Intraoperative estimated blood loss and postoperative analgesia usage were reduced in the MIS group, and patients undergoing microendoscopy-assisted MIS-TLIF ambulated earlier than those receiving open TLIF postoperatively. Nevertheless, surgical duration and fluoroscopy time were prolonged in the MIS group. Complication incidences were similar in both groups. Visual analog scale (back and leg), Japanese Orthopaedics Association, and Oswestry Disability Index were improved at 1 month, 2 years, and 5 years postoperatively in both groups when compared with preoperative scores. Significant improvements in these scores were found in the MIS group at 1 month postoperatively, while at 2 years and 5 years postoperatively, both groups revealed comparable aforementioned scores. Excellent and perfect scale rating, interbody fusion rate, and adjacent segment degeneration prevalence between the groups were almost similar. Conclusions Microendoscopy-assisted MIS-TLIF is comparable with open TLIF in terms of 5-year outcomes with additional benefits of reduced intraoperative iatrogenic injury, decreased initial pain, minimized activity restrictions, and accelerated ambulation recovery after surgery. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the risk factors and explore effective treatments for epistaxis in nasopharyngeal carcinoma (NPC) patients., Methods: From March 2006 to February 2020, 351 epistaxis patients visited our center and 195 patients meeting the inclusion criteria were enrolled in the study. Characteristics and treatments, including step-up hemostatic treatment (including medication, anterior ± posterior nostril packing, or further surgical hemostasis) and the CTPI emergency hemostasis method (including common carotid artery compression, tracheotomy / intubation, packing of nasal and nasopharynx, and interventional treatment), were analyzed., Results: The median total bleeding volume was 100.0 ml (range 20-4430 ml). 126 (64.6 %) and 69 (35.4 %) patients suffered from non-massive epistaxis and massive epistaxis. The 1-year overall survival (OS) rate was 60.1 % for patients with massive epistaxis and 97.3 % for those with non-massive epistaxis treated with step-up hemostatic treatment. Among patients with massive epistaxis, the 1-year OS rate was 80.0 % for those who received CTPI and 13.3 % for those who received step-up hemostatic treatment., Conclusion: ICA exposure and hemostasis failure was adverse prognostic factors for OS in NPC patients with epistaxis. The step-up hemostatic treatment is effective for controlling non-massive epistaxis. The CTPI emergency method might be an effective hemostasis treatment for NPC patients with massive epistaxis, especially those with PRNN and ICA exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine., Methods: The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively., Results: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01)., Conclusion: HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine., Competing Interests: Conflict of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47 phox , p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts., (© 2024 Wiley Periodicals LLC.)

Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue repair/remodeling and the subepithelial stroma region in whose nasal mucosa has been reported by us to have thromboxane A 2 (TXA 2 ) prostanoid (TP) receptor and overexpress connective tissue growth factor (CTGF). Therefore, this study aimed to investigate the relationship between TP receptor activation and CTGF production/function in human CRSsNP nasal mucosa stromal fibroblasts. We found that TP agonists including U46619 and IBOP ([1S-[1α,2α(Z),3β(1E,3 S*),4α]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) could promote CTGF protein/messenger RNA expression and secretion. The pharmacological intervention and TP activation assay with U46619 identified the possible participation of PKCμ, PKCδ, nuclear factor-κB (NF-κB), and cyclic AMP response element-binding protein (CREB) phosphorylation/activation in the CTGF induction. Moreover, a phorbol ester-phorbol-12-myristate 13-acetate (PMA) exhibited a similar cellular signaling and CTGF production profile to that elicited by TP activation. However, further small interfering RNA interference analysis revealed that only NF-κB and PKCδ-CREB pathways were necessarily required for TP-mediated CTGF production, which could not be completely supported by those findings from PMA. Finally, in a functional assay, although CTGF did not affect fibroblast proliferation, TP-mediated CTGF could drive novel self-migration in fibroblasts both in the scratch/wound healing and transwell apparatus assays. Meanwhile, the overall staining for stress fibers and formation of the lamellipodia and filopodia-like structures was concomitantly increased in the treated migrating cells. Collectively, we provided here that novel TP mediates CTGF production and self-migration in human nasal fibroblasts through NF-κB and PKCδ-CREB signaling pathways. More importantly, we also demonstrated that thromboxane, TP receptor, CTGF, and stromal fibroblasts may act in concert in the tissue remodeling/repair process during CRSsNP development and progression., (© 2024 Wiley Periodicals LLC.)

Background & Aims: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH., Methods: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target., Results: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4 + resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4 + /CD8 + T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice., Conclusion: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment., Impact and Implications: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Ovarian follicular fluid (FF) has a direct impact on oocyte quality, playing key roles in fertilization, implantation, and early embryo development. In our recent study, we found FF thromboxane (TX) to be a novel factor inversely correlated with oocyte maturation and identified thrombin, transforming growth factor β (TGFβ), TNF-α, and follicular granulosa cells (GCs) as possible contributors to FF TX production. Therefore, this study sought to investigate the role of TGFβ3 in regulating TX generation in human ovarian follicular GCs. TGFβ3 was differentially and significantly present in the FF of large and small follicles obtained from IVF patients with average concentrations of 68.58 ± 12.38 and 112.55 ± 14.82 pg/mL, respectively, and its levels were correlated with oocyte maturity. In an in vitro study, TGFβ3 induced TX generation/secretion and the converting enzyme-COX-2 protein/mRNA expression both in human HO23 and primary cultured ovarian follicular GCs. While TGFβRI and Smad2/3 signaling was mainly required for COX-2 induction, ERK1/2 appeared to regulate TX secretion. The participation of Smad2/3 and COX-2 in TGFβ3-induced TX generation/secretion could be further supported by the observations that Smad2/3 phosphorylation and nuclear translocation and siRNA knockdown of COX-2 expression compromised TX secretion in GCs challenged with TGFβ3. Taken together, the results presented here first demonstrated that FF TGFβ3 levels differ significantly in IVF patients' large preovulatory and small mid-antral follicles and are positively associated with oocyte maturation. TGFβ3 can provoke TX generation by induction of COX-2 mRNA/protein via a TGFβR-related canonical Smad2/3 signaling pathway, and TX secretion possibly by ERK1/2. These imply that TGFβ3 is one of the inducers for yielding FF TX in vivo, which may play a role in folliculogenesis and oocyte maturation.

The purpose of this study is to clarify the role of IL-33 in the immune response to angiostrongyliasis, especially in terms of antibody production and isotype switching. In our experiment, C57BL/6 mice were each infected with 35 infectious larvae and were divided into groups that received an intraperitoneal injection of IL-33, anti-IL-33 monoclonal antibody (mAb), or anti-ST2 mAb 3 days post-infection (dpi) and were subsequently administered booster shots at 5-day intervals with the same dose. Serum samples from each group were collected weekly for ELISA assays. The levels of total IgG, IgG1, and IgG3 were significantly increased in A. cantonensis -infected mice that were treated with IL-33, and the levels decreased significantly in infected groups treated with anti-IL-33 or anti-ST2 mAb. These results suggest that IL-33 may play a critical role in the pathogenesis of human angiostrongyliasis and could be useful for understanding protective immunity against this parasitic infection.

Objective: Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC., Methods: Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery., Results: Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0-151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS., Conclusions: Due to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC., (© 2024. The Author(s).)