Aloe-emodin Attenuates Staphylococcus aureus Pathogenicity by Interfering With the Oligomerization of α-Toxin

α-toxin, an essential virulence factor secreted by Staphylococcus aureus (S. aureus), is a critical exotoxin in multiple infections. In this study, we found that aloe-emodin (AE), a natural compound lacking anti-S. aureus activity, could inhibit the hemolytic activity of α-toxin. Oligomerization assays, molecular dynamics simulations, and fluorescence-quenching analyses were used to determine the mechanism of this inhibition. The oligomerization of α-toxin was restricted by the engagement of AE with K110, T112, and M113 of the toxin, which eventually resulted in inhibition of the hemolytic activity. Lactate dehydrogenase and live/dead assays demonstrated that AE decreased the injury of human lung epithelial cells (A549) and mouse lung macrophages (MH-S) mediated by S. aureus. Furthermore, treatment with AE showed robust protective effects in mice infected by S. aureus. These findings suggest that AE effectively inhibited the pore-forming activity of α-toxin and showed a protective effect against S. aureus virulence in vitro and in vivo, which may provide a new strategy and new antibacterial agent for clinical treatment of S. aureus infections

Effects of nerve block in different areas on opiate dosage and stress response in patients undergoing thoracoscopic radical resection of lung cancer

Objective: To explore the effects of ultrasound-guided serratus anterior plane block (SAPB) and thoracic paravertebral block (TPVB) on opiate dosage and stress response in patients undergoing thoracoscopic radical resection of lung cancer. Methods: A total of 130 patients undergoing elective thoracoscopic radical resection of lung cancer in Changshu Second Peoples Hospital between June 2019 and January 2022 were enrolled. According to the random number table method, they were divided into SAPB group (65 cases, ultrasound-guided SAPB before anesthesia induction) and TPVB group (65 cases, ultrasound-guided TPVB before anesthesia induction). After surgery, all underwent patient-controlled intravenous analgesia with analgesia pumps. The timepoints including preoperative, thoracic closure, and postoperative 2, 6, and 24 hours were set as T1, T2, T3, T4 and T5, respectively, and the intraoperative blood loss and fluid supplement, operation time, intraoperative dosages of sufentanil and propofol, and postoperative cumulative dosages of sufentanil at T3, T4 and T5 in the two groups were recorded. At T3, T4 and T5, pain changes were evaluated by Prince-Henry scores. The levels of prostaglandins E2 (PGE2), norepinephrine (NE) and cortisol (Cor) were detected by enzyme-linked immunosorbent assay. The partial pressure of arterial oxygen was detected by a blood gas analyzer, and oxygenation index (OI) was calculated. The occurrence of postoperative adverse events (PAEs) in the two groups was recorded. Results: From T3 to T5, levels of PGE2, NE, and Cor in SAPB group were significantly lower than those in TPVB group (P＜0.05). OI at T2 to T4 was significantly lower than that at T1, while OI at T5 was significantly higher than that at T2, T3, and T4 in both groups (P＜0.05). From T2 to T4, OI in SAPB group was significantly higher than that in TPVB group (P＜0.05). Compared with TPVB group, the cumulative consumption of sufentanil in SAPB group slightly decreased from T3 to T5, but the differences were not statistically significant (P>0.05). The incidences of nausea and vomiting (6.15% vs 18.46%, χ2=4.561, P=0.033), atelectasis(3.08% vs 12.31%, χ2=3.900, P=0.048) and hypotension (7.69% vs 20.00%, χ2=4.127, P=0.042) in SAPB group were lower than those in TPVB group. Conclusion: Compared with TPVB, ultrasound-guided SAPB can relieve stress response, promote the recovery of pulmonary oxygenation and reduce PAEs in patients undergoing thoracoscopic radical resection of lung cancer, but whether it can significantly reduce the dosage of opiates needs to be further explored

Phloretin Attenuates Listeria monocytogenes Virulence Both In vitro and In vivo by Simultaneously Targeting Listeriolysin O and Sortase A

The critical roles of sortase A (SrtA) and listeriolysin O (LLO) in Listeria monocytogenes pathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents against L. monocytogenes infection. Additionally, the structures of SrtA and LLO are highly conserved among the members of sortase enzyme family and cholesterol dependent toxin family. Here, phloretin, a natural polyphenolic compound derived from apples and pears that has little anti-L. monocytogenes activity, was identified to simultaneously inhibit LLO expression and neutralize SrtA catalytic activity. Phloretin neutralized SrtA activity by causing a conformational change in the protein's active pocket, which prevented engagement with its substrate. Treatment with phloretin simultaneously reduced L. monocytogenes invasion into host cells and blocked the escape of vacuole-entrapped L. monocytogenes into cytoplasm. Further, L. monocytogenes-infected mice that received phloretin showed lower mortality, decreased bacterial burden and reduced pathological injury. Our results demonstrate that phloretin is a promising anti-infective therapeutic for infections caused by L. monocytogenes due to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output [preprint]

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires the precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output

Cardiac commitment driven by MyoD expression in pericardial stem cells

Cellular therapy holds immense promise to remuscularize the damaged myocardium but is practically hindered by limited allogeneic sources of cardiac-committed cells that engraft stably in the recipient heart after transplantation. Here, we demonstrate that the pericardial tissue harbors myogenic stem cells (pSCs) that are activated in response to inflammatory signaling after myocardial infarction (MI). The pSCs derived from the MI rats (MI-pSCs) show in vivo and in vitro cardiac commitment characterized by cardiac-specific Tnnt2 expression and formation of rhythmic contraction in culture. Bulk RNA-seq analysis reveals significant upregulation of a panel of genes related to cardiac/myogenic differentiation, paracrine factors, and extracellular matrix in the activated pSCs compared to the control pSCs (Sham-pSCs). Notably, we define MyoD as a key factor that governs the process of cardiac commitment, as siRNA-mediated MyoD gene silencing results in a significant reduction of myogenic potential. Injection of the cardiac-committed cells into the infarcted rat heart leads to long-term survival and stable engraftment in the recipient myocardium. Therefore, these findings point to pericardial myogenic progenitors as an attractive candidate for cardiac cell-based therapy to remuscularize the damaged myocardium

The proper class generated by weak supplements

We show that, for hereditary rings, the smallest proper classes containing respectively the classes of short exact sequences determined by small submodules, submodules that have supplements and weak supplement submodules coincide. Moreover, we show that this class can be obtained as a natural extension of the class determined by small submodules. We also study injective, projective, coinjective and coprojective objects of this class. We prove that it is coinjectively generated and its global dimension is at most 1. Finally, we describe this class for Dedekind domains in terms of supplement submodules.TUBITAK (107T709

Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>P21^(WAF1/Cip1)binds to cyclin-dependent kinase complexes and inhibits their activities. It was originally described as an inhibitor of cancer cell proliferation. However, many recent studies have shown that p21 promotes tumor progression when accumulated in the cell cytoplasm. So far, little is known about the correlation between cytoplasmic p21 and drug resistance. This study was aimed to investigate the role of p21 in the cisplatin resistance of ovarian cancer.</p> <p>Methods</p> <p>RT-PCR, western blot and immunofluorescence were used to detect p21 expression and location in cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008. Regulation of cytoplasmic p21 was performed through transfection of p21 siRNA, Akt2 shRNA and Akt2 constitutively active vector in the two cell lines; their effects on cisplatin-induced apoptosis were evaluated by flow cytometry. Tumor tissue sections of clinical samples were analyzed by immunohistochemistry.</p> <p>Results</p> <p>p21 predominantly localizes to the cytoplasm in C13* compared to OV2008. Persistent exposure to low dose cisplatin in OV2008 leads to p21 translocation from nuclear to cytoplasm, while it had not impact on p21 localization in C13*. Knockdown of cytoplasmic p21 by p21 siRNA transfection in C13* notably increased cisplatin-induced apoptosis through activation of caspase 3. Inhibition of p21 translocation into the cytoplasm by transfection of Akt2 shRNA into C13* cells significantly increased cisplatin-induced apoptosis, while induction of p21 translocation into the cytoplasm by transfection of constitutively active Akt2 in OV2008 enhanced the resistance to cisplatin. Immunohistochemical analysis of clinical ovarian tumor tissues demonstrated that cytoplasmic p21 was negatively correlated with the response to cisplatin based treatment.</p> <p>Conclusions</p> <p>Cytoplasmic p21 is a novel biomarker of cisplatin resistance and it may represent a potential therapeutic target for ovarian tumors that are refractory to conventional treatment.</p

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output