ZBP1-mediated PANoptosis: A possible novel mechanism underlying the therapeutic effects of penehyclidine hydrochloride on myocardial ischemia-reperfusion injury.

Although penehyclidine hydrochloride (PHC) has been identified to alleviate myocardial injury induced by ischemia/reperfusion (I/R), the regulatory molecules and related mechanisms are unknown. In this study, bioinformatics, molecular biology, and biochemistry methods were used to explore the molecular mechanisms and targets of PHC. In the myocardial ischemia-reperfusion injury (MIRI)-induced rat model, PHC pretreatment significantly improved cardiac function (p < 0.01). Multiple differentially expressed genes, including Z-DNA binding protein 1 (ZBP1), were identified through mRNA sequencing analysis of myocardial ischemic penumbra tissue in MIRI rats. The transduction of the ZBP1 adenovirus vector (Ad-Zbp1) in PHC-pretreated rats exhibited a reversible augmentation in myocardial infarct size (p < 0.01), pronounced pathological damage to the myocardial tissue, as well as a significant elevation of serum myocardial enzymes (p < 0.05). The interaction among ZBP1, fas-associating via death domain (FADD), and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) leads to a remarkable up-regulation of cleaved-Caspase-1 (Cl-Casp-1), N-terminal gasdermin D (N-GSDMD), phospho-mixed lineage kinase domain-like Ser358 (p-MLKLS358), and other regulatory proteins, thereby triggering pyroptosis, apoptosis, and necroptosis (PANoptosis) in cardiomyocytes of MIRI rats. Moreover, the transduction of Ad-Zbp1 in the oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced H9c2 cell model also dramatically augmented the number of cell deaths. However, the intervention of PHC considerably enhanced cell viability (p < 0.01), effectively mitigated the release of myocardial enzymes (p < 0.05), and markedly attenuated the expression levels of PANoptosis regulatory proteins through restraint of ZBP1 expression. Therefore, the therapeutic efficacy of PHC in improving MIRI might be attributed to targeting ZBP1-mediated PANoptosis.

Penehyclidine hydrochloride alleviates lung ischemia-reperfusion injury by inhibiting pyroptosis.

OBJECTIVE: The aim of this research was to examine how penehyclidine hydrochloride (PHC) impacts the occurrence of pyroptosis in lung tissue cells within a rat model of lung ischemia-reperfusion injury. METHODS: Twenty-four Sprague Dawley (SD) rats, weighing 250 g to 270 g, were randomly distributed into three distinct groups as outlined below: a sham operation group (S group), a control group (C group), and a test group (PHC group). Rats in the PHC group received a preliminary intravenous injection of PHC at a dose of 3 mg/kg. At the conclusion of the experiment, lung tissue and blood samples were collected and properly stored for subsequent analysis. The levels of malondialdehyde, superoxide dismutase, and myeloperoxidase in the lung tissue, as well as IL-18 and IL-1ß in the blood serum, were assessed using an Elisa kit. Pyroptosis-related proteins, including Caspase1 p20, GSDMD-N, and NLRP3, were detected through the western blot method. Additionally, the dry-to-wet ratio (D/W) of the lung tissue and the findings from the blood gas analysis were also documented. RESULTS: In contrast to the control group, the PHC group showed enhancements in oxygenation metrics, reductions in oxidative stress and inflammatory reactions, and a decrease in lung injury. Additionally, the PHC group exhibited lowered levels of pyroptosis-associated proteins, including the N-terminal segment of gasdermin D (GSDMD-N), caspase-1p20, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). CONCLUSION: Pre-administration of PHC has the potential to mitigate lung ischemia-reperfusion injuries by suppressing the pyroptosis of lung tissue cells, diminishing inflammatory reactions, and enhancing lung function. The primary mechanism behind anti-pyroptotic effect of PHC appears to involve the inhibition of oxidative stress.

Penehyclidine for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Gynecological Laparoscopic Surgery Under Combined Intravenous and Inhalation Anesthesia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: We designed this study to investigate the effect of intravenous use of penehyclidine on postoperative nausea and vomiting (PONV) after gynecological laparoscopic surgery. Patients and Methods: Ninety-two Women Patients (Aged ≥ 18) Scheduled for Elective Gynecologic Laparoscopy Were Enrolled in the Current Study. Patients Were Equally Randomized Assigned Into Penehyclidine group (PHC group: received a bolus of penehyclidine 10 µg/kg during the induction of anesthesia, then followed by a continuous infusion of 10 µg/kg penehyclidine at a fixed rate of 2.0 mL/h in postoperative intravenous analgesia pump over 48h, 0.5 mg upper limit respectively) or Control group (received 0.9% saline in replace of penehyclidine at the same time points). The primary outcome measure was the incidence of postoperative nausea and vomiting in the postanesthesia care unit and ward area. Quality of Recovery-15 (QoR-15) scores and general comfort questionnaire (GCQ) scores were assessed on postoperative day (POD) 1, 2. Results: Patients between two groups had comparable baseline characteristics. Compared with the Control group, the incidence and severity of PONV, postoperative nausea (PON), and postoperative vomiting (POV) were significantly lower in the PHC group at 2h (PONV: P = 0.002, P = 0.004, respectively; PON: P = 0.018, P = 0.038, respectively; POV: P = 0.011, P = 0.072, respectively), 24h (PONV: P = 0.003, P = 0.001, respectively; PON: P = 0.010, P = 0.032, respectively; POV: P = 0.006, P = 0.044, respectively), and 48h (PONV: P = 0.003, P = 0.002, respectively; PON: P = 0.007, P = 0.019, respectively; POV: P = 0.002, P = 0.013, respectively) after surgery. The QoR-15 and GCQ scores of the PHC group were significantly higher than those of the Control group at POD 1, 2 (P < 0.001; P < 0.001, respectively). Conclusion: Our findings suggest that perioperative intravenous application of penehyclidine can effectively prevent postoperative nausea and vomiting in gynecological laparoscopic surgery patients and improve postoperative recovery.

Penehyclidine hydrochloride alleviates LPS-induced inflammatory responses and oxidative stress via ROS/Nrf2/HO-1 activation in RAW264.7 cells.

BACKGROUND: Inflammation is a biological response of the immune system to harmful stimuli. Penehyclidine hydrochloride (PCH) can alleviate inflammation and oxidative stress by activating reactive oxygen species (ROS), nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase 1 (HO-1) in animal models, but there is a lack of cellular evidence. OBJECTIVES: This study investigated the effects of PHC on lipopolysaccharide (LPS)-induced inflammation response and oxidative stress in RAW264.7 cells. MATERIAL AND METHODS: RAW264.7 cells were treated with 1 µg/mL or 5 µg/mL of PHC, with interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-1ß, and prostaglandin E2 (PGE2) levels measured with enzyme-linked immunosorbent assay (ELISA) and nitric oxide (NO) measured using the Griess test. Reactive oxygen species were examined with flow cytometry and immunofluorescence, and b-related factor 2 (BRF-2) and NAD(P)H-quinone oxidoreductase 1 (NQO1) using western blot. RESULTS: Penehyclidine hydrochloride partly, but substantially, reversed LPS-related NO and PGE2 production by RAW264.7 cells in a dose-dependent manner and suppressed LPS-induced expression of IL-6, TNF-α and IL-1ß messenger ribonucleic acid (mRNA), secretion of IL-6, TNF-α and IL-1ß, and ROS production. Lipopolysaccharide stimulation did not affect Nrf2, heme oxygenase 1 (HO-1) or NQO1 protein expression in RWA264.7 cells not treated with PHC. However, PHC treatment significantly elevated Nrf2, HO-1 and NQO1 protein in LPS-treated RWA264.7 cells, an effect that was dose-dependent. The ROS scavenging using N-acetyl-L-cysteine abolished the PHC-induced upregulation of Nrf2 and HO-1. CONCLUSIONS: Penehyclidine hydrochloride may alleviate LPS-induced inflammation and oxidative stress by activating Nrf2 signaling in RAW264.7 macrophages. These findings suggest that PHC could alleviate inflammation by targeting activated macrophages.

Effect of intravenous vs. inhaled penehyclidine on respiratory mechanics in patients during one-lung ventilation for thoracoscopic surgery: a prospective, double-blind, randomised controlled trial.

BACKGROUND: Minimising postoperative pulmonary complications (PPCs) after thoracic surgery is of utmost importance. A major factor contributing to PPCs is the driving pressure, which is determined by the ratio of tidal volume to lung compliance. Inhalation and intravenous administration of penehyclidine can improve lung compliance during intraoperative mechanical ventilation. Therefore, our study aimed to compare the efficacy of inhaled vs. intravenous penehyclidine during one-lung ventilation (OLV) in mitigating driving pressure and mechanical power among patients undergoing thoracic surgery. METHODS: A double-blind, prospective, randomised study involving 176 patients scheduled for elective thoracic surgery was conducted. These patients were randomly divided into two groups, namely the penehyclidine inhalation group and the intravenous group before their surgery. Driving pressure was assessed at T1 (5 min after OLV), T2 (15 min after OLV), T3 (30 min after OLV), and T4 (45 min after OLV) in both groups. The primary outcome of this study was the composite measure of driving pressure during OLV. The area under the curve (AUC) of driving pressure from T1 to T4 was computed. Additionally, the secondary outcomes included mechanical power, lung compliance and the incidence of PPCs. RESULTS: All 167 participants, 83 from the intravenous group and 84 from the inhalation group, completed the trial. The AUC of driving pressure for the intravenous group was 39.50 ± 9.42, while the inhalation group showed a value of 41.50 ± 8.03 (P = 0.138). The incidence of PPCs within 7 days after surgery was 27.7% in the intravenous group and 23.8% in the inhalation group (P = 0.564). No significant differences were observed in any of the other secondary outcomes between the two groups (all P > 0.05). CONCLUSIONS: Our study found that among patients undergoing thoracoscopic surgery, no significant differences were observed in the driving pressure and mechanical power during OLV between those who received an intravenous injection of penehyclidine and those who inhaled it. Moreover, no significant difference was observed in the incidence of PPCs between the two groups.

A New Aspect of Penehyclidine Hydrochloride in Alleviating Myocardial Ischemia-Reperfusion Injury: Ferroptosis.

Penehyclidine hydrochloride (PHC) is an anticholinergic drug with cardioprotective effects. Ferroptosis is closely related to myocardial ischaemia-reperfusion injury (MIRI). In the present study, MIRI was induced in rats by left anterior descending coronary artery ligation. PHC pretreatment increased haemodynamic parameters and histopathological damage and reduced myocardial infarction size in the MIRI model. PHC pretreatment also inhibited ferroptosis, which was characterized by the decreased levels of Fe2+, 4-hydroxynonenal and ACSL4, and increased levels of GPX4, GSH-Px and GST. In response to 6 h of oxygen-glucose deprivation and 18 h of reoxygenation, PHC pretreatment had the same effects on these factors in H9c2 cells and reduced lipid ROS levels. Furthermore, ACSL4 overexpression reversed the protective effects of PHC on H9c2 cells. These results indicated that PHC inhibited MIRI through ACSL4-mediated ferroptosis. This study demonstrated that PHC could inhibit ferroptosis in MIRI and the relationship among PHC, ACSL4, ferroptosis and MIRI. This study demonstrated the inhibitory effect of PHC on ferroptosis and showed that PHC affects MIRI through ACSL4-mediated ferroptosis in vivo and in vitro.

Effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery: a double-blind, randomized trial.

AIM: To investigate the effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery with cardiopulmonary bypass (CPB). METHODS: A total of 180 patients undergoing elective heart valve surgery with CPB were randomly divided into four groups: 45 in group P (intravenous penehyclidine hydrochloride 0.02 mg/kg 10 min before anesthesia induction and at the beginning of CPB, total 0.04 mg/kg); 43 in group D (dexmedetomidine 0.5 µg/kg/h after induction of anesthesia until the end of anesthesia); 44 in group PD ( penehyclidine hydrochloride 0.04 mg/kg combined with dexmedetomidine 0.5 µg/kg/h intravenously during anesthesia); and 43 in group C (same amount of normal saline 10 min before and after anesthesia induction, to the end of anesthesia, and at the beginning of CPB). The main outcomes were the incidence and severity of postoperative pulmonary complications (PPCs). The secondary outcomes were: (1) extubation time, length of stay in intensive care, and postoperative hospital stay, and adverse events; and (2) pulmonary function evaluation indices (oxygenation index and respiratory index) and plasma inflammatory factor concentrations (tumor necrosis factor-α, interleukin-6, C-reactive protein and procalcitonin) during the perioperative period. RESULTS: The incidence of PPCs in groups P, D and PD after CPB was lower than that in group C (P < 0.05), and the incidence in group PD was significantly lower than that in groups P and D (P < 0.05). The scores for PPCs in groups P, D and PD were lower than those in group C (P < 0.05). CONCLUSION: Combined use of penehyclidine hydrochloride and dexmedetomidine during anesthesia reduced the occurrence of postoperative pulmonary dysfunction, and improved the prognosis of patients undergoing heart valve surgery with CPB. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry on 3/11/2020 (Registration No.: ChiCTR2000039610).

Penehyclidine hydrochloride protects against lipopolysaccharide-induced acute lung injury by promoting the PI3K/Akt pathway.

INTRODUCTION: Acute lung injury (ALI) attracted attention among physicians because of its high mortality. We aimed to determine whether the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway is involved in the protective effects of penehyclidine hydrochloride (PHC) against lipopolysaccharide (LPS)-induced ALI. METHODS: H&E staining was used to observed pathological changes in the lung tissues. ELISA was used to evaluate the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF). White-light microscopy was performed to observe the TUNEL-positive nuclei. The viability of NR8383 alveolar macrophages was determined by using CCK-8. The levels of MPO, MDA, SOD, and GSH-Px were analyzed using ELISA kits. Western blotting was used to evaluate the ERS-associated protein levels and the phosphorylation of PI3K and Akt. RESULTS: PHC administration defended against LPS-induced histopathological deterioration and increased pulmonary edema and lung injury scores, while all of these beneficial effects were inhibited by LY. In addition, PHC administration mitigated oxidative stress as indicated by decreases in lung myeloperoxidase (MPO) and malondialdehyde (MDA) concentrations, and increases in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) concentrations. It also alleviated LPS-induced inflammation. PHC administration attenuated apoptosis-associated protein levels, improved cell viability, and decreased the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells. Furthermore, PHC inhibited ERS-associated protein levels. Meanwhile, the protection of PHC against inflammation, oxidative stress, apoptosis, and ERS was inhibited by LY. Moreover, PHC administration increased PI3K and Akt phosphorylation, indicating that the upregulation of the PI3K/Akt pathway, while this pathway was inhibited by LY. CONCLUSION: PHC significantly activates the PI3K/Akt pathway to ameliorate the extent of damage to pulmonary tissue, inflammation, oxidative stress, apoptosis, and ERS in LPS-induced ALI.

The advantages of penehyclidine hydrochloride over atropine in acute organophosphorus pesticide poisoning: A meta-analysis.

Background: Penehyclidine hydrochloride (PHC) has been used for many years as an anticholinergic drug for the treatment of acute organophosphorus pesticide poisoning (AOPP). The purpose of this meta-analysis was to explore whether PHC has advantages over atropine in the use of anticholinergic drugs in AOPP. Methods: We searched Scopus, Embase, Cochrane, PubMed, ProQuest, Ovid, Web of Science, China Science and Technology Journal Database (VIP), Duxiu, Chinese Biomedical literature (CBM), WanFang, and Chinese National Knowledge Infrastructure (CNKI), from inception to March 2022. After all qualified randomized controlled trials (RCTs) were included, we conducted quality evaluation, data extraction, and statistical analysis. Statistics using risk ratios (RR), weighted mean difference (WMD), and standard mean difference (SMD). Results: Our meta-analysis included 20,797 subjects from 240 studies across 242 different hospitals in China. Compared with the atropine group, the PHC group showed decreased mortality rate (RR=0.20, 95% confidence intervals [CI]: 0.16-0.25, P <0.001), hospitalization time (WMD=-3.89, 95% CI: -4.37 to -3.41, P <0.001), overall incidence rate of complications (RR=0.35, 95% CI: 0.28-0.43, P <0.001), overall incidence of adverse reactions (RR=0.19, 95% CI: 0.17-0.22, P <0.001), total symptom disappearance time (SMD=-2.13, 95% CI: -2.35 to -1.90, P <0.001), time for cholinesterase activity to return to normal value 50-60% (SMD=-1.87, 95% CI: -2.03 to -1.70, P <0.001), coma time (WMD=-5.57, 95% CI: -7.20 to -3.95, P <0.001), and mechanical ventilation time (WMD=-2.16, 95% CI: -2.79 to -1.53, P <0.001). Conclusion: PHC has several advantages over atropine as an anticholinergic drug in AOPP.

Penehyclidine hydrochloride for treating postoperative nausea and vomiting after laparoscopic bariatric surgery: a double-blinded randomized controlled trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common and distressing complication of laparoscopic bariatric surgery (LBS). Penehyclidine hydrochloride has been reported to be effective in preventing PONV. Considering the potential preventive effects of penehyclidine against PONV, we hypothesized that intravenous infusion of penehyclidine may alleviate PONV within the first 48 h in patients scheduled for LBS. METHODS: Patients who underwent LBS were randomly assigned (1:2) to receive saline (Control group, n = 113) or a single intravenous dose of penehyclidine 0.5 mg (PHC group, n = 221). The primary outcome was incidence of PONV within the first 48 h postoperatively. Secondary endpoints included severity of PONV, need for rescue antiemetic therapy, volume of water intake, and time to first flatus. RESULTS: PONV occurred in 159 (48%) patients within the first 48 h postoperatively, including 51% in the Control group and 46% in the PHC group. There was no significant difference in the incidence or severity of PONV between the two groups (P > 0.05). Within the first 24 h and 24-48 h, no significant difference was found in incidence or severity of PONV, postoperative nausea, postoperative vomiting, need for rescue antiemetic therapy, or volume of water intake (P > 0.05). Kaplan-Meier curves showed that penehyclidine was significantly associated with a prolonged time to first flatus (median onset time: 22 h vs. 21 h, P = 0.036). CONCLUSIONS: Penehyclidine did not decrease incidence and severity of PONV in patients undergoing LBS. However, a single intravenous dose of penehyclidine (0.5 mg) was associated with a slightly prolonged time to first flatus. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052418, http://www.chictr.org.cn/showprojen.aspx?proj=134893 , date of registration: 25/10/2021).

Penehyclidine Hydrochloride Protects Rat Cardiomyocytes from Ischemia- Reperfusion Injury by Platelet-derived Growth Factor-B.

AIMS AND OBJECTIVE: The lack of effective treatments for myocardial ischemiareperfusion (MI-R) injury severely restricts the effectiveness of the treatment of ischemic heart disease. In the present research, we aimed to investigate the protective effect and molecular mechanism of penehyclidine hydrochloride (PHC) on MI-R cells. METHODS: Cell viability was quantified using CCK8. Cell apoptosis was analyzed using flow cytometry. Western blot and Elisa assays were used for the detection of target proteins. RESULTS: PHC pretreatment attenuated the inhibition of cell viability and decreased the percentage of apoptosis induced by simulated ischemia reperfusion (SIR). Platelet-derived growth factor B (PDGF-B) and its downstream AKT pathway were activated in PHC pretreated cells. After siRNAPDGF- B transfection, cell viability was inhibited and apoptosis was activated in PHC pretreated SIR cells, suggesting that PHC protected cells from SIR. PDGF-B knockdown also increased the levels of CK, LDH, IL-6 and TNF-α in PHC pretreated SIR cells. The effect of AKT inhibitor on H9C2 cells was consistent with that of PDGF-B knockdown. CONCLUSION: PHC pretreatment can protect cardiomyocytes from the decrease of cell activity and the increase of apoptosis caused by reperfusion through up-regulating PDGF-B to activate PI3K pathway. Our study indicates that PHC is a potential drug to protect cells from reperfusion injury and PDGF-B is a potential target for preventing MI-R injury.

[A case of acute poisoning with thiamethoxam].

Thiamethoxam belongs to the second generation of neonicotinoid insecticides, and case of acute poisoning with thiamethoxam had never reported in China. This paper reviewed a case of oral poisoning with thiamethoxam pesticides, the patient suffered vomiting, generalized convulsions, confusion, and decreased oxygen saturation. After treated with gastric lavage, ventilator support, and the use of propofol, midazolam, sodium phenobarbital, and sodium valproate, the convulsions could not be controlled. Untill treated with penehyclidine hydrochloride and hemoperfusion combined with hemofiltration, the patient finally recovered and was discharged from the hospital. We suggest that the main treatments for acute severe thiamethoxam poisoning are decontamination and symptomatic support, pentoxifylline hydrochloride and hemoperfusion combined with hemofiltration may improve the patients' prognosis.

Evaluation of penehyclidine for prevention of post operative nausea and vomitting in patients undergoing total thyroidectomy under total intravenous anaesthesia with propofol-remifentanil.

BACKGROUD: Postoperative nausea and vomiting (PONV) is one of the most common complications after total thyroidectomy under general anesthesia. Total intravenous anesthesia (TIVA) has been documented to prevent PONV in patients undergoing total thyroidectomy. Penehyclidine, an anticholinergic agent with an elimination half-life of over 10 h, is widely used as premedication to reduce glandular secretion. This study aimed to explore the preventative effects of penehyclidine with propofol-remifentanil-TIVA to single-TIVA on PONV in patients undergoing total thyroidectomy. METHODS: A total of 100 patients scheduled for total thyroidectomy were randomly assigned to either the penehyclidine group (n = 50) or TIVA group (n = 50). Propofol and remifentanil were was used for TIVA in all patients. No patients who received premedication. Patients were administrated with either 5 ml of normal saline or 0.5 mg of penehyclidine soon after anesthesia induction. The incidence of nausea and vomiting, the severity of nausea, the requirement of rescue antiemetics, and adverse effects were investigated during the first 24 h in two time periods (0-2 h and 2-24 h). RESULTS: The overall PONV incidence during the 24 h after surgery was significantly lower in the penehyclidine group compared with the TIVA group (12% vs 36%, P < 0.005). Besides, the incidence of nausea and the incidence of vomiting were significantly lower in the penehyclidine group compared with the TIVA group at 2-24 h after surgery. However, there was no significant difference between the two groups at 0-2 h after surgery. CONCLUSIONS: Administration of penehyclidine under TIVA with propofol-remifentanil is more effective for prevention of PONV than TIVA alone, especially 2-24 h after total thyroidectomy. TRIAL REGISTRATION: https://www.chictr.org.cn/edit.aspx?pid=132463&htm=4 (Ref: ChiCTR2100050278, the full date of first registration: 25/08/2021).

A new choice for human rabies diagnosis: A case report of metagenomics next-generation sequencing in diagnosis of human rabies.

PURPOSE: We report a case of human rabies diagnosed by the metagenomics next-generation sequencing (mNGS). A 59-year-old man developed clinical rabies 20 days after he was bitten by dogs. Treatment included induction of coma initially; rabies vaccine was not administered. The patient was treated with propofol, midazolam, recombinant human interferon α2b, ribavirin, and amantadine. Penehyclidine was administrated to relieved the rabies induced pulmonary edema and the salivation. RESULTS: The patient's situation got worse on the 26th day after admition, and died on the 29th day finally. CONCLUSION: The mNGS might be a new choice for human rabies diagnosis，penehyclidine was effective in decreasing the rabies induced pulmonary edema and the salivation.

Effects of penehyclidine hydrochloride on myocardial ischaemia-reperfusion injury in rats by inhibiting TLR4/MyD88/NF-κB pathway via miR-199a-3p.

This study was to probe the role of penehyclidine hydrochloride (PHC) mediating the impact of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signalling pathway on myocardial ischaemia-reperfusion injury (MI/RI) in rats through miR-199a-3p. The rat MI/RI model was established through ligating left anterior descending (LAD) coronary artery. PHC was injected preoperatively into the model rats, and injected with miR-199a-3p lentiviral vector or TLR4 antagonist (TAK-242). Next, cardiac function of rats was examined by echocardiography, and rat serum indicators, oxidative stress levels and inflammatory factors were detected. HE staining was applied to detect pathological tissue structure, TUNEL staining to detect apoptosis rate, qRCR and western blot to detect miR-199a-3p and TLR4/MyD88/NF-κB expressions in rat myocardial tissues. Dual luciferase reporter experiment was conducted to confirm the relationship between miR-199a-3p and TLR4. In conclusion, PHC suppresses TLR4/MyD88/NF-κB signalling pathway through miR-199a-3p, thereby improving MI/RI in rats.

Penehyclidine hydrochloride ameliorates renal ischemia reperfusion-stimulated lung injury in mice by activating Nrf2 signaling.

Introduction: Penehyclidine hydrochloride (PHC) is an anticholinergic with anti-inflammatory and anti-oxidation activities. PHC displayed protectivity against renal ischemia reperfusion (RIR) injury. Nevertheless, the precise protectivity of PHC on RIR-induced lung injury remains unknown. Methods: We examined the effects of PHC on RIR-induced lung injury and investigated the underlying mechanism. We induced RIR in mice and administrated PHC to RIR mice. Kidney function was monitored by measuring the blood urea nitrogen (BUN) and creatinine level in serum. We evaluated the lung injury, myeloperoxidase (MPO) activity in lung, pro-inflammatory cytokine level, and oxidative markers in serum and lung tissues. We tested the expression level of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) in lung of RIR mice after PHC treatment. Finally, we evaluated the effects of PHC in RIR Nrf2-/- mice. Results: PHC greatly downregulated the serum levels of BUN, creatinine, IL-6, NO, malondialdehyde (MDA), and matrix metalloproteinase-2. PHC also ameliorated the lung injury, decreased the MPO activity, and suppressed production of IL-6, TNF-α, IFN-γ, MDA, and O2-, while it promoted production of superoxide dismutase (SOD) and catalase (CAT) in lung. PHC improved the production of Nrf2 and HO-1. Conclusion: The protectivity of PHC was absent in Nrf2-/- mice. PHC ameliorated RIR-induced lung injury through Nrf2 pathway.

Penehyclidine hydrochloride suppresses inflammation response and reduces podocyte injury in diabetic nephropathy by targeting fibrinogen-like protein 2.

BACKGROUND: Diabetic nephropathy (DN) is one of the main complications of diabetes. Penehyclidine hydrochloride (PHC) has anti-inflammatory, anti-apoptotic and anti-oxidative stress effects. Nevertheless, whether PHC can be used to prevent podocyte injury has not been reported. OBJECTIVES: This present study aimed to identify the functional role of PHC in DN as well as its underlying mechanism. METHODS: The high-glucose (HG)-induced podocyte damage in vitro model was established. The proliferation, apoptotic rate, inflammatory factors, and gene/protein expressions of HG-induced MPC5 cells were determined using CCK-8 assay, flow cytometry, ELISA, real-time PCR, and Western blot upon PHC treatment. Co-immunoprecipitation experiments and pull-down assay were performed to verify the interactions between fibrinogen-like protein 2 (Fgl2) and toll-like receptor 4 (TLR4) as well as TLR4 and NLRP3. A rat in vivo model was used to confirm the effect of PHC treatment. RESULTS: PHC treatment reduced Fgl2 expression and inhibited HG-induced podocyte injury and DN-induced kidney damage. Flg2 was associated with TLR4 and NLRP3. It was further proved that PHC treatment suppressed the TLR4-NF-кB and NLRP3-Caspase-1 pathways through Fgl2, which eventually inhibited inflammatory cytokines and prevented HG-induced podocyte injury both in vitro and in vivo. CONCLUSION: PHC treatment possibly ameliorates DN by preventing podocyte injury via inactivating the TLR4-NF-кB and NLRP3-Caspase-1 signaling pathways by Flg2.

Penehyclidine for prevention of postoperative nausea and vomiting following bimaxillary orthognathic surgery: a randomized, double-blind, controlled trial.

PURPOSE: To investigate the efficacy and safety of low-dose bolus plus continuous infusion of penehyclidine in preventing postoperative nausea and vomiting (PONV) following bimaxillary surgery. METHODS: Three hundred fifty-four patients were randomly allocated into three groups. In the Control group, placebo (normal saline) was injected before anesthesia and infused over 48 h after surgery; in the Bolus group, 0.5 mg penehyclidine was injected before anesthesia, whereas placebo was infused after surgery; in the Infusion group, 0.25 mg penehyclidine were injected before anesthesia, another 0.25 mg penehyclidine was infused after surgery. The primary endpoint was the incidence of PONV within 72 h. RESULTS: A total of 353 patients were included in intention-to-treat analysis. The PONV incidence was 61.0% (72/118) in the Control group, 40.2% (47/117) in the Bolus group, and 28.0% (33/118) in the Infusion group. The incidence was significantly lower in the Bolus group than in the Control group (RR 0.66; 95% CI 0.51-0.86; adjusted P = 0.003) and in the Infusion group than in the Control group (RR 0.46; 95% CI 0.33-0.63; adjusted P < 0.001); the difference between the Infusion and Bolus groups was not statistically significant (RR 0.70; 95% CI 0.48-1.00; adjusted P = 0.144). Emergence agitation occurred more frequently in the Bolus group than in the Control group (36.8% [43/117] vs. 21.2% [25/118], adjusted P = 0.027), but did not differ significantly between the Infusion and Control groups. CONCLUSIONS: A low-dose bolus plus continuous infusion of penehyclidine was effective in preventing PONV without increasing emergence agitation. TRIAL REGISTRATION: Clinicaltrials.gov. Identifier: NCT04454866.

The Protective Activity of Penehyclidine Hydrochloride against Renal Ischemia/Reperfusion-Mediated NLRP3 Inflammasome Activation is Induced by SIRT1.

Background: The activation of alveolar macrophages (AMs) modulated via leucine-rich repeat (NLR) pyrin domain containing 3 (NLRP3) inflammasome activation is key to the progression of renal ischemia/reperfusion (rI/R)-mediated acute lung injury (ALI). Sirtuin-1 (SIRT1) can attenuate NLRP3 inflammasome activation during I/R stress and may be an important mechanism underlying ALI pathogenesis. Penehyclidine hydrochloride (PHC), an anticholinergic drug, exerts protective effects against rI/R-mediated ALI. This study aimed to decipher the effects of PHC on SIRT1 activation and the underlying mechanism of the protective activity of PHC against rI/R-mediated ALI.Materials and methods: We used an ALI rat model and the rat AMs cell line NR8383 to assess the degree of lung injury in vivo and in vitro.Results: The results show that PHC attenuates rI/R-mediated lung injury indices, myeloperoxidase, and apoptosis in vivo. It decreases the rI/R-mediated release of prostaglandin E2 and nitric oxide, mitochondrial reactive oxygen species production, and the activity of NADPH oxidase-4 in vitro. PHC ameliorates the rI/R-induced activation of the thioredoxin-interacting protein, caspase 1 (P10 unit), and NLRP3 inflammasome, along with reduced activation of interleukin-1ß and interleukin-18 in vitro. We show that PHC alleviates the rI/R-induced reduction of SIRT1 and the depletion of SIRT1 eliminates the ameliorating activity of PHC on the NLRP3 inflammasome activation in vitro. Conclusions: In summary, the findings suggest that PHC ameliorates the rI/R-mediated ALI through the SIRT1-mediated NLRP3 inflammasome activation.

Clinical study on revised penehyclidine hydrochloride treatment program for acute severe organophosphorus pesticide poisoning / 环境与职业医学

Background The current treatment program with penehyclidine hydrochloride (PHC) for acute severe organophosphorus pesticide poisoning (ASOPP) patients exerts a positive effect but with concerned adverse reactions. Objective To evaluate the treatment effect of a revised ASOPP treatment program with PHC. Methods A prospective single-blind randomized controlled trial was conducted. A total of 157 patients with ASOPP were divided into a revised treatment group (82 cases) and a conventional treatment group (75 cases) by random number table. The two groups received the same basic treatment measures including active life support, routine gastric lavage, catharsis, and pralidoxime treatment. The revised treatment group followed a revised PHC treatment protocol initiated by first a small dose of PHC and followed by small doses of PHC administration/discontinuation through frequent observations at different time points. The conventional treatment group received the conventional program. Treatment effects and incidence rates of possible adverse reactions were compared between the two groups. Results Compared with the conventional treatment group, the revised treatment group obtained delay in penetrogenation time point, higher success rate in catharsis, earlier cholinesterase-turning time, and shorter hospitalization period with statistical significance (all Ps＜0.05). No differences were found in terms of time for symptoms of poisoning to disappear, incidence rates of intermediate myasthenic syndrome and delayed polyneuropathy, mechanical ventilation time, and cure rate (all Ps＞0.05). Less adverse reactions occurred in the revised treatment group including tachycardia and delirium than in the conventional treatment control group (all Ps＜0.05). Conclusion The revised ASOPP treatment program with PHC is similar to the current recommended treatment program in treatment effects, but with less adverse reactions.