Icariside II prevents kidney fibrosis development in chronic kidney disease by promoting fatty acid oxidation.

Renal interstitial fibrosis (RIF) is the main pathological basis for the progression of chronic kidney disease (CKD), however, effective interventions are limited. Here, we investigated the effect of Icariside II (ICA-II) on RIF and explored the underlying mechanisms. Rats receiving 5/6 ablation and infarction (A/I) surgery were gavaged with ICA-II (5 or 10 mg/kg) for 8 weeks. In vitro, TGF-ß1-stimulated NRK-52E cells were treated with ICA-II and (or) oleic acid, etomoxir, ranolazine, fenofibrate, and GW6471. The effects of ICA-II on RIF, fatty acid oxidation, lipid deposition, and mitochondrial function were determined by immunoblotting, Oil red O staining, colorimetric, and fluorometric assays. Using adeno-associated virus injection and co-culture methods, we further determined mechanisms of ICA-II anti-RIF. ICA-II ameliorated the fibrotic responses in vivo and in vitro. RNA-seq analysis indicated that ICA-II regulated fatty acid degradation and PPAR pathway in 5/6 (A/I) kidneys. ICA-II attenuated lipid accumulation and up-regulated expression of PPARα, CPT-1α, Acaa2, and Acadsb proteins in vivo and in vitro. Compared to ICA-II treatment, ICA-II combined with Etomoxir exacerbated mitochondrial dysfunction and fibrotic responses in TGF-ß-treated NRK-52E cells. Importantly, we determined that ICA-II improved lipid metabolism, fatty acid oxidation, mitochondrial function, and RIF by restoring PPARα. Co-culture revealed that ICA-II decreased the expression of Fibronectin, Collagen-I, α-SMA, and PCNA proteins in NRK-49F cells by restoring PPARα of renal tubular cells. ICA-II may serve as a promising therapeutic agent for RIF in 5/6 (A/I) rats, which may be important for the prevention and treatment of CKD.

Association between white blood cell count and adverse pregnancy outcomes: a retrospective cohort study from a tertiary hospital in China.

OBJECTIVES: This study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes. DESIGN: A total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded. SETTING: Minhang Hospital, China. PARTICIPANTS: A total of 24 143 pregnant women were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the adverse pregnancy outcomes. RESULTS: For the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress. CONCLUSIONS: Our results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.

Nonalcoholic Fatty Liver Disease and Adverse Pregnancy Outcomes in Women With Normal Prepregnant Weight.

CONTEXT: Existing studies focusing on the effects of nonalcoholic fatty liver disease (NAFLD) combined with normal prepregnant weight on pregnancy outcomes are limited. OBJECTIVE: This study aimed to explore the relationship between maternal NAFLD and adverse pregnancy outcomes in different body mass index (BMI) groups. METHODS: Using an antenatal care and delivery database, we retrospectively analyzed women who delivered in Minhang Hospital affiliated to Fudan University, Shanghai, China from January 1, 2013, to June 30, 2020. NAFLD was confirmed by ultrasound in early pregnancy. A logistic regression model with adjustment for confounders was used to examine potential associations between NAFLD and pregnancy outcomes. RESULTS: A total of 14 708 pregnant women (mean prepregnant BMI 21.0 [SD, 2.8] kg/m2) were included in our final study, of whom 554 (3.8%) had NAFLD. After fully adjusting for potential confounders, NAFLD significantly increased the risk of gestational diabetes mellitus (adjusted odds ratio 2.477; 95% CI, 1.885-3.254), gestational hypertension (3.054; 2.191-4.257), preeclampsia/eclampsia (3.994; 2.591-6.005), cesarean section (1.569; 1.315-1.872), preterm births (1.831; 1.229-2.727), and macrosomia (1.691; 1.300-2.198). It is notable that 83.9% (12 338) of women were of normal weight at the start of pregnancy (prepregnant 18.5 ≤ BMI < 24 kg/m2), and they still had higher odds of adverse pregnancy outcomes. CONCLUSION: Women with NAFLD and a normal weight have a higher risk for adverse pregnancy outcomes. Pregnant women with NAFLD, regardless of obesity status, should be offered a more qualified surveillance to optimize pregnancy outcomes.

Low-dose naloxone for prophylaxis of sufentanil-induced choking and postoperative nausea and vomiting.

Sufentanil, a potent opioid, serves as the first option for perioperative analgesia owing to its analgesic effect, long duration and stable hemodynamics, whereas its side effects frequently blunt its application. The intravenous (IV) injection of sufentanil during anesthesia induction has high incidence of choking or bucking reaction, which is defined as sufentanil-induced cough (SIC). Moreover, postoperative nausea and vomiting (PONV) is a common and stressful complication, which is also related to the usage of opioid. High incidence of PONV is reported in the patients with SIC. Hence, we sought to determine whether naloxone, an opioid antagonist, at low dose would decrease the incidences of SIC and PONV. 216 female patients undergoing gynecological laparoscopic operation (<2 h) under general anesthesia were recruited in this study, and randomly assigned into two groups: Group N (patients receiving naloxone and Group C (patients receiving vehicle). Sufentanil (0.5 µg/kg within 5 s) was given in anesthesia induction, and low-dose naloxone (1.25 µg/kg) or identical vehicle was initially injected 5 min prior to induction, with the incidence and severity of SIC estimated. Subsequently, naloxone or vehicle was continuously infused at the rate of 0.5 µg/kg/h in the initiation of operation until the end of the operation, and the transverse abdominal fascia block (TAP) was performed for postoperative analgesia. The PONV profiles such as incidence and the severity, grading, and the frequencies of antiemetic usage within 24 h were evaluated, with VAS scores and remedial measures for analgesia during the first 24 h postoperatively were recorded. Our results revealed that one bolus of low-dose naloxone prior to the induction significantly mitigated the incidence of SIC, and intraoperative continuous infusion of low-dose naloxone reduced the incidence and the severity of PONV, so that the postoperative VAS scores and further remedial analgesia were not altered. These results not only provide clinical solutions for prophylaxis of SIC and PONV, but also suggests that opioids may act as a key role in both SIC and PONV, whereas opioid antagonist may hit two tasks with one stone. Moreover, further investigations are required to address the underlying mechanism of SIC and PONV. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2200064865].

Comparison of hepatic gene expression profiles between three mouse models of Nonalcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder worldwide. Murine models of NAFLD have been widely used to explore its pathogenesis. In this study, we performed a systematic evaluation of hepatic genome-wide mRNA expression by RNA-Sequencing using three mouse models of NAFLD: leptin receptor deficient db/db mice, high-fat high-sugar diet (HSHF)-induced obese mice, and dexamethasone (DEX)-induced NAFLD mice. As a result, we found both distinct and common pathways in the regulation of lipid metabolism from transcriptomes of three mouse models. Moreover, only a total of 12 differentially expressed genes (DEGs) were commonly detected among all three mouse groups, indicating very little overlap among all three models. Therefore, our results suggest that NAFLD is a heterogeneous disease with highly variable molecular mechanisms.

Effects of resveratrol on renal ischemia-reperfusion injury: A systematic review and meta-analysis.

Renal ischemia-reperfusion (I/R) injury may lead to acute kidney injury, which is characterized by high morbidity and mortality rates. Resveratrol (RSV) can be extracted from Chinese herbs, and multiple animal experiments have demonstrated its potential for renal protection. This systematic review evaluates the protective effect of RSV against renal I/R injury in animal models. The PubMed, Embase, Web of Science, and Science Direct databases were searched for animal experiments related to RSV in renal I/R injury from their establishment to June 2022. In total, 19 studies were included with 249 animals (129 treated with RSV and 120 as controls). The pooled analysis revealed that RSV administration significantly decreased serum creatinine (SCr) levels (16 studies, n = 243, WMD = -58.13, 95% CI = -79.26 to -37.00, p < 0.00001) and blood urea nitrogen (BUN) levels (12 studies, n = 163, WMD = -34.37, 95% CI = -46.70 to -22.03, p < 0.00001) in the renal I/R injury model. The level of malondialdehyde (MDA), an oxidative stress index, was alleviated [7 studies, n = 106, standardized mean difference (SMD) = -6.05, 95% CI = -8.90 to -3.21, p < 0.0001] and antioxidant enzymes such as glutathione (GSH) (7 studies, n = 115, SMD = 9.25, 95% CI = 5.51-13.00, p < 0.00001) and catalase (CAT) (4 studies, n = 59, SMD = 8.69, 95% CI = 4.35-13.03, p < 0.0001) were increased after treatment of RSV. The subgroup analysis suggested that 5-10 mg/kg of RSV optimally protects against renal I/R injury as both the BUN and SCr levels were significantly decreased at this dosage. The protective effects of RSV against renal I/R injury might be attributed to multiple mechanisms, such as inhibiting oxidative stress, apoptosis, inflammation, fibrillation, and promoting autophagy. For a deeper understanding of the protective effects of RSV, experimental studies on animal models and large randomized controlled trials in humans are needed.

Dexmedetomidine upregulates the expression of miR-493-5p, inhibiting growth and inducing the apoptosis of lung adenocarcinoma cells by targeting RASL11B.

Numerous studies have indicated that microRNAs (miRNAs) play critical roles in the development and progression of cancer. However, how changes to the expression levels of miRNAs in response to dexmedetomidine affects the progression of lung cancer remains poorly understood. In this study, we treated the lung adenocarcinoma cell line-A549 with dexmedetomidine and then examined the changes to the expression levels of miRNAs. We found that one of the most significantly upregulated miRNAs was miR-493-5p, which has an important role in the growth and apoptosis of lung adenocarcinoma (LUAD) cells. In addition, bioinformatics searches and luciferase reporter assays revealed that miR-493-5p targets RASL11B, which has a high degree of similarity to RAS. Finally, database searches revealed that RASL11B is associated with survival of LUAD cells. In conclusion, dexmedetomidine causes changes to the expression levels of miRNAs in LUAD, including significant upregulation of miR-493-5p. MiR-493-5p targets RASL11B, thereby inhibiting cell growth and inducing apoptosis in LUAD.

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor.

Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.

MKP1 in the medial prefrontal cortex modulates chronic neuropathic pain via regulation of p38 and JNK1/2.

Aim: The medial prefrontal context (mPFC) plays pivotal roles in initiation, development, and maintenance of chronic pain, whereas the underlying molecular mechanisms remain elusive, which invited investigation of potential involvement of MKP1 in mPFC in mice in neuropathic pain, and its cellular and molecular mechanisms.Materials and methods: Neuropathic pain model was established in adult male Kunming mice via chronic constrictive injury (CCI) of the sciatic nerve. Paw withdrawal latency (PWL) was measured at the plantar area by radiant heat test. Stereotaxic microinjection was applied in mice as per the atlas of Mouse Brain in Stereotaxic Coordinates. mRNA levels of MKP1 in mPFC in CCI mice were assessed by RT-PCR; protein expressions of MKP1, p-p38, p-JNK and p-ERK in mPFC in CCI mice were analyzed by Western blotting, and expressions of the c-Fos in mPFC in CCI mice evaluated by immunohistochemistry. Moreover, Lenti-MKP1 particles or BCI treatment was employed to inhibit MKP1 in mPFC contralateral to the injury.Results: MKP1 was activated and persistently upregulated in mPFC neurons in CCI mice. Inhibition of MKP1 in the mPFC contralateral to the injury could reverse CCI-induced pain behavior and neuronal activity either via employment of Lenti-MKP1 particles or BCI treatment. MKP1 in the mPFC modulated neuropathic pain via dephosphorization of p38 and JNK1/2.Conclusion: The findings demonstrated that MKP1 in mPFC could play a paramount role in the modulation of neuropathic pain, which might be associated to the increased neuronal excitability in the mPFC and downregulated p-p38 and p-JNK expression.

Doxapram alleviates low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy.

BACKGROUND: Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of anxiety that propofol provides, low SpO2 may also result. Doxapram is a respiratory stimulant with a short half-life. The primary aim of this study was to investigate the effects of doxapram on alleviating low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy. METHODS: In this prospective study, patients scheduled for painless gastrointestinal endoscopy were randomly assigned to group D or S with 55 patients per group. Initially, both groups received a combination of propofol and fentanyl. Patients in group D received 50 mg doxapram after propofol injection, while patients in group S received an equal volume of saline. Vital signs of the patients, propofol dose, examination duration, and incidences of low SpO2 were recorded. RESULTS: There were no statistical differences in propofol consumption and examination duration between the two groups. Twenty-six patients in group S experienced low SpO2 versus 10 in group D (P = 0.001). Nineteen patients in group S underwent oxygenation with a face mask in contrast to 8 in group D (P = 0.015). Eighteen patients in group S were treated with jaw lifting compared to 5 in group D (P = 0.002). Four patients in group S underwent assisted respiration compared to 2 in group D (without statistical difference). The average oxygen saturation in group S was significantly lower than that in group D at 1, 2 and 3 min after propofol injection (P < 0.001, P = 0.001 and P = 0.020, respectively). There were no statistical differences in oxygen saturation at other time points. There were no statistical differences in MAP and HR (except for the time point of 1 min after the induction) between the two groups. CONCLUSIONS: Low dose of doxapram can effectively alleviate low SpO2 in painless gastrointestinal endoscopy with intravenous propofol, without affecting propofol consumption, examination duration, MAP, or HR. TRAIL REGISTRATION: The study was approved by the Institutional Ethics Committee of Clinical and New Technology of Wuxi People's Hospital on 20th July, 2018 (KYLLH2018029) and registered in the Chinese Clinical Trial Register on 16th August, 2018 (ChiCTR1800017832).

Intrathecal injection of dexmedetomidine ameliorates chronic neuropathic pain via the modulation of MPK3/ERK1/2 in a mouse model of chronic neuropathic pain.

Objective: Despite the application of dexmedetomidine (DEX) as a perioperative adjuvant in local analgesia, the exact analgesic mechanism underpinning chronic neuropathic pain (CNP) awaits our elucidation. Methods: We investigated the molecular mechanisms of the anti-nociceptive effect of DEX on neuropathic pain in a mouse model induced by chronic constriction injury (CCI). Results: DEX administration significantly increased the paw withdrawal latency (PWL) values 0.5 to 2 h post-injection in CCI-induced CNP mice at day 5 to 21 versus dimethyl sulfoxide (DMSO)-treated mice, confirming its analgesic effect. The c-Fos expression was significantly elevated in CCI mice versus the sham-operated group, whereas the elevation was mitigated by DEX injection. Subsequently, the involvement of MKP1 and MKP3 in the pathogenesis of chronic neuropathic pain was evaluated. Western blotting analyses revealed significant decrease in both MKP1 and MKP3 in the spinal cord in CCI group versus the sham group. DEX markedly elevated the MKP3 expression and modestly reduced the MKP1 expression, with insignificant difference in the latter. Co-injection of BCI (an MKP3 inhibitor) and DEX evidently reduced the PWL values in CCI mice. Furthermore, DEX significantly downregulated the phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2, down-stream effector of MKP3 in CCI mice, whereas the downregulation was reversed by BCI. Conclusion: We confirmed that DEX exerts the analgesic effect on chronic neuropathic pain via the regulation of MKP3/ERK1/2 signaling pathway, which may contribute to clarification of the molecular mechanism and novel therapy for chronic neuropathic pain.

Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain.

BACKGROUND: The mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown. METHODS: Chronic constrictive injury (CCI) of the sciatic nerve was used to model neuropathic pain. Projection-specific in vitro recordings in mouse brain slices and in vivo recordings from anesthetized animals were used to measure firing of dopaminergic neurons in the ventral tegmental area (VTA). The role of VTA-nucleus accumbens (NAc) circuitry in nociceptive regulation was assessed using optogenetic and pharmacological manipulations, and the underlying molecular mechanisms were investigated by Western blotting, enzyme-linked immunosorbent assays, and conditional knockdown techniques. RESULTS: c-Fos expression in and firing of contralateral VTA-NAc dopaminergic neurons were elevated in CCI mice, and optogenetic inhibition of these neurons reversed CCI-induced thermal hyperalgesia. CCI increased the expression of brain-derived neurotrophic factor (BDNF) protein but not messenger RNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA dopaminergic neuron activity, which induced an antinociceptive effect that was neutralized by injecting exogenous BDNF into the NAc. Moreover, inhibition of BDNF synthesis in the VTA with anisomycin or selective knockdown of BDNF in the VTA-NAc pathway was antinociceptive in CCI mice. CONCLUSIONS: These results reveal a novel mechanism of nociceptive modulation in the mesolimbic reward circuitry and provide new insight into the neural circuits involved in the processing of nociceptive information.