Caffeic acid and diabetic neuropathy: Investigating protective effects and insulin-like growth factor 1 (IGF-1)-related antioxidative and anti-inflammatory mechanisms in mice.

Diabetic neuropathy (DN) represents a common and debilitating complication of diabetes, affecting a significant proportion of patients. Despite available treatments focusing on symptom management, there remains an unmet need for therapies that address the underlying pathophysiology. In pursuit of novel interventions, this study evaluated the therapeutic effects of caffeic acid-a natural phenolic compound prevalent in various foods-on diabetic neuropathy using a mouse model, particularly examining its interaction with the Insulin-like Growth Factor 1 (IGF-1) signaling pathway. Caffeic acid was administered orally at two dosages (5 mg/kg and 10 mg/kg), and a comprehensive set of outcomes including fasting blood glucose levels, body weight, sensory behavior, spinal cord oxidative stress markers, inflammatory cytokines, and components of the IGF-1 signaling cascade were assessed. Additionally, to determine the specific contribution of IGF-1 signaling to the observed benefits, IGF1R inhibitor Picropodophyllin (PPP) was co-administered with caffeic acid. Our results demonstrated that caffeic acid, at both dosages, effectively reduced hyperglycemia and alleviated sensory behavioral deficits in diabetic mice. This was accompanied by a marked decrease in oxidative stress markers and an increase in antioxidant enzyme activities within the spinal cord. Significantly lowered microglial activation and inflammatory cytokine expression highlighted the potent antioxidative and anti-inflammatory effects of caffeic acid. Moreover, increases in both serum and spinal levels of IGF-1, along with elevated phosphorylated IGF1R, implicated the IGF-1 signaling pathway as a mediator of caffeic acid's neuroprotective actions. The partial reversal of caffeic acid's benefits by PPP substantiated the pivotal engagement of IGF-1 signaling in mediating its effects. Our findings delineate the capability of caffeic acid to mitigate DN symptoms, particularly through reducing spinal oxidative stress and inflammation, and pinpoint the integral role of IGF-1 signaling in these protective mechanisms. The insights gleaned from this study not only position caffeic acid as a promising dietary adjunct for managing diabetic neuropathy but also highlight the therapeutic potential of targeting spinal IGF-1 signaling as part of a strategic treatment approach.

Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping.

Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-ß/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-ß/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

Burnout and job stress of anesthesiologists in the tertiary class A hospitals in Northwest China: A cross-sectional design.

Purpose: Our purpose was to assess job stress and burnout among anesthesiologists in the tertiary class A hospitals in Northwest China, analyze the possible causes and adverse consequences of increased job stress and burnout of anesthesiologists in this region, and put forward suggestions in combination with the current national policies. Methods: We sent 500 electronic questionnaires to all anesthesiologists practicing in the tertiary class A hospitals in Northwest China from 1960 to 2017 on April 2020. A total of 336 (67.2%) questionnaires were returned and could be used for analysis. Burnout and job stress were assessed by using the modified Maslach Burnout Inventory-Human Services Survey and Chinese Perceived Stress Scale, respectively. Results: First, as for emotional exhaustion, the situations of anesthesiologists with different working years and workloads are different with statistical significance (P < 0.05). Second, as for depersonalization, the situations of anesthesiologists with different ages, professional titles, working years, physical health status, and workload are different (P < 0.05). Third, as for personal accomplishment, the situations of anesthesiologists with different physical health status are different (P < 0.05). Finally, the regression results showed that the longer the fatigue working years and the worse the physical health of anesthesiologists in Northwest China, the more likely these two factors were to cause burnout (P < 0.05), as for job stress, there was a negative correlation between job stress and physical health status (P < 0.05). Conclusion: Burnout and high job pressure are common among anesthesiologists in tertiary class A hospitals in Northwest China. We should focus on the allocation of labor intensity, pay attention to the physical and mental health of employees, establish targeted incentive mechanism, and improve the system of promotion and income rises for grassroots doctors. This may be not only conducive to the quality of medical care for patients but also conducive to the development of anesthesiology in China. Trial registration: Identifier: ChiCTR2000031316.

Efficacy and Safety of Esketamine Combined with Antidepressants for Treatment-Resistant Depression: A Meta-Analysis.

Objective: To evaluate the efficacy and safety of esketamine + antidepressant in treatment-resistant depression. Methods: We searched PubMed, Web of Science, Embase, CNKI, and Wanfang databases to obtain published information on esketamine + antidepressant from inception to July 2022. We searched for randomized controlled studies on the treatment of depression with a double-blind induction phase. Outcome indicators included changes in Montgomery-Asberg Depression Rating Scale (MADRS) scores before and after treatment, effective response rate, remission rate, and changes in self-rating depression scale (SDS). We analyzed data using Review Manager 5.4 and assessed the quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis. Results: A total of seven articles were included, including 701 patients in the esketamine + antidepressant group and 551 in the placebo group. Meta-analysis results showed that esketamine + antidepressant could improve the MADRS score in patients with treatment-resistant depression (MD = -2.68, 95% CI -3.98 to -1.37, P < 0.0001), SDS (MD = -2.9, 95% CI -4.01 to -1.79, P < 0.00001), response rate at the end of the double-blind induction period (RR = 1.28, 95% CI 1.12 to 1.46, P = 0.0002), remission rate at the end of the double-blind induction period (RR = 1.39, 95% CI 1.18 to 1.63, P < 0.0001), Five-Dimensional Health Scale (EQ-5D-5L) (MD = 0.05, 95% CI 0.02 to 0.08, P = 0.00009), Visual Analogue Scale of Health Status (EQ-VAS) (MD = 5.54, 95% CI 2.37 to 8.71, P = 0.0006). Conclusion: Esketamine + antidepressant has an obvious curative effect in treatment-resistant depression and can rapidly improve depression in patients, quality of life and satisfaction, but minor adverse reactions can occur.

Comparative efficacy and safety of prophylactic norepinephrine and phenylephrine in spinal anesthesia for cesarean section: A systematic review and meta-analysis with trial sequential analysis.

Background: Phenylephrine is the first-line drug used to maintain blood pressure in cesarean delivery. However, it poses a high risk of bradycardia and depression of cardiac activity in pregnant women. Consequently, norepinephrine has gained popularity over the recent years, as an alternative to Phenylephrine because it is thought that prophylactic use of vasopressors may reduce the incidence of hypotension after spinal anesthesia. This systematic review compared the efficacy of both treatments. Methods: We searched the following databases; CNKI, PubMed, Embase, Web of science, clinicaltrials.gov, Medline and Cochrane Library, for randomized controlled trials comparing the prophylactic efficacy of norepinephrine and phenylephrine on elective cesarean delivery under spinal anesthesia. The search period was from inception to July 2022, and the primary outcome indicator was incidence of bradycardia. Statistical analysis was conducted on Rev manager 5.4, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the quality of evidence from each main finding. Results: A total of 12 papers were included in the analysis. The incidence of bradycardia (RR = 0.37, 95% CI: 0.28 to 0.49, p < 0.00001) and reactive hypertension (RR = 0.58, 95% CI 0.40 to 0.83, p = 0.003) was significantly lower in the norepinephrine (NE) group compared with the phenylephrine (PE) category. In contrast, there were no statistical differences in the umbilical cord blood gas analysis pH values between the groups (arterial: MD = 0.00, 95% CI -0.00 to 0.01, p = 0.22, vein: MD = 0.01, 95% CI -0.00 to 0.02, p = 0.06). The incidence of hypotension, nausea, and vomiting did not differ significantly between the NE and PE groups (hypotension: 23% vs. 18%; nausea: 14% vs. 18%; vomiting: 5% vs. 7%, respectively). Conclusion: Prophylactic use of norepinephrine is safe and effective in maintaining maternal hemodynamics without causing adverse events to either the pregnant woman or fetus. Systematic Review Registration: website https://www.crd.york.ac.uk/prospero/, identifier CRD42022347095.

Andrographolide inhibits secretagogue-induced pseudo-allergic reaction.

Many kinds of drugs induce pseudo-allergic reactions due to activation of mast cells. We investigated the anti-pseudo-allergic effect of andrographolide (Andro). The effects of Andro on pseudo-allergic reactions were investigated in vivo and in vitro. Andro suppressed compound 48/80 (C48/80) induced pseudo-allergic reactions in mice in a dose-dependent manner. Andro also inhibited C48/80-induced local inflammatory reactions in mice. In vitro studies revealed that Andro reduced C48/80-induced mast cells degranulation. Human phospho-kinase array kit and western blotting showed that Andro could inhibit pseudo-allergic responses via the calcium signaling pathway.

The Effect of Dexmedetomidine Added to Preemptive Ropivacaine Infiltration on Postoperative Pain After Lumbar Fusion Surgery: A Randomized Controlled Trial.

STUDY DESIGN: A prospective and controlled study of dexmedetomidine added to preemptive ropivacaine infiltration in lumbar fusion surgery. OBJECTIVE: Assessment of dexmedetomidine added to preemptive ropivacaine infiltration for the relief of postoperative pain after lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: Single local anesthetic preemptive wound infiltration for the relief of postoperative pain does not translate into major or consistent clinical benefits after lumbar fusion surgery. Dexmedetomidine added to local anesthetics prolonged the duration of blockade and enhanced the analgesic in peripheral nerve block. The effect of dexmedetomidine added to preemptive ropivacaine infiltration in lumbar fusion surgery for the relief of postoperative pain has yet not been studied. METHODS: Fifty-seven patients with elective posterior lumbar fusion were randomly divided into two groups. Five minutes before incision, the skin and subcutaneous tissues were injected with 20 mL 0.5% ropivacaine in group R (n = 28) and 20 mL 0.5% ropivacaine and 1 ug/kg of dexmedetomidine in group RD (n = 29) in two divided doses (i.e., 10 mL per side of the incision line). After the operation, all patients received intravenous morphine for analgesia. The total morphine consumption, the time of first analgesic demand, numbers of PCA analgesia, Visual Analog Scale, and postoperative adverse effects were collected. RESULTS: In group RD, cumulative morphine dose and numbers of PCA analgesia in group RD were significantly reduced, the time of first analgesic demand was significantly delayed compared to the group R. Visual Analog Scale in group RD showed a marked reduction at 8 hours, 12 hours, 16 hours after operation and less patients in group RD experienced postoperative nausea or vomiting compared to the group R. CONCLUSION: The addition of dexmedetomidine to preemptive ropivacaine wound infiltration provided a superior analgesic effect, reduced postoperative morphine consumption, and prolonged the time of the first analgesic demand with no serious side effects. LEVEL OF EVIDENCE: 2.

Repression of neuronal nitric oxide (nNOS) synthesis by MTA1 is involved in oxidative stress-induced neuronal damage.

The Metastasis-associated protein 1 (MTA1) coregulator, an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, potentiates neuroprotective effects against ischemia/reperfusion (I/R) injury. But the underlying mechanism(s) remain largely unknown. Here, we discovered that neuronal MTA1 was a target of oxidative stress, and stimulation of neurons with oxygen glucose deprivation (OGD) treatment significantly inhibited MTA1 expression. Additionally, MTA1 depletion augmented ischemic oxidative stress and thus promoted oxidative stress-induced neuronal cell death by OGD. While studying the impact of MTA1 status on global neuronal gene expression, we unexpectedly discovered that MTA1 may modulate OGD-induced neuronal damage via regulation of distinct nitric oxide synthase (NOS) (namely neuronal NOS, nNOS) signaling. We provided in vitro evidence that NOS1 is a chromatin target of MTA1 in OGD-insulted neurons. Mechanistically, neuronal ischemia-mediated repression of NOS1 expression is accompanied by the enhanced recruitment of MTA1 along with histone deacetylases (HDACs) to the NOS1 promoter, which could be effectively blocked by a pharmacological inhibitor of the HDACs. These findings collectively reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the neuronal oxidative stress, in the regulation of acute neuronal responses against brain I/R damage. Our study also provides a molecular mechanistic explanation for the previously reported neurovascular protection by selective nNOS inhibitors.

[Effect of Femoral and Sciatic Nerve Block on Tourniquet Reaction and Postoperative Pain during Total Knee Arthroplasty].

OBJECTIVE: To observe the effect of femoral and sciatic nerve block on tourniquet reaction and postoperative pain during total knee arthroplasty (TKA). METHODS: Totally 60 patients scheduled for TKA were equally divided into two groups according to the random number table (n=30):femoral nerve block (F) group and femoral and sciatic nerve block (SF) group. The changes of mean arterial pressure (MAP) and heart rate (HR) in each group were recorded at the tourniquet inflated immediately (T1),30 minutes (T2),60 minutes (T3),90 minutes (T4),loose tourniquet (T5) and post extubation (T6). The total amount of anesthetics drugs propofol and remifentanil were calculated. The pain score after extubation and the location of pain were recorded. RESULTS: MAP and HR in group SF were steady at T1-T6 (all P>0.05). Compared with group SF,MAP in group F were significantly increased at T2-T4 and T6 (all P<0.05),and the HR at T4 and T6 were significantly increased (all P<0.05). Compared with the group F,the total amount of propofol and remifentanil were significantly decreased in group SF (all P<0.05),and pain scores at rest and on movement were reduced (P<0.05);in addition,90% patients in group F complained of posterior popliteal pain. CONCLUSION: Femoral nerve and sciatic nerve block applied in TKA can obviously inhibit the tourniquet reaction,keep hemodynamic stability,reduce the dosage of anesthetic drug,and relieve the postoperative pain.