Introduction Bullous pemphigoid (BP) is the most common subepidermal bullous disease and involves an immune response directed against two hemidesmosome components in basal keratinocytes: BP antigen 180 (BP180) and BP antigen 230. The major epitope in patients with BP is the noncollagenous 16A (NC16A) domain of BP180.1 BP most commonly occurs in people of advanced age, especially those aged >70 years. The worldwide incidence of BP ranges from 12 to 66 cases per million people per year, and the disease prevalence increases with age.2 Degenerative neurological diseases, psychiatric disorders, and the chronic use of neuroleptics or spironolactone are known independent risk factors for the development of BP.3 Dipeptidyl peptidase 4 (DPP-4) inhibitors are a drug class that was first introduced into the market in 2006 to treat type 2 diabetes mellitus.4 In recent years, an increasing body of evidence has suggested that DPP-4 inhibitors may be implicated in the development of BP.5 Current knowledge regarding the association between DPP-4 inhibitor intake and BP is based mainly on case reports.5 We herein report the first case of DPP-4 inhibitor-associated BP in China, and the DDP-4 inhibitor in this case was linagliptin. Case report A 74-year-old woman was admitted to Peking Union Medical College Hospital because of a 20-day history of widespread erythematous tense bullae over her whole body. She had a history of type 2 diabetes mellitus, hyperlipidemia, arterial hypertension, hyperuricemia, and moderate chronic kidney disease. She had used linagliptin for 15 months before the onset of the skin lesions, and she was still using it upon presentation. Physical examination showed mild erythema and small tense blisters over the trunk and extremities along with extensive erosions and excoriations; however, this patient had less severe erythema than that seen in patients with typical non-drug-induced BP (Fig. 1A). Adjunctive laboratory tests showed the following results: leukocytes, 10.44 × 109/L; serum C-peptide, 6.26 μg/L; glycated hemoglobin, 8.7%; fasting glucose, 7.9 mmol/L; 2-hour postprandial glucose, 10.4 mmol/L; glycated albumin, 22.9%; serum creatine, 121 μmol/L; serum urea, 8.71 mmol/L; and urinary albumin:creatinine ratio, 44 mg/g.Figure 1: The clinical and pathological features of the patient with A: Physical examination showed widespread erythematous tense blisters and extensive erosions and excoriations over the trunk. B: Indirect immunofluorescence showed linear deposition of immunoglobulin G and C3 along the basement membrane zone.A skin biopsy showed a subepidermal blister and eosinophil infiltration in the blister fluid. Direct immunofluorescence showed linear deposition of immunoglobulin G and C3 along the basement membrane zone. Her anti-basement membrane immunoglobulin G titer (as detected by indirect immunofluorescence) was 1:40 (Fig. 1B). The index of anti-BP180 antibody detected by ELISA was 48 IU/mL. The BP disease area index score was 116. According to her clinical manifestations, immunologic findings, and pathologic results, a tentative diagnosis of BP was made. The patient had been taking linagliptin for 15 months before the eruption of skin lesions. She had also been taking atorvastatin for treatment of hyperlipidemia as well as losartan potassium and metoprolol for treatment of cardiovascular disease. However, we considered that her skin lesions had been induced by linagliptin for the following two reasons. First, the patient had taken atorvastatin, losartan potassium, and metoprolol for 6 years, whereas she had taken linagliptin for only 15 months before eruption of the skin lesions. Second, the skin lesions rapidly improved after she discontinued the linagliptin while continuing the other drugs. The patient was treated with topical halometasone, which mostly controlled the skin lesions; only sporadic blisters reappeared. Her condition significantly improved after discontinuation of linagliptin. Discussion BP is the most common autoimmune disease that involves blistering. It can be induced by diuretics, β-blockers, or antibiotics.3 DPP-4 inhibitors are standard treatments for type 2 diabetes mellitus but are also causative agents for BP. Advanced age (60–70 years) is a risk factor for BP associated with use of DPP-4 inhibitors.1 The mean time from introduction of DPP-4 inhibitors to BP onset is 10 months (range, 8 days to 37 months). The mean time to improvement after drug withdrawal is 10 days.6 Although the pathogenic mechanism has not been elucidated, it might be related to a modified immune response and antigenic alteration of the epidermal basement membrane. Several studies have shown that patients in whom BP is induced by DPP-4 inhibitors usually have noninflammatory manifestations characterized by mild erythema, and these patients also usually have autoantibodies to the midportion of the extracellular domain of BP180 but not the common NC16A domain.6 Hence, BP induced by DPP-4 inhibitors seems to be a different scenario from conventional BP. Although anti-BP180-NC16A antibodies may be absent, autoantibodies to full-length BP180 are present. This is because DPP-4 can activate plasminogen to form plasmin, an enzyme that usually cleaves BP180 within the immunodominant NC16A domain. Hence, plasmin inhibition by DPP-4 inhibitors can lead to antigenic alteration from the NC16A domain to outside the NC16A domain.5 ELISA of full-length BP180 is useful for monitoring disease activity. After cessation of the use of DPP-4 inhibitors, the epitope can return to the NC16A domain.7 Some studies have also shown that DPP-4 inhibitors can promote eosinophil activation by a C-C motif chemokine-11/eotaxin-mediated mechanism and contribute significantly to blister formation.4 Ujiie et al.8 found that the frequency of carriers of certain human leukocyte antigen alleles (HLA-DQB1∗03:01, HLA-DQA1∗05:05, HLA-DRB1∗11:01, and HLA-DRB1∗12:01) was significantly higher among patients with BP using DPP-4 inhibitors (especially HLA-DQB1∗03:01). Additionally, 86% of patients with noninflammatory DPP-4 inhibitor-associated BP carried HLA-DQB1∗03:01.8 Genomic tests revealed that our patient had the HLA-DQB1∗03:01, HLA-DQA1∗05:05, HLA-DQA1∗06:01, HLA-DRB1∗11:01, and HLA-DRB1∗12:02 haplotypes, which is highly consistent with previous reports. Izumi et al.9 demonstrated that DPP-4 inhibitors are involved in the development of noninflammatory BP and that patients with NC16A-positive BP usually present with much more severe erythema than patients with non-NC16A BP. Our patient presented with noninflammatory manifestations, exhibiting little erythema and pruritus; however, autoantibodies to BP180-NC16A were present, which differs from the findings of other studies. Moreover, some studies have shown that patients with DPP-4 inhibitor-associated BP usually have a high prevalence of mucosal involvement and low eosinophil count in peripheral blood.5 Our patient had involvement of the vulvar mucous membrane, but the eosinophil count in peripheral blood was within the normal range. Several cases of DPP-4 inhibitor-associated BP have been reported in recent years, but not in China. There are two possible reasons for the absence of such cases in China. First, there is a lack of concern about the association between use of DPP-4 inhibitors and BP among Chinese clinicians. Second, the autoantibodies in many patients with DPP-4 inhibitor-associated BP usually target the non-NC16A domain of BP180; thus, commercially available ELISAs for NC16A may misdiagnose these patients. Hence, application of ELISAs for full-length BP180 is expected in the future. For our patient, prompt withdrawal of the DPP-4 inhibitor achieved clinical remission within a short time. In conclusion, there is a possible link between the use of DPP-4 inhibitors and BP, which should be paid with more attention, and further studies are needed to demonstrate this correlation and underline mechanisms. Acknowledgements This work was supported by the National Key Research and Development Program of China Grant (No. 2016YFC0901500), the National Natural Science Foundation of China (No. 81972945), the Milstein Medical Asian American Partnership Foundation and Education Reform Projects of Peking Union Medical College (No. 2016zlgc0106).
OBJECTIVE To establish the method of aspiration of airway dead space (ASPIDS) and evaluate the effects of ASPIDS on elimination of CO2 and improvement of ventilation efficiency. METHODS Using self-designed ASPIDS device, physiological parameters such as PaCO2, P(peak), P(pause), end expiratory carbon dioxide pressure (PaCO2), lung statistic compliance (Cst), respiratory resistance (Re) and hemodynamics in two animal groups of conventional mechanical ventilation (CMV) and hypercapnia (HC) were observed by applying tracheal gas insufflation (TGI 4.0 L/min) and ASPIDS (4.0 L/min). RESULTS ASPIDS significantly decreased PaCO2 level, enhanced CO2 elimination and maintained PaCO in normal range while decreased VT by 30%, the elimination of CO2 of ASPIDS was superior to that of TGI. ASPIDS significantly decreased airway pressure in both animal groups . P(et)CO2 and Re levels significantly decreased after ASPIDS. ASPIDS showed no influence on Cst, hemodynamics and oxygenation. CONCLUSIONS The ASPIDS device is a simple and practical adjunct method to mechanical ventilation, it can more effectively decrease PaCO2 than TGI, and maintain lower airway pressure.
Abstract Temperature affects both the thermodynamics of intermediate adsorption and the kinetics of elementary reactions. Despite its extensive study in thermocatalysis, temperature effect is typically overlooked in electrocatalysis. This study investigates how electrolyte temperature influences CO2 electroreduction over Cu catalysts. Theoretical calculations reveal the significant impact of temperature on *CO and *H intermediate adsorption thermodynamics, water microenvironment at the electrode surface, and the electron density and covalent property of the C–O bond in the *CH–COH intermediate, crucial for the reaction pathways. The theoretical calculations are strongly verified by experimental results over different Cu catalysts. Faradaic efficiency (FE) toward multicarbon (C2+) products is favored at low temperatures. Cu nanorod electrode could achieve a FEC2+ value of 90.1% with a current density of ~ 400 mA cm− 2 at − 3°C. FEC2H4 and FEC2H5OH show opposite trends with decreasing temperature. The FEC2H4/FEC2H5OH ratio can decrease from 1.86 at 40°C to 0.98 at − 3°C. Introduction Electrochemical CO2 reduction reaction (CO2RR) into high-value products stands as one of the most promising strategies for mitigating CO2 emissions through the utilization of renewable electricity1–2. CO2RR is a complex process involving multiple reaction pathways that harvest a diverse array of chemical products3–4. However, the simultaneous occurrence of various CO2RR routes alongside the hydrogen evolution reaction (HER) can diminish the selectivity toward desired products5–8. The adsorption behavior of carbonous intermediates and the intricate water microenvironment at the electrode surface are pivotal factors for influencing these reaction pathways, thereby dictating the distribution of products9–12. By far, researchers have developed a wide range of electrode materials and electrolytes tailored to finely control intermediate adsorption and the water microenvironment on the electrode surface13–16. These advancements hold significant promise for steering the CO2RR pathway toward desired product with enhanced efficiency and selectivity. The adsorption or dispersion of intermediates, as well as the water microenvironment, are significantly influenced by temperature since they are thermodynamically controlled17–19. For instance, both C2H4 and C2H5OH share the same precursor *CH–COH, leading to their simultaneous production20–23. The kinetics of their distinct reduction pathways can be influenced by temperature, offering a feasible means to control the ratio of C2H4 to C2H5OH. Hence, adjusting the temperature of the electrolyte to regulate both thermodynamic and kinetics processes emerges as a potent method for steering the CO2RR pathway. Consequently, a comprehensive investigation into the relationship between performance and temperature is crucial, providing invaluable insights and guiding significance for optimizing CO2RR performance4, 24. CO2RR experiments are typically conducted at room temperature, which can vary, for example from − 3°C to 40°C, depending on seasons and regions. The environmental temperature, typically indicated by the electrolyte temperature, can significantly influence the performance of CO2RR, yet it is often ignored in CO2RR studies25–28. In this study, we systematically investigated the impact of temperature on CO2RR performance. We initiated our study with theoretical calculations, including density functional theory (DFT) and molecular dynamics (MD) simulations, to explore the impact of temperature on intermediate adsorption and kinetics of elementary reactions in CO2RR. Subsequently, Cu catalysts were synthesized and employed for CO2RR at various temperatures. The theoretical findings aligned well with experimental observations, indicating that lower temperatures favor C2+ production and promote the formation of C2H5OH over C2H4. For instance, a Faradaic efficiency toward multicarbon products (FEC2+) of 90.1% was achieved with a current density of ~ 400 mA cm− 2 at − 1.3 V vs RHE over a Cu nanorod (Cu-NR) electrode at − 3°C. Moreover, the FEC2H4/FEC2H5OH ratio decreases gradually from 1.86 to 0.98 in 1 M KOH as the temperature decreases from 40°C to − 3°C. Further characterizations, including in situ surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS), in situ Raman spectroscopy and electrochemical analysis, provide a comprehensive understanding of the temperature effect on CO2RR performance.
The novel selective synthesis of symmetrical and unsymmetrical dithienoheteroaromatic rings (DTHAs) has been developed via intramolecular cyclization of 4,4′-dibromo-3,3′-bithiophene (3). Four reaction conditions including n-BuLi/Et2O, n-BuLi/THF, s-BuLi/Et2O, and t-BuLi/Et2O were employed to react with 3 for selective formation of two types of dicarbanions, which generate the symmetrical and unsymmetrical DTHAs after quenching with three electrophilic reagents (4a–c). The possible mechanism of formation of DTHAs was proposed. In addition, two unsymmetrical DTHAs were confirmed by X-ray single-crystal analyses.
To the Editor: Hailey-Hailey disease (HHD), first discovered by the brothers Howard and Hugh Hailey,[1] is a genodermatosis at intertriginous sites. Mutation of ATP2C1 on chromosome 3q21-2 coding a calcium-dependent ATPase gives rise to calcium dysfunction within keratinocytes, resulting in acantholysis due to a signal transduction disorder.[2] It has been suggested that this gene mutation combined with irritation such as frequent friction, cold, and ultraviolet exposure leads to the development of HHD.[3] A 51-year-old woman diagnosed with pemphigus vulgaris (PV) 1 year previously [Figure 1A] complained of persistent lesions around her anus for 7 months [Figure 1B] despite resolution of all other lesions. Erythema with erosions appeared 7 months previously when she reported consistent mild diarrhea. No family members had similar lesions. Physical examination revealed clustered white or skin-colored, hard, smooth papules of 0.1- to 0.5-cm diameter around the anus. White lichenoid lesions were found in her gluteal sulcus. Antinuclear antibody, extractable nuclear antigen antibody, and ELISA testing of anti-pemphigus antibody were negative. A biopsy specimen was taken from the lesions around the anus [Figure 1C and 1D]. A genetic test for ATP2C1 showed a heterogeneous mutation: ATP2C1 c.1504C>T (p. Arg502Ter) [Figure 1E]. She was diagnosed with HHD and treated with topical 0.1% tacrolimus twice daily. The lesions resolved within 2 months [Figure 1F]. No relapse occurred for 1 year after treatment.Figure 1: (A) Blisters and erythema on chest, left axilla, and waist. (B) White or skin-colored hard, smooth papules of 0.1- to 0.5-cm diameter around anus. (C) Hyperkeratosis, parakeratosis, and acantholysis (hematoxylin-eosin, original magnification ×25). (D) Acantholytic cells (green arrow), spherical body (red arrow), and grain cell (blue arrow) (hematoxylin-eosin, original magnification ×125). (E) Mutation in ATP2C1 gene. (F) Resolved lesions.After a systematic search of “ATP2C1 mutation” on PubMed, Embase, and Chinese SinoMed (http://www.sinomed.ac.cn/), we found that ATP2C1 c.1504C>T (p. Arg502Ter) on exon 16 in chromosome 3 in this patient is a novel mutation site for HHD. HHD had been misdiagnosed as PV in this patient 1 year previously. Systemic corticosteroid treatment controlled her other lesions well but did not control the perianal lesions. Mild diarrhea was a source of frequent friction that gave rise to the chronic course of HHD and resulted in manifestation of the perianal lesions as papular acantholytic dyskeratosis (PAD).[4] PAD was first described in 1972 as localized papules and lichenoid lesions that histologically show acantholysis and dyskeratosis. More cases of ATP2C1 mutation have been reported in patients with PAD, suggesting that PAD is allelic to HHD; however, this remains controversial.[5] Localized perianal lichenoid lesions with papules should be clinically differentiated from extramammary Paget disease and bowenoid papulosis. Fungal or virus infection must also be excluded because of the warmth and humidity in the anal area. Histopathologically, PV, PAD, Darier disease,[6] and Grover disease should also be differentiated. This patient was diagnosed with HHD because of typical histopathological features, negative indirect immunofluorescence, ATP2C1 mutation, and previous extensive lesions. Treatment of refractory perianal HHD can be challenging due to regular defecation and diarrhea. Diarrhea must be controlled to prevent a chronic course. Previous studies have shown that corticosteroids and topical antiseptics may be employed in mild cases of perianal HHD. Surgical therapy, CO2 or Er:YAG laser ablation, dermabrasion, and argon plasma coagulation are reportedly useful for extensive perianal lesions of HHD.[7,8] This case has proven that tacrolimus ointment may also be helpful for chronic perianal HHD. Declaration of patient consent The authors certify that they have obtained the appropriate patient consent form. In the form, the patient provided her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and that due efforts will be made to conceal her identity but that anonymity cannot be guaranteed. Funding This study was supported by National Natural Science Foundation of China (81371731), Milstein Medical Asian American Partnership foundation (2017, dermatology), and Education Reform Projects of Peking Union Medical College (No. 2016zlgc0106). Conflicts of interest None.
Objective
To evaluate the curative effect of Huoxue-Xiaozhi capsule on non-alcoholic fatty liver disease (NAFLD).
Methods
A total of 100 patients with NAFLD who met the inclusion criteria were divided into 2 groups with 50 patients in each group by random number table method. The treatment group was treated with Huoxue-Xiaozhi capsule, while the control group was treated with Compound Methionine Choline Tablets. Both groups were treated for 8 weeks. The ALT, AST, γ-GT (γ- glutamyltranspeptidase ), ALP (alkaline phosphatase, alkaline phosphate) were detected by automatic blood biochemical analyzer. The serum high sensitivity-C reactive protein (hs-CRP) and Homocysteine (Hcy) were detected by supplementary detection method. The serum IL-18 was detected by ELISA method, and liver imaging was performed before and after treatment. The symptoms and signs were evaluated, and clinical efficacy was evaluated.
Results
The total effective rate was 90.0% (45/50) in the treatment group and 74.0% (37/50) in the control group. The difference between the two groups was statistically significant (Z=-2.328, P=0.020 ). After treatment, the serum hs-CRP (2.4 ± 2.9 mg/L vs. 3.6 ± 2.8 mg/L, t=2.105), Hcy (11.2 ± 5.5 μmol/L vs. 13.9 ± 6.4 μmol/L, t=2.262), IL-18 (690.6 ± 61.3 ng/L vs. 775.4 ± 60.5 ng/L, t=6.962) in the treatment group were significantly lower than those in the control group (P<0.05 or P<0.01). After treatment, the improvement of hypochondriac lump, sallow complexion, dark complexion and hypochondriac dull pain in the treatment group were superior to those in the control group (Z values were -2.563, -2.788, -2.780, -2.220 respectively, all Ps<0.05 ). The Serum ALT, AST, γ-GT and ALP levels were significantly lower than those of the control group (t values were 18.820, 19.811, 10.221 and 3.248 respectively, all Ps<0.001 ).
Conclusions
The Huoxue-Xiaozhi capsule can improve the liver function and reduce the levels of serum hs-CRP, HCY and IL-18, and its curative effect of NAFLD.
Key words:
Non-alcoholic fatty liver disease; Huoxue-Xiaozhi capsule; Alanine aminotransferase; Aspartate aminotransferase; Glutamyl transpeptidase-γ; C-Reactive protein; Homo cyst eine; Interleukin-18
To the Editor: A 73-year-old man presented with erythemas on his trunk and limbs with significant itching, which he had experienced for 11 months [Figure 1A and 1B]. Histological examination of his skin biopsy revealed sub-epidermal blister formation with eosinophilic and lymphocytic infiltration in the dermis. Direct immunofluorescence revealed the presence of a linear deposition along the basement membrane zone (BMZ). Indirect immunofluorescence revealed that the patient's serum was positive (titer ≥1:320) for anti-BMZ antibodies. Anti-BP180 antibody was 102 U/mL. Based on these findings, a diagnosis of bullous pemphigoid (BP) was established.Figure 1: Clinical features of the patient with BP and the T2-weighted magnetic resonance imaging of brain. (A and B) Erythemas were seen on his trunk and limbs, along with blisters on his hands. (C) Mild hippocampal atrophy. BP: Bullous pemphigoid.The patient was admitted to our hospital on September 21, 2017. During his hospitalization, we noticed that he exhibited bluntness and impaired short-term memory. Further investigation revealed a history of about 2 years of memory decline and a positive family history of dementia; both his father and sister had had dementia. Screening tests for dementia revealed an impaired cognition, as revealed by a score of 25 on the mini-mental state examination (MMSE) and a score of 19 on the montreal cognitive assessment (MoCA). A detailed neuropsychological test battery was implemented by a neurologist at our hospital, and the results demonstrated cognitive deficits in multiple domains, including memory, executive function, and visuospatial abilities. His apolipoprotein E (ApoE) genotype was ε4/ε4, which has been shown to be directly correlated with Alzheimer's disease (AD).[1] Electroencephalogram was mildly abnormal. The T2-weighted magnetic resonance imaging of brain showed mild hippocampal atrophy [Figure 1C] and high-signal intensities in periventricular white matter. The patient was diagnosed with AD by the neurologist, who then prescribed him with vitamin B6 (10 mg/day), folic acid (5 mg/day), and cobalamin (0.5 mg/day). This patient was treated with methylprednisolone (48 mg/day) and tripterygium glycosides (60 mg/day). He was reminded to visit a neurologist regularly for his AD control and had no recurrence of BP after 18 months of follow-up. In recent decades, BP has been shown to be associated with neurological disease (ND). AD is the most common ND associated with BP, and usually progress gradually, such that it can go undiagnosed for years. Indeed, dermatologists are sometimes the first to discover neurological abnormities in patients with BP.[2] Diagnosing ND earlier would result in more effective health care and a better quality of life. Early-stage dementia is associated with relatively mild symptoms and is thus often overlooked in clinical practice. Comprehensive diagnosis of dementia requires multiple evaluations performed by neurologists, including cognitive functioning tests and brain imaging. In this case, the neurologist diagnosed AD based on clinical appearance, various imaging examinations, laboratory tests, and the results of dementia screening scales. This allowed us to intervene and medicate the patient in a timely way, which might improve his prognosis. MMSE and MoCA are widely used scales for screening dementia, and are adopted around the world. Studies have shown that while the MMSE could effectively distinguish between normal patients and those with dementia, it is less able to differentiate between normal patients and those with mild cognitive impairment (MCI).[3] The MoCA can go some way to make up for this, since it has a higher sensitivity in the diagnosis of MCI than does the MMSE.[4] This case study suggests that, when identifying a patient with BP and suspected mental disorders, clinicians should be aware of the possibility of ND. We recommend the combined use of the MMSE and MoCA to examine this, as these are sensitive tools for cognitive impairment screening. Declaration of patient consent The authors certify that they obtained all appropriate patient consent forms. The patient also provided consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and all efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Funding This study was supported by grants from the Milstein Medical Asian American Partnership Foundation (2017, Dermatology), the National Natural Science Foundation of China (No. 81371731), and the Education Reform Projects of Peking Union Medical College (No. 2016zlgc0106). Conflicts of interest None.
Abstract Neuropathic pain affects up to 10% of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a voltage-independent cation channel, mediates the background Na + leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely reversed by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel therapeutic target for neuropathic pain.
Realgar, a Chinese herbal decoction, has been used to treat various types of tumors with positive outcomes; however, there is a lack of convincing evidence on its use for the treatment of esophageal cancer (EC). In this study, the role of the p62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the regulation of EC cell proliferation, migration, and ferroptosis in response to realgar was assessed.Different concentrations of realgar (0, 10, 20, 40, 60, 80, and 100 μmol/L) were applied to the EC cell lines Eca109 and KYSE150. The inhibition rate and half-inhibitory concentration (IC50) were determined using the Cell Counting Kit-8 (CCK-8) method. Subsequently, the cells were treated with realgar (1/2IC50, IC50, 2IC50). Cell migration was measured using the scratch assay, and cell invasion was measured using the transwell assay. The mRNA expression of p62, Keap1, and Nrf2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expression of p62, Keap1, Nrf2, matrix metalloproteinase (MMP)-2, MMP-9, E-cadherin, Slug, N-cadherin, and vimentin was measured by Western blot. The control, 2IC50, shRNA-NC, shRNA-p62, 2IC50 + shRNA-NC, 2IC50 + shRNA-p62, shRNA-Keap1, 2IC50 + shRNA-Keap1, and 2IC50 + shRNA-p62 + shRNA-Keap1 groups were defined. The CCK-8 method was used to measure the cell inhibition rate, and the clone formation assay was used to measure the clone formation ability. Moreover, the scratch assay was used to detect the cell migration ability, and the transwell assay was used to detect the cell invasion ability. Transmission electron microscopy was used to observe the mitochondrial morphology, Prussian blue staining was used to observe the intracellular iron particle distribution, and flow cytometry was used to detect changes in intracellular reactive oxygen species. In addition, qRT-PCR was performed to detect p62, Keap1, Nrf2, and glutathione peroxidase 4 (GPX4) mRNA expression, and Western blot was performed to detect p62, Keap1, Nrf2, E-cadherin, Slug, N-cadherin, and GPX4 protein expression.Realgar inhibited Eca109 and KYSE150 cell proliferation in a time- and concentrationdependent manner. It also significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and affected the mRNA and protein expression of p62, Keap1, and Nrf2. In response to realgar, low p62 expression inhibited the proliferation, migration, and invasion of Eca109 and KYSE150 cells, as well as ferroptosis induction.The findings demonstrate that inhibiting the p62-Keap1-Nrf2 signaling pathway promotes the inhibitory effects of realgar on EC cells.
An experimental set-up was designed to observe whether adding dexmedetomidine to QX-314 would enhance the onset and duration of sensory and motor function in a rat sciatic nerve block model. Fifty-six Sprague-Dawley rats received unilateral sciatic nerve blocks with 0.2 mL of 35 mmol/L QX-314 alone, dexmedetomidine (5.3 μmol/L (1 μg/kg), 26.4 μmol/L (5 μg/kg), 52.8 μmol/L (10 μg/kg)) alone, or a combination of the two. Thermal nociception and motor function were assessed by an investigator blinded to the drug treatment, and sciatic nerves and perineural tissues were harvested at 14 days after injection. In addition, we examined the effects of these solutions on compound action potentials in isolated frog sciatic nerves. Dexmedetomidine added to QX-314 enhanced the onset and duration of thermal nociception block and motor block (P < 0.05) without aggravating histopathological injuries. Furthermore, 52.8 μmol/L dexmedetomidine added to 35 mmol/L QX-314 showed less inflammation than QX-314 alone at 14 days (P = 0.003). Dexmedetomidine plus QX-314 was shown to dose-dependently reduce the compound action potentials relative to QX-314 alone (P < 0.05). It was concluded that co-administration of QX-314 with a clinical dose of dexmedetomidine produced a synergistic anesthetic effect to enhance the effect of sciatic nerve block.
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