Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (Tric^CKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, Tric^CKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
Sjogren's Syndrome/complications* ; Animals ; Xerostomia/etiology* ; Mice ; Mice, Inbred NOD ; MARVEL Domain Containing 2 Protein/metabolism* ; Humans ; Mice, Knockout ; Disease Models, Animal ; Interferon-gamma ; Salivary Glands/metabolism* ; Tight Junctions/metabolism* ; MicroRNAs/metabolism* ; Female

Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6-CREB-SOD2-dependent pathway in IgG4-RS.
Cellular Senescence/genetics* ; Humans ; Immunoglobulin G/metabolism* ; Interleukin-13/pharmacology* ; Mitochondria/metabolism* ; Sialadenitis/metabolism*

Objective To evaluate the effect of electroacupuncture (EA) on postoperative outcome in the patients undergoing cardiac valve replacement with cardiopulmonary bypass (CPB).Methods Forty-four patients of both sexes,aged 18-55 yr,with body mass index of 18-25 kg/m2,of American Society of Anesthesiologists physical status Ⅲ,with New York Heart Association Ⅱ[or Ⅲ,scheduled for elective cardiac valve replacement with CPB,were divided into 2 groups (n =22 each) using a random number table:control group (group C) and group EA.In group EA,patients received EA stimulation with needles at bilateral Neiguan,Ximen,Shenmen and Baihui acupoints (disperse-dense waves,frequency 2 Hz,intensity 1.0-1.2 mA) from 20 min before anesthesia induction to the end of surgery.After induction of general anesthesia,the patients were endotracheally intubated and mechanically ventilated,and combined intravenous-inhalational anesthesia was used to maintain anesthesia.Quality of Recovery 9 and Minimum Mental State Examination scores were assessed on the day before surgery and 1 and 3 days after surgery.The development of nausea and vomiting,postoperative cognitive dysfunction,requirement for rescue analgesics and ventricular arrhythmia was recorded within 3 days after surgery.The consumption of sufentanil in surgery,extubation time,the first flatus time,the first postoperative off-bed time,duration of stay in the intensive care unit and length of hospital stay after sugery were recorded.Results Compared with group C,the consumption of sufentanil in surgery was significantly decreased,Quality of Recovery 9 scores were increased at 1 and 3 days after surgery,the incidence of nausea and vomiting,postoperative cognitive dysfunction and ventricular arrhythmia was decreased within 3 days after surgery,and the extubation time,the first flatus time,the first postoperative off-bed time and length of hospital stay after surgery were significantly shortened in group EA (P＜0.05).Conclusion EA can promote postoperative outcome in the patients undergoing cardiac valve replacement with CPB.

Objective To compare the efficacy of continuous lumbar plexus block (LPB) with different concentrations of dexmedetomidine added to ropivacaine for postoperative analgesia in elderly patients undergoing hip replacement.Methods Sixty elderly patients of both sexes,aged 65-85 yr,weighing 50-71 kg,of American Society of Anesthesiologists physical status Ⅱ or Ⅲ,scheduled for elective total hip replacement,were divided into 2 groups (n =30 each) using a random number table:0.5 μg/ml dexmedetomidine+0.1％ ropivacaine group (group D1) and 1.0 μg/ml dexmedetomidine + 0.1％ ropivacaine group (group D2).Lumbar-sacral plexus block combined with general anesthesia was used.At the end of operation,LPB pump was started and set up to deliver a 4 ml bolus dose with a 30 min lockout interval and background infusion at a rate of 8 ml/h.The analgesia solution contained 0.5 μg/ml dexmedetomidine and 0.1％ ropivacaine in group D1 and 1.0 μg/ml dexmedetomidine and 0.1％ ropivacaine in group D2.Postoperative analgesia lasted for 48 h,and the visual analogue scale score was maintained ≤ 3.Patientcontrolled intravenous analgesia (PCIA) pump was connected when break-through pain happened.PCIA solution contained morphine 50 mg diluted to 50 ml in 0.9％ sodium chloride.PCIA pump was set up to deliver a 1 ml bolus dose with a 5 min lockout interval and no background infusion.When the visual analogue scale score ＞3,the patient-controlled LPB pump was used first,and 15 min later if analgesia was still ineffective,PCIA pump was applied.The number of patients in whom analgesia was effective and occurrence of adverse reactions were recorded.Results Compared with group D1,the rate of effective analgesia was significantly increased,and the incidence of nausea,vomiting and pruritus was decreased in group D2 (P＜ 0.05).No bradycardia,hypotension,over-sedation,respiratory depression,urinary retention or local skin infection was found in the two groups.Conclusion Continuous LPB with 1.0 μg/ml dexmedetomidine added to 0.1％ ropivacaine provides better efficacy for postoperative analgesia in elderly patients undergoing hip replacement.

Objective To observe the effect of stress caused by neuropathic pain on serum cortisol concentration and expres-sion of 11β-hydroxysteroid dehyarogenase 1(11βHSD1)and investigate the action mechanism of curcumin for alleviating neuropathic pain. Methods The 72 male SD rats were randomly divided into 4 groups with 18 rats in each group:sham operation group(Sham), chronic constrictive injury group(CCI),solvent contrast group(SC)and curcumin treated group(Cur100). Curcumin(100 mg/kg/d) was given after the operation in Cur100 group. Paw thermal withdrawal(PTWL)and paw mechanical withdrawal threshold(PMWT)of rats were measured on 2 pre-operative and 1,3,5,7,10,and 14 post-operative days. The animals were deeply anesthetized,the blood was taken from the heart,and the L4-L5 dorsal root ganglion(DRG)of the operated side was removed. The change of cortisol was measured by ELISA and the change of 11βHSD1 expression in spinal cord and DRG was determined by immunochemistry and Western blot. Results Compared with sham group,PTWL and PMWT decreased significantly after operation in CCI group(P<0.01),serum cortisol concentration was significantly increased(P<0.01)and the expression of 11βHSD1 was significantly increased in CCI group(P<0.01). Compared with CCI group,the PMWT and PTWL was increased in CCI group(P<0.05),the serum cortisol concentration was decreased(P<0.05)and the expression of 11βHSD1 was inhibited in Cur100 group(P<0.05). Conclusion Stress caused by neuropathic pain triggered the release of cortisol to the blood and increased the expression of 11βHSD1 at the same time. Cur-cumin could alleviate thermal hyperalgesia and mechanical hyperalgesia induced by CCI and could also inhibit the serum cortisol con-centration and the expression of 11βHSD1 in spinal cord and DRG,which was likely to be related to pathogenesy and maintenance of neuropathic pain.

Objective To determine the median effective concentration (EC50) of ropivacaine blocking the motor nerve in aged patients of different age stratification.Methods Ninety-six patients of both sexes,aged 66-85 yr,of American Society of Anesthesiologists physical status Ⅰ-Ⅲ,with body mass index of 20-27 kg/m2,scheduled for elective hip replacement,were divided into 4 groups (n=24 each) according to the age:group Ⅰ 66-70 yr,group Ⅱ 71-75 yr,group Ⅲ 76-80 yr and group Ⅳ 81-85 yr.The concentration of ropivacaine was determined by up-and-down sequential trial.In each group,0.2％ ropivacaine 10 ml was epidurally injected in the first patient,and the difference between two successive concentrations was 0.025％.Each time the concentration of ropivacaine increased or decreased in the next patient depending on whether or not the Bromage score was 0 at 30 min after epidural injection.The EC50 and 95％ confidence interval of epidurally administered ropivacaine blocking the motor nerve were determined using probit analysis.The sensory block level and development of intraoperative hypotension and nausea and vomiting were recorded.Results The EC50 (95％ confidence interval) of ropivacaine was 0.24％ (0.19％-0.29％),0.22％ (0.17％-0.26％),0.19％ (0.15％-0.24％) and 0.17％(0.14％-0.22％) in Ⅰ,Ⅱ,Ⅲ and Ⅳ groups,respectively,and the EC50 of epidurally administered ropivacaine blocking the motor nerve was gradually decreased with increasing age stratification (P＜0.05).The sensory block level was all at T7.8-S1 in the four groups.There were no significant differences between the four groups in the incidence of intraoperative hypotension or nausea and vomiting (P＞0.05).Conclusion For aged patients of different age stratification,the EC50 of epidurally administered ropivacaine blocking the motor nerve is as follows:0.24％ in patients aged 66-70 yr;0.22％ in patients aged 71-75 yr;0.19％ in patients aged 76-80 yr;0.17％ in patients aged 81-85 yr.

Objective To evaluate the effect of isoflurane preconditioning on autophagy during focal cerebral ischemia-reperfusion (I/R) injury in rats.Methods Thirty-six healthy male Sprague-Dawley rats,weighing 250-280 g,aged 7-8 weeks,were divided into 3 groups (n =12 each) using a random number table:sham operation group (group S),cerebral I/R group (group I/R) and isoflurane preconditioning group (group IP).Focal cerebral I/R was induced by 2 h middle cerebral artery occlusion followed by 24 reperfusion.Group IP inhaled 1.5％ isoflurane for 1 h per day for 5 consecutive days,the other two groups only inhaled 30％ oxygen,and focal cerebral I/R was induced at 24 h after the last inhalation.At 24 h of reperfusion,neurologic deficit was assessed and scored,the rats were then sacrificed,and brains were removed for determination of cerebral infarct size (using triphenyl tetrazolium chloride staining) and expression of microtubule-associated protein 1 light chain 3-Ⅱ (LC3-Ⅱ) and Beclin-1 (by Western blot).Results Compared with group S,the neurologic deficit scores and cerebral infarct size were significantly increased,and the expression of hippocampal LC3-Ⅱ and Beclin-1 was significantly up-regulated in I/R and IP groups (P＜0.05).Compared with group I/R,the neurologic deficit scores and cerebral infarct size were significantly decreased,and the expression of hippocampal LC3-Ⅱ and Beclin-1 was significantly upregulated in group IP (P ＜ 0.05).Conclusion The mechanism by which isoflurane preconditioning ameliorates focal cerebral I/R injury is related to enhancement of autophagy in the rats.

Objective To explore the effect of dexmedetomidine combined with ropivacaine for continuous lumbar plexus block on the quality of early recovery in patients undergoing total hip ar-throplasty.Methods Sixty patients (35 males and 25 females)with ASA physical status Ⅱ or Ⅲ, aged 65-84 years,undergoing total hip replacement were randomly assigned to dexmedetomidine com-bined with ropivacaine group (group D)or ropivacaine group (group C).All patients received ropiva-caine which was administered via continuous lumbar plexus block as patient-controlled analgesia (PCA)after surgery.The PCA were programmed with a background infusion 8 ml/h of ropivacaine, bolus dose was 4 m1 and the block time was 30 min;the patients in group C received 0.2% ropiva-caine,and the patients in group D received 0.1% ropivaciane combined with 1 μg/ml of dexmedeto-midine by the way of intravenous infusion.In addition,all patients received another patient-controlled intravenous analgesia (PCIA)with 1 mg/ml of morphine for relieving the explosive pain.The PCIA was programmed with a lobus dose of morphine 1 mg without background dose,the block time was 5 min.Consumption of morphine and visual analog scale (VAS)score,muscle strength and maximum flexion and abduction of hip joint were recorded at the time points of 6,12,24 and 48 h after opera-tion.The side-effect reactions such as nausea,vomiting,drowsiness and itching were recorded.The sleep quality was assessed with Pittsburgh sleep quality index (PSQI)on day 1 before operation,day 1 and day 7 after operation.Results The consumption of morphine in group D was significantly fewer than group C (P <0.05).Compared with group C,muscle strength and maximum flexion and abduc-tion of hip joint in group D were increased at 6,12,24 and 48 h after operation (P <0.05 ).PSQI scores were decreased on the day 1 and day 7 after operation.The incidence of delirium,nausea and vomiting,drowsiness and itching in group D were decreased (P <0.05).Conclusion 0.1% ropiva-ciane continuous lumbar plexus block combined with 1 μg/ml of dexmedetomidine by the way of in-travenous infusion could provide satisfied analgesia for the operation of total hip arthroplasty;the sleep quality is improved,the functional exercise of hip joint is promoted.

Objective To evaluate the effect of curcumin on diabetic neuropathic pain (DNP) in rats. Methods Forty-eight male SD rats weighing 200-230 g were randomly divided into 6 groups ( n = 8 each) : group Ⅰ normal control (group C); group Ⅱ DNP (group D) ; group Ⅲ DNP+ DMSO (solvent of curcumin) (group DD) and group Ⅳ , Ⅴ , Ⅵ DNP + curcumin 50, 100 or 200 mg/kg ( group DC50, 100, 200 ). Diabetes was induced with intraperitoneal (IP) streptozocin 75 mg/kg in group Ⅱ -Ⅵ. Curcumin 50, 100 and 200 mg/kg were given IP once a day for 14 consecutive days starting from 14 d after streptozocin in group Ⅳ , Ⅴ and Ⅵ respectively. Venous blood samples were taken before and 72 h after IP streptosocin for determination of blood glucose level. Successful induction of diabetes was defined as blood glucose > 14.6 mmol/L. Mechanical paw withdrawal threshold to yon Frey stimuli (MWT) and paw withdrawal latency to thermal nociceptive stimulus (TWL) were measured 2 d before and 14 d after IP streptesocin and on the 1, 3, 7, 14 d of curcumin administration. Animals with pain threshold measured at 14 d after IP streptozocin decreasing by less than 15% of the baseline were excluded from the study. The animals were sacrificed after the last pain threshold measurement and the lumbar segment of the spinal cord and p65 was significantly higher in group D than in group C ( P < 0.05). Curcumin administration significantly reduced thermal and mechanical hyperalgesia induced by diabetes and down-regulated the expression of p-JNK and horn and DRG.