Vitamin D and Pancreatitis: A Narrative Review of Current Evidence.

Emerging research indicates that vitamin D metabolic disorder plays a major role in both acute pancreatitis (AP) and chronic pancreatitis (CP). This has been demonstrated by studies showing that vitamin D deficiency is associated with pancreatitis and its anti-inflammatory and anti-fibrotic effects by binding with the vitamin D receptor (VDR). However, the role of vitamin D assessment and its management in pancreatitis remains poorly understood. In this narrative review, we discuss the recent advances in our understanding of the molecular mechanisms involved in vitamin D/VDR signaling in pancreatic cells; the evidence from observational studies and clinical trials that demonstrate the connection among vitamin D, pancreatitis and pancreatitis-related complications; and the route of administration of vitamin D supplementation in clinical practice. Although further research is still required to establish the protective role of vitamin D and its application in disease, evaluation of vitamin D levels and its supplementation should be important strategies for pancreatitis management according to currently available evidence.

Buyang Huanwu Decoction Enhances Revascularization via Akt/GSK3ß/NRF2 Pathway in Diabetic Hindlimb Ischemia.

BACKGROUND: Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3ß/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. MATERIALS AND METHODS: All db/db mice (n = 60) were randomly divided into 6 groups by table of random number. (1) Sham group (N = 10): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group (N = 15): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group (N = 15): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group (N = 8): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group (N = 8): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group (N = 4): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3ß). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of P < 0.05 were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice (P > 0.05). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT (P < 0.05) and decrease the expression of IL-1ß, IL-6, and TNF-α (P < 0.05) in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3ß during revascularization (P < 0.05). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI (P < 0.05). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3ß pathway (P < 0.05). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3ß/NRF2 pathway.

A Preclinical Systematic Review of Curcumin for Protecting the Kidney with Ischemia Reperfusion Injury.

Renal ischemia-reperfusion injury (RIRI) refers to a phenomenon associated with dysfunction of the kidney and tissue damage. Unfortunately, no specific drugs have been found that effectively prevent and treat RIRI. Curcumin (Cur), a polyphenol extracted from turmeric, possesses a variety of biological activities involving antioxidation, inhibition of apoptosis, inhibition of inflammation, and reduction of lipid peroxidation. Eight frequently used databases were searched using prespecified search strategies. The CAMARADES 10-item quality checklist was used to evaluate the risk of bias of included studies, and the RevMan 5.3 software was used to analyze the data. The risk of bias score of included studies ranged from 3 to 6 with an average score of 5.22. Compared with the control group, Cur significantly alleviated renal pathology, reduced blood urea nitrogen and serum creatinine levels, and improved inflammatory indexes, oxidant, and apoptosis in RIRI animal models. Despite the heterogeneity of the response to Cur in terms of serum creatinine, BUN, TNF-alpha, and SOD, its effectiveness for improving the injury of RIRI was remarkable. In the mouse model subgroup of serum creatinine, the effect size of the method of unilateral renal artery ligation with contralateral nephrectomy and shorter ischemic time showed a greater effect than that of the control group. No difference was seen in the methods of model establishment, mode administration, or medication times. The preclinical systematic review provided preliminary evidence that Cur partially improved RIRI in animal models, probably via anti-inflammatory, antioxidant, antiapoptosis, and antifibrosis activities and via improving microperfusion. ARRIVE guidelines are recommended; blinding and sample size calculation should be focused on in future studies. These data suggest that Cur is a potential renoprotective candidate for further clinical trials of RIRI.

Clinical and Preclinical Systematic Review of Astragalus Membranaceus for Viral Myocarditis.

Astragalus membranaceus (AM) is a traditional Chinese medicine, which possesses a variety of biological activities in the cardiovascular systems. We conducted a clinical and preclinical systematic review of 28 randomized clinical control studies with 2522 participants and 16 animal studies with 634 animals to evaluate the efficacy, safety, and possible mechanisms of AM for viral myocarditis (VM). The search strategies were performed in 7 databases from inception to January 2020. Application of the Cochrane Collaboration's tool 7-item checklist, SYRCLE's tool 10-item checklist, and Rev-Man 5.3 software to analyze the risk of bias of studies and data. The results show the score of clinical study quality ranged from 3 to 7 points with an average of 3.32, and the score of animal study quality ranged from 2 to 5 points with an average of 3. In clinical study, AM significantly reduced serum myocardial enzymes and cardiac troponin I levels and improved the clinical treatment efficiency in VM patients compared with the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions (P > 0.05). Significant increase of the survival rate and decrease of the cardiac cardiology score, cardiac enzymes, and cardiac troponin I were compared with the placebo group in animal studies (P < 0.05). The possible mechanisms of AM are largely through antivirus and antivirus receptors, anti-inflammatory, antioxidation, antiapoptotic, antifibrosis, and reducing cardiac calcium load. In conclusion, the findings suggested that AM is a cardioprotection candidate drug for VM.

Chai-Qin-Cheng-Qi Decoction and Carbachol Improve Intestinal Motility by Regulating Protein Kinase C-Mediated Ca2+ Release in Colonic Smooth Muscle Cells in Rats with Acute Necrotising Pancreatitis.

Chai-Qin-Cheng-Qi decoction (CQCQD) improves intestinal motility in acute pancreatitis (AP), but the mechanism(s) require elucidation. We investigated the effects of CQCQD and carbachol, a prokinetic agent, on colonic smooth muscle cells (SMCs) in L-arginine-induced necrotising AP model in rats. In treatment groups, intragastric CQCQD (20 g/kg, 2 hourly × 3 doses) or intraperitoneal carbachol (60 µg/kg) was given 24 hours after induction of AP. Both CQCQD and carbachol decreased the severity of pancreatic and colonic histopathology (all P < 0.05). Both CQCQD and carbachol reduced serum intestinal fatty acid binding protein, vasoactive intestinal peptide, and substance P and increased motility levels. CQCQD upregulated SMC phospholipase C-beta 1 (PLC-ß1) mRNA and PLC protein (both P < 0.05), while both treatments upregulated protein kinase C-alpha (PKC-α) mRNA and PKC protein and downregulated adenylate cyclase (AC) mRNA and protein compared with no treatment (all P < 0.05). Neither treatment significantly altered L-arginine-induced PKC-ß1 and PKC-ε mRNA reduction. Both treatments significantly increased fluorescence intensity of SMC intracellular calcium concentration [Ca2+]i (3563.5 and 3046.9 versus 1086.9, both P < 0.01). These data suggest CQCQD and carbachol improve intestinal motility in AP by increasing [Ca2+]i in colonic SMCs via upregulating PLC, PKC and downregulating AC.

[Hot issues on the treatment of severe acute pancreatitis by Integrated Traditional Chinese and Western Medicine].

Severe acute pancreatitis (SAP) is recognized as critical refractory disease. The case fatality rate of SAP is as high as 36%-50%. Although significant progress has been achieved on the treatment of severe acute pancreatitis (SAP) by Integrated Traditional Chinese Medicine (TCM) and Western Medicine (WM), there still exist some difficulties hindering the further improvement of therapeutic efficacy. The hot issues includes: unconfirmative curative effects and diverse treatment principles, complicated predictive scoring systems and inaccurate markers for the severity stratification, unproved new therapeutic tools and controversial methods waiting more high qualified evidence, unclarified mechanism of Integrated TCM and WM. In order to overcome the difficulties, we aim to launch the clinical pathway of Integrated TCM and WM, to strengthen the unity of multidisciplinary cooperation. We also need to keep the efforts on screening the markers for early evaluation and prediction of disease severity, improving the diagnosis and treatment, exploring the mechanism of Traditional Chinese Medicine in treating SAP with more high quality basic and clinical research. Based on these efforts, we could provide better treatments and prognosis for SAP patients.

Effects of Chai-Qin-Cheng-Qi Decoction on cefotaxime in rats with acute necrotizing pancreatitis.

AIM: To investigate the effect of Chai-Qin-Cheng-Qi Decoction (CQCQD) on cefotaxime (CTX) concentration in pancreas of rats with acute necrotizing pancreatitis (ANP). METHODS: Sixty healthy male Sprague-Dawley rats were divided randomly into an ANP group (ANP model + CTX, n = 20), treatment group (ANP model + CTX + CQCQD, n = 20) and control group (normal rats + CTX, n = 20). ANP models were induced by retrograde intraductal injection of 3.5% sodium taurocholate (1 mL/kg), and the control group was injected intraductally with normal saline. All rats were injected introperitoneally with 0.42 g/kg CTX (at 12-h intervals for a continuous 72 h) at 6 h after intraductal injection. Meanwhile, the treatment group received CQCQD (20 mL/kg) intragastrically at 8-h intervals, and the ANP and control group were treated intragastrically with normal saline. At 15 min after the last CTX injection, blood and pancreas samples were collected for the determination of CTX concentration using validated high-performance liquid chromatography. Pathological changes and wet-to-dry-weight (W/D) ratio of pancreatic tissue were examined. RESULTS: Serum CTX concentrations in three groups were not significantly different. Pancreatic CTX concentration and penetration ratio were lower in ANP group vs control group (4.4 +/- 0.6 microg/mL vs 18.6 +/- 1.7 microg/mL, P = 0.000; 5% vs 19%, P = 0.000), but significantly higher in treatment group vs ANP group (6.4 +/- 1.7 microg/mL vs 4.4 +/- 0.6 microg/mL, P = 0.020; 7% vs 5%, P = 0.048). The histological scores and W/D ratio were significantly decreased in treatment group vs ANP and control group. CONCLUSION: CQCQD might have a promotive effect on CTX concentration in pancreatic tissues of rats with ANP.

[Non-preventive use of antibiotics in patients with severe acute pancreatitis treated with integrated traditional Chinese and Western medicine therapy: a randomized controlled trial].

OBJECTIVE: To investigate the prognostic effects of integrated traditional Chinese and Western medicine therapy without antibiotics in treatment of patients with severe acute pancreatitis (SAP). METHODS: SAP patients were randomly divided into treatment group (26 cases included) and control group (28 cases included). In addition to the same protocol of integrated traditional Chinese and Western medicine treatment for both groups, intravenous drip infusion of 0.5 g imipenem-cilastatin was administered to the patients in the control group every eight hours for ten days. The 48-hour Ranson score, 24-hour acute physiology and chronic heath evaluation II score, and incidence rates of complications were observed. The concentrations of serum C-reactive protein (CRP) on days 1, 3, 7 and 10 were measured, and strains of infection were detected with smear and culture examination for bacteria and fungi. RESULTS: There were no statistical differences in demographic information, baseline data and incidence rates of complications between the two groups (P>0.05), but fungal infection rate in the control group was higher than that in the treatment group (P<0.05). There were no statistical differences in infection rates of G- and G+ germs between the two groups; blood and some organs including lung, pancreas, intestine, and urethra were infected with bacteria and fungi. There were also no significant differences in the serum CRP concentrations on days 1, 3, 7 and 10 between the two groups (P>0.05), but the serum CRP concentrations on days 1, 3, 7 and 10 in infected patients were higher than those in non-infected patients (P<0.05, P<0.01). CONCLUSION: The study cannot confirm that the incidence rates of secondary infection and mortality in SAP patients treated with integrated traditional Chinese and Western medicine are reduced by prophylaxis with imipenem-cilastatin.

[Chaiqin Chengqi Decoction decreases pancreatic acinar cell calcium overload in rats with acute pancreatitis].

OBJECTIVE: To investigate the mechanism of Chaiqin Chengqi Decoction (CQCQD), a compound of traditional Chinese herbal medicine, acting on the pancreatic acinar cell calcium overload in rats with acute pancreatitis (AP). METHODS: A total of 30 SD rats were randomly divided into normal control group, untreated group and CQCQD group (n=10, respectively). AP was induced in rats by caerulein (5x50 mug/kg) intraperitoneal injection within 4 h. The pancreatic tissue SERCA1 and SERCA2 mRNA expressions were detected by fluorescent quantization polymerase chain reaction method; intracellular calcium fluorescence intensity (FI) of pancreatic acinar cells and the pancreatic pathological score were measured by laser scanning confocal microscopy and light microscopy respectively. RESULTS: There were no SERCA1 mRNA expressions in pancreatic acinar cells of rats in the normal control group and the untreated group. The expression of pancreatic SERCA2 mRNA in the untreated group was down-regulated compared with that in the normal control group (expression ratio=0.536; P=0.001); the expression of pancreatic SERCA2 mRNA in the CQCQD group was up-regulated compared with that in the untreated group (expression ratio=2.00; P=0.012). The pancreatic pathological score in the CQCQD group was lower than that in the untreated group and the FI of Ca(2+) was also lower. CONCLUSION: CQCQD can up-regulate the expression of pancreatic SERCA2 mRNA, release the calcium overload, and hence reduce the pathological changes in pancreatic tissue.

[Effects of Chaiqinchengqi decoction on exocrine function of pancreatic acinar cells of acute pancreatitis rats].

OBJECTIVE: To investigate the effects of Chaiqinchengqi decoction(CQCQ-D) on exocrine function of pancreatic acinar cells and the changes of intracellular calcium concentration ([Ca2+]i) of acute pancreatitis (AP) rats, so as to explore the mechanism of CQCQ-D. METHODS: Acute pancreatitis model was induced in Sprague-Dawley rat by ligation of bile-pancreatic duct, pancreatic acinar cells were isolated by collagenase digestion and in vitro co-incubated with the drug serum containing Chaiqingchengqi decoction(CQCQ-S) which was collected from normal rats intragastrically fed on CQCQ-D, then the amylase activity secreted into the buffer was assayed and intracellular fluorescent intensity were observed and analyzed to investigate the changes of intracellular calcium concentration ([Ca2+]i). RESULTS: Amylase secretion in AP group was lower than that in sham-operation(SO) group (P < 0.01), while CQCQ-S treatment led to more significant decrease (P < 0.05); [Ca2+]i elevated in AP rats (P < 0.05), while the level of [Ca2+]i elevation was reduced after CQCQ-S treatment (P < 0.05). CONCLUSION: CQCQ-D has inhibitive effects on exocrine function of pancreatic acinar cells and the calcium overload of AP rats.

Effect of Chaiqinchengqi decoction on sarco/endoplasmic reticulum Ca2+-ATPase mRNA expression of pancreatic tissues in acute pancreatitis rats.

AIM: To investigate the effect of Chaiqinchengqi decoction (CQCQD) on sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) mRNA expression of pancreatic tissues in acute pancreatitis (AP) rats. METHODS: Thirty Sprague-Dawley (SD) rats were randomized into control group, AP group and CQCQD group (n = 3 x 10). The rats in the CQCQD group were intragastrically administered with CQCQD (10 mL/kg every 2 h) after induction of AP by intraperitoneal injection of caerulein (50 microg/kg.h x 5) within 4 h. At 6 h after the induction of AP model, pancreatic tissues were collected for the pathological observation, mRNA extraction for determination of SERCA1 and SERCA2 mRNA expression or pancreatic acinar cell isolation for measurement of fluorescence intensity (FI) of intracellular calcium ion concentration [Ca2+]i. RESULTS: There was no expression of pancreatic SERCA1 mRNA in the control group and the AP group. The expression of pancreatic SERCA2 mRNA in the AP group was down-regulated (expression ratio = 0.536; P = 0.001) compared with the control group, while that in the CQCQD group was up-regulated (expression ratio = 2.00; P = 0.012) compared with AP group. The FI of intracellular [Ca2+] of pancreatic acinar cells in the AP group (138.2 +/- 23.1) was higher than the C group (111.0 +/- 18.4) and the CQCQD group (118.7 +/- 15.2 ) (P < 0.05) and the pancreatic pathological score in the CQCQD group was lower than that in the AP group (5.7 +/- 1.9 vs 9.2 +/- 2.7, P < 0.05). CONCLUSION: CQCQD can up-regulate the expression of SERCA2 mRNA of pancreatic tissues, reduce intracellular calcium overload and relieve pancreatic tissue lesions.

[Clinical study of Yihuo Qingxia method in treating hyperlipoidemia-related severe acute pancreatitis in early stage].

OBJECTIVE: To investigate the therapeutic effect of Yihuo Qingxia method, a traditional Chinese medicine therapeutic method for replenishing qi to activate blood, clearing away heat and dredging intestines, in treating hyperlipoidemia-related severe acute pancreatitis (SAP) in early stage. METHODS: One hundred and four patients with hyperlipoidemia-related SAP were divided into two groups: early group (admitted to hospital within 3 days after onset) and late group (admitted to hospital from 3 days to 7 days after onset). There were 52 cases in each group. All the patients were treated by Yihuo Qingxia method. RESULTS: There were no statistical differences in 48-hour Ranson scores, CT scores, 24-hour acute physiology and chronic heath evaluation II scores (APACHE II scores), and the levels of 24-hour serum triglyceride (TG) and serum glucose in the two groups (P>0.05). At the 10th day after onset, the serum TG level in early group was lower than that in late group (P<0.01). The incidences of acute respiratory distress syndrome, acute renal failure, hepatic inadequacy, congestive heart failure, shock, encephalopathy, infection and alimentary tract hemorrhage in early group were higher than those in late group (P<0.05). The mortality in early group was lower than that in the late group (P<0.05). The length of hospital stay in early group was shorter than that in late group (P<0.05). CONCLUSION: Yihuo Qingxia method has a good efficacy in treating hyperlipoidemia-related SAP in early stage.

[Protective effects of Chaiqin Chengqi Decoction on isolated pancreatic acinar cells in acute pancreatitis rats and the mechanisms].

OBJECTIVE: To investigate the protective effects of Chaiqin Chengqi Decoction (CQCQD), a compound traditional Chinese herbal medicine, on acinar cells and the changes of intracellular calcium concentration ([Ca(2+)]i) in acute pancreatitis (AP) rats. METHODS: CQCQ serum (CQCQS) was prepared by intragastric administration of CQCQD in SD rats, and AP was induced in SD rats by biliary-pancreatic duct ligation method. Pancreatic acinar cells were isolated by collagenase digestion and co-incubated with the drug serum containing CQCQD in vitro, then cell viability was determined by methyl thiazolyl tetrazolium (MTT) method and intracellular fluorescent intensity (FI) was observed and analyzed to investigate the changes of intracellular calcium concentration ([Ca(2+)]i). RESULTS: Both 5% and 10% CQCQS could improve the viability of pancreatic acinar cells in AP rats (P<0.05), and 10% CQCQS was more effective than 5% CQCQS (P<0.05). [Ca(2+)]i was elevated in AP rats (P<0.05), while the level of [Ca(2+)]i elevation was reduced after CQCQS treatment (P<0.05). CONCLUSION: CQCQD has a protective effect on pancreatic acinar cells of AP rats, which may be associated with its inhibition effect on intracellular calcium overload.