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Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.

Background: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity., Purpose: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis., Methods: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma., Results: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress., Conclusions: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, and all authors report no conflicts of interest in this work., (Copyright © 2024. Published by Elsevier GmbH.)

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE -/- mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Metformin (MTF) and berberine (BBR) share several therapeutic benefits in treating metabolic-related disorders. However, as the two agents have very different chemical structure and bioavailability in oral route, the goal of this study is to learn their characteristics in treating metabolic disorders. The therapeutic efficacy of BBR and MTF was systemically investigated in the high fat diet feeding hamsters and/or ApoE (-/-) mice; in parallel, gut microbiota related mechanisms were studied for both agents. We discovered that, although both two drugs had almost identical effects on reducing fatty liver, inflammation and atherosclerosis, BBR appeared to be superior over MTF in alleviating hyperlipidemia and obesity, but MTF was more effective than BBR for the control of blood glucose. Association analysis revealed that the modulation of intestinal microenvironment played a crucial role in the pharmacodynamics of both drugs, in which their respective superiority on the regulation of gut microbiota composition and intestinal bile acids might contribute to their own merits on lowering glucose or lipids. This study shows that BBR may be a good alternative for MTF in treating diabetic patients, especially for those complicated with dyslipidemia and obesity., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear., Aim of the Study: The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases., Materials and Methods: The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored., Results: We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia., Conclusions: Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis., Competing Interests: Declaration of competing interest All the authors had no potential conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The phenylalanine-tyrosine-dopa-dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (L-dopa) with tetrahydrobiopterin (BH 4 ) as a coenzyme. Here, we show that oral berberine (BBR) might supply H • through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH 4 from dihydrobiopterin; the increased BH 4 enhances TH activity, which accelerates the production of L-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The L-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut-brain dialog activated by BBR's effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson's disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine. These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of L-dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal L-dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of L-dopa in the gut microbiota through a vitamin-like effect.

Aims: The effect of algae and its extract supplementation on glycolipid metabolism has not been finalized. Therefore, the purpose of the meta-analyses was to assess the effects of its supplementation on glycolipid metabolism concentration., Methods: We have systematically searched PubMed, Web of Science, the Cochrane Library and Embase to identify randomized controlled trials (RCTs) that investigated the impact of algae and its extracts supplementation on glycolipid metabolism. Effect size analysis was performed using weighted mean difference (WMD) and 95% CI between the methods of the experiment group and the control group. Subgroup analyses were performed to explore the possible influences of study characteristics. Publication bias and sensitivity analysis were also performed., Results: A total of 27 RCTs (31 trials) with 1221 participants were finally selected for the meta-analysis. The algae and its extract intervention significantly decreased glycosylated hemoglobin (HbA1c, WMD = -0.18%; 95% CI: -0.27 to -0.10; p < 0.001), high-density lipoprotein cholesterol (HDL-C, WMD = -0.22 mmol/L; 95% CI: -0.38 to -0.06; p = 0.008), and triglycerides (TC, WMD = -0.31 mmol/L; 95% CI: -0.37 to -0.25; p < 0.001) levels and increased insulin (WMD = 6.05 pmol/mL; 95% CI: 4.01 to 8.09; p < 0.001) levels. It did not significantly change the blood glucose, homeostasis model assessment-insulin resistance index (HOMA-IR), 2-h post-meal blood glucose (2hPBG) and other lipid profiles. Subgroup analyses based on the duration of intervention and subjects demonstrated that the intervention of algae and its extracts for 10 weeks or fewer and more than 40 subjects decreased TC levels ( p < 0.05). Moreover, the intervention reduced TC and 2hPBG concentrations for East Asians ( p < 0.05)., Conclusions: Our findings provided evidence that algae and its extract interventions were beneficial for the regulation of human glycolipid metabolism. More precise RCTs on subjects are recommended to further clarify the effect of algae, seaweed polysaccharide, seaweed polypeptide, algae polyphenol and its products intervention on glycolipid metabolism.

One key to malignant progression of pancreatic cancer (PC) is the acquired ability of tumour cells to escape immune-mediated lysis. Hypoxic microenvironment plays a causal role in PC metastasis. According to previous studies, hypoxia could induce the upregulation of HIF1A, ADAM10 and sMICA, leading to decreased NKG2D in NK cells and tumour cells escape from immune surveillance and NK cell-mediated lysis. In the present study, in NK cells derived from high-HIF1A expression patients, the levels of internalization of MICA/B and NKG2D were obviously higher than those in low-HIF1A expression group; hypoxia dramatically upregulated the levels of sMICA culture supernatant of Panc-1 cells. Regarding the molecular mechanism, dysregulated circRNAs and miRNAs that might modulate HIF1A-mediated immune escape were selected and examined for detailed functions. The expression of circ&#95;0000977 could be induced by hypoxia, and circ&#95;0000977 knockdown enhanced the killing effect of NK cells on PC cells under hypoxia through HIF1A and ADAM10. HIF1 and ADAM10 were direct downstream targets of miR-153; circ&#95;0000977 served as a sponge for miR-153 to counteract miR-153-mediated repression of HIF1 and ADAM10 mRNA through direct targeting in both 293T cells and Panc-1 cells. miR-153 inhibition exerted an opposing effect on HIF1A-mediated immune escape of PC cells to circ&#95;0000977 knockdown; the effect of circ&#95;0000977 knockdown were partially attenuated by miR-153 inhibition. In summary, circ&#95;0000977/miR-153 axis modulates HIF1A-mediated immune escape of PC cells through miR-153 downstream targets HIF1A and ADAM10. We provided a novel mechanism of HIF1A-mediated immune escape of PC cells from the perspective of circRNAs-miRNA-mRNA axis. Abbreviations: Pancreatic cancer (PC); peripheral blood lymphocytes (PBLs); A Disintegrin and Metalloproteinase Domain 10 (ADAM10); MHC class I-related molecule A (MICA); soluble MICA (sMICA); membrane MICA (mMICA); Hypoxia-inducible factor 1-alpha (HI1FA); long non-coding RNAs (lncRNAs); non-coding RNAs (ncRNAs); natural killer (NK); Haematoxylin and eosin (H&E); Immunohistochemistry (IHC); natural killer group 2 member D (NKG2D).

Nowadays, although research of proton conductive materials has been extended from traditional sulfonated polymers to novel crystalline solid materials such as MOFs, COFs, and HOFs, research on crystalline ferrocene-based carboxylate materials is very limited. Herein, we selected two hydrogen-bonded and π-π interactions-supported ferrocenyl carboxylate frameworks (FCFs), [FcCO(CH 2 ) 2 COOH] (FCF 1 ) and [FcCOOH] (FCF 2 ) (Fc = (η 5 -C 5 H 5 )Fe(η 5 -C 5 H 4 )) to fully investigate their water-mediated proton conduction. Their excellent thermal, water, and chemical stabilities were confirmed by the means of thermogravimetric analyses, PXRD, and SEM determinations. The two FCFs indicate temperature- and humidity-dependent proton conductive features. Intriguingly, their ultrahigh proton conductivities are 1.17 × 10 -1 and 1.01 × 10 -2 S/cm, respectively, under 100 °C and 98% RH, which not only are comparable to the commercial Nafion membranes but also rank among the highest performing MOFs, HOFs, and COFs ever described. On the basis of the structural analysis, calculated E a value, H 2 O vapor adsorption, PXRD, and SEM measurements, reasonable conduction mechanisms are highlighted. Our research provides a novel inspiration for finding new high proton conducting crystalline solid materials. Importantly, the outstanding conducting performance of 1 and 2 suggests their, hopefully, potential in fuel cells and related electrochemical fields.

Aims: To clone and express Siva1 protein, and to investigate the role of Siva1 protein in proliferation, apoptosis, invasion, and migration of human nasopharyngeal carcinoma cell line CNE-2 in vitro and in vivo., Methods: The PCR fragment of Siva1 from human nasopharyngeal carcinoma cell line CNE-2 were double digested with BamHI and SalI and then induced into the pQE30 vector double digested by the same enzymes. The pQE30 vector harboring Siva1 was introduced into M15 competent cells and then induced by isopropyl β -D-1-thiogalactopyranoside (IPTG). The Siva1 fusion protein was identified by 12% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and then separated and purified by Ni-affinity chromatography. Subsequently, the effects of recombinant Siva1 protein on proliferation, apoptosis, invasion and migration were assayed in vitro and in vivo., Results: The transformed cells expressed Siva1 fusion protein with a molecular weight of approximately 12 kDa. Cell counting kit-8 (CCK-8) assay showed that the Siva1 protein significantly inhibited the proliferation of the CNE-2 cells at a concentration of 10 μ mol/L. In addition, compared to the control, the Siva1 protein promoted the apoptosis of the cancer cells. And, the Siva1 protein greatly suppressed the invasion and migration of the cancer cells. In vivo, the Siva1 protein significantly inhibited the tumor growth of the tumor-bearing mice. Further, the Siva1 treatment markedly upregulated Bax, caspase-3, and downregulated Bcl-2 protein levels in the transplanted tumor tissue., Conclusions: The Siva1 protein has a significant anticancer activity on human nasopharyngeal carcinoma cell line CNE-2 including inhibiting proliferation, invasion, migration and promoting apoptosis of the cancer cells.

Background: Multiple MicroRNAs (miRNAs) have been identified in the development and progression of osteosarcoma. However, the expression and roles of miR-212 in osteosarcoma remain largely undefined., Methods: Real-time PCR assays were used to detect the expression of miR-212 in human osteosarcoma tissues. MiR-212 mimics were introduced into MG63 and U2OS cells. Bioinformatic prediction was used to identify the potential targets of miR-212. Protein expression analysis, luciferase assays and rescue assays were used to confirm the substrate of miR-212., Results: miR-212 was significantly down-regulated in human osteosarcoma tissues, compared with adjacent normal tissues. Introduction of miR-212 mimics into MG63 and U2OS cells inhibited cell proliferation and invasion. Besides, miR-212 overexpression could also inhibit tumor growth in the nude mice. Additionally, bioinformatic prediction suggested that the sex-determining region Y-box 4 (Sox4) is a target gene of miR-212. Sox4 inhibition phenocopied the roles of miR-212, while restored expression of Sox4 dampened miR-212-mediated suppression of tumor progression., Conclusion: The miR-212/Sox4 interaction plays an important role of in the osteosarcoma progression.

Objective: To detect the changes of the antioxidant level, cell cycle progression, necrosis and apoptosis, calcium ion concentration ([Ca2+] i) and mitochondrial membrane potential (deltapsim) in the model rats of impaired glucose regulation (IGR) induced by long-range high-fat diet, and to explore IGR-induced male reproductive injury and its mechanisms., Methods: Forty male Wistar rats were randomly divided into a normal control (n = 10) and an IGR model group (n = 30), and the IGR model was established by 20 weeks of long-range high-fat diet. Pathological changes in the rat spermatogenic cells were detected by HE staining; the content of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were measured with biochemical methods; changes in the cell cycle progression, necrosis and apoptosis were determined using flow cytometry with propidium iodide (PI) dyeing and the Annexin V-FITC kit, respectively, and [Ca2+]i and deltapsim were detected by flow cytometry with Fluo-3 and Rhodamine probe labeling, respectively., Results: After 20 weeks of continuous high-fat diet, fasting blood glucose was kept at 6.1 - 7.0 mmol/L and blood glucose at 7.8 - 11.1 mmol/L after 2 h glucose load in 12 rats, with a 40% success rate of modeling. Lots of dividing spermatocytes and spermatids were seen in the tissue sections of the normal control rats under the microscope, but few or none in the IGR models. Compared with the normal controls, the IGR model rats showed remarkably increased MDA content and decreased SOD, CAT and GSH-Px activities in the testis tissue (P < 0.05 or P < 0.01) , reduced G0/G1 cells and increased G2/M cells (P < 0.05 or P < 0.01), decreased necrotic cells and increased apoptotic cells (P < 0.05 or P < 0.01), increased [Ca2+]i and decreased deltapsim (P < 0.01), but no significant changes in the percentages of S cells and normal cells., Conclusion: IGR can cause spermatogenic cell division disorder in rats, which may be attributed to increased oxidative damage, decreased antioxidant enzyme activities, G2/M phase arrest, [Ca2+]i elevation, deltapsim reduction, and apoptosis of testicular cells.

Coxsackievirus B3 (CVB3) is the most important causal agent of viral heart muscle disease, but no specific antiviral drug is currently available. Small interfering RNA (siRNA) has been used as an antiviral therapeutic strategy via posttranscriptional gene silencing. In this study, eleven siRNAs were designed to target seven distinct regions of the CVB3 genome including VP1, VP2, VP3, 2A, 2C, 3C, and 3D. All of the siRNAs were individually transfected into HeLa cells, which were subsequently infected with CVB3. The impacts of RNA interference (RNAi) on viral replication were evaluated using five measures: cytopathic effect (CPE), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 50% tissue culture infectious dose (TCID(50)), real-time RT-PCR, and Western blot. Five of the eleven siRNAs were highly efficient at inhibiting viral replication. This was especially true for siRNA-5, which targeted the ATPase 2C. However, antiviral activity varied significantly among siRNA-9, -10, and -11 even though that they all targeted the 3D region. Our results revealed several effective targets for CVB3 silencing, and provided evidence that sequences except CRE within the 2C region may also be potential targets for CVB3-specific siRNAs design. These data supported a potential role of RNA interference in future antiviral intervention therapies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To investigate the expression of heme oxygenase-1 (HO-1) at different intervals and to provide evidence for estimation on injury intervals after brain contusion in human., Methods: Twenty-four patients died of serious brain injury were assigned as injury group and 4 patients died of non-brain injury were served as control group. HO-1 expression was analyzed in brain tissue at different time intervals (3 h, 6-9 h, 12-24 h, 36 h-3d, 5-8d, 17-20d) by immunohistochemistry and auto-image analysis system., Results: The level of HO-1 expression started to increase in 3 h after brain contusion compared to the control group (P < 0.05). The level of HO-1 expression highest level in 12-24 h group, and maintained high level in 36 h-3 d, then decreased gradually., Conclusion: The expression of HO-1 might be a strong evidence for human brain contusion time estimation.

Background and Purpose: Arterial remodeling may enable atherosclerotic disease without luminal stenosis. We sought to assess the prevalence and characteristics of atherosclerosis in angiographically normal carotid arteries., Materials and Methods: Forty-six arteries with 0% stenosis by MRA were evaluated with multicontrast carotid MR imaging at 3T. For each artery, the percentage wall volume (wall volume/[lumen volume + wall volume] x 100%) and the presence versus absence of an LRNC, calcification, IPH, and fibrous cap rupture were recorded. In addition, the relative size of each plaque component (eg, percentage LRNC = LRNC volume/wall volume x 100%), when present, was calculated., Results: The mean of percentage wall volume in arteries with 0% stenosis was 43.0 +/- 6.9% with a range from 31.6% to 60.1%. An LRNC was present in 67.4% (31/46) of arteries, calcification was present in 65.2% (30/46), IPH was present in 8.7% (4/46), and fibrous cap rupture was present in 4.3% (2/46). In arteries with an LRNC (n = 31), the average percentage LRNC volume was 8.8 +/- 7.3% with a range from 1.0% to 31.5%. For calcification (n = 30), the mean percentage calcification volume was 3.8 +/- 4.2% with a range of 0.1%-17.4%. The mean percentage IPH volume (n = 4) was 2.7 +/- 1.7% with a range of 0.5%-4.1%., Conclusions: These findings indicate that stenosis by MRA may underestimate the presence of carotid atherosclerosis, and they demonstrate the need for improved methods for accurately identifying carotid atherosclerotic plaque severity.

Purpose: To study the effect of simvastatin on osteoblast proliferation, differentiation and mineralization and to explore the mechanism of stimulation of bone formation by simvastatin., Methods: Six 8-hour healthy SD rats were used for the experiment. In order to harvest vital osteoblast, this research modified the traditional tissue piece method to culture primary osteoblast of rat calvarias.The effect of simvastatin in different concentration(1.0micromol/L,0.5micromol/L,0.25micromol/L,0.125micromol/L) on osteoblast was measured using MTT to assay osteoblasts proliferation, alkaline phosphatase activity of osteoblasts was measured, the level of osteocalcin (OC) was detected, the capacity of mineralization was investigated by counting the mean mineralization area with Image-Pro Plus 6.0.The data was analyzed with SPSS 13.0 software package for one-way ANOVA., Results: Compared with the control group, the osteoblasts proliferation was inhibited in the experimental groups in a dose-dependent manner. It showed that the alkaline phosphatase activity of osteoblast was increased in all experimental groups. The level of OC of osteoblasts showed a significant increase in all treatment groups. With regard to osteoblast capability of mineralization, the mineralization area was also increased, compared with the control group (P<0.05)., Conclusion: Simvastatin inhabits the proliferation of osteoblasts in vitro, but promotes differentiation and mineralization of osteoblast.

The protective effects of ischemic preconditioning on ischemia-reperfusion injury was investigated using isolated Langendorff perfusing hearts from ground squirrel and rat. In Preconditioning I group hearts were first perfused with Krebs-Henseleit solution for 10 min to establish a steady state, then stopped for 15 min to establish global ischemia, and finally followed by 10 min ischemia and 10 min reperfusion. In Preconditioning II group there were three cycles of 5 min ischemia + 5 min reperfusion after 10 min equilibration and then the final 10 min ischemia and 10 min reperfusion were followed. It was found that in group I during the final 10 min ischemia period there was remarkable augmentation of CK release from both animal's hearts. But in group II CK release decreased markedly during the same ischemic period. CK release during final 10 min reperfusion period also decreased significantly in group II in comparison with group I. The incidence of arrhythmias occurred in both animal's hearts was markedly reduced in group II rather than group I. In conclusion, short episode ischemic preconditioning protect subsequent ischemia-reperfusion injury on isolated hearts from ground squirrel and rat.

By means of microelectrode techniques the electrophysiological effects of a new class III antiarrhythmic agent, UK-68798 (Dofetilide), were investigated on atrionodal (AN), nodal (N), nodal-His (NH) and His (H) cells in the AVN area of rabbit heart. UK-68798 (5 x 10(-9) to 5 x 10(-6) mol/L) had no effect on APA and RP of the 4 kinds of cells but caused a dose-dependent decrease in AVN spontaneous rhythm without changing the A-H conduction time. APD50 and APD90 were prolonged markedly by the drug in a dose-dependent manner. Among the 4 kinds of cells, N cell had the highest percentage increment in APD, indicating a prominent sensitivity to the drug. For example, at 5 x 10(-6) mol/L, the prolongation percentages of APD90 are: 95 +/- 26% (N), 75 +/- 22% (AN), 63 +/- 26% (H), 46 +/- 26% (NH). The effective refractory periods (ERP) of the 4 kinds of cells were lengthened also in a dose-dependent manner, while the ERP increment percentages (delta ERP%) of the 4 kinds of cells did not show significant difference. However, ERP corresponding repolarization membrane potentials (ERP-RMP) of the 4 kinds of cells were not affected by the drug. The above results suggested that though ERP increased in parallel with APD prolongation, the homogeneous delta ERP% and unchanged ERP-RMP values of the 4 kinds of cells would prevent the AVN area from becoming a source of reentry arrhythmias under the action of UK-68798.

The present study provided a model with which the kinetics of CK release in the early phase of reperfusion was investigated. By using Langendroff method the isolated rat heart was first perfused for 10 min for establishing equilibrium, then stopped for 10 min to establish global ischemia, and finally followed by reperfusion for sample collection in every 15 s for the measurement of CK activity (U/L) as an index of cellular damage. A characteristic biphasic release of CK was shown under condition of 3 min reperfusion with Krebs-Henseleit (K-H) solution without glucose. The 1st peak of CK release appeared abruptly in the first 15 s of reperfusion and the 2nd one, during 120-180 s of reperfusion. The appearance of the 2nd peak was shifted to 30-75 s by adding glucose (11.1 mmol/L) into the perfusate. The 1st peak mainly reflects ischemic injury while the 2nd represents reperfusion injury. Anoxia (95% N2 + 5% CO2) or glucose addition may delay or decrease both peaks, but low Ca2+ (0.05 mmol/L) only delays the appearance of the 2nd peak to 3 min. The results suggest that the oxygen paradox rather than calcium paradox is involved in both phases of CK release. As for low Ca2+ decreasing the 2nd peak may be attributed to its effect of reducing Ca2+ inflow and overload injury secondary to oxygen paradox.

By means of Langendorff method the isolated rat heart was perfused with Krebs Henseleit solution. Following ligation of the left descending coronary artery for 10 min the heart was reperfused for 3 min. The incidence of ventricular fibrillation in the reperfusion period was 100%, and the normal sinus rhythm time was shortened to 29 s within 3 min of reperfusion. Administration of lipoic acid (6.8 X 10(-6)-1.7 X 10(-4) mol/L) to the perfusate significantly reduced the incidence of ventricular fibrillation to 33-50% and prolonged the normal sinus rhythm time to 97-107 s. APA, RP, and Vmax recorded from the guinea pig papillary muscle were depressed due to the deleterious effect of xanthine oxidase and hypoxanthine free radical generating system. Under the treatment of lipoic acid (3.5 X 10(-5) mol/L), the depression of APA, RP, and Vmax were significantly relieved. This confirms that lipoic acid treatment, owing to its free radical scavenger effect, is able to protect myocardium from free radical induced electrophysiological abnormalities, and consequently decrease the incidence of malignant arrhythmias.

The effect of the new antiarrhythmic drug lorcainide was studied on the specialized conducting system of isolated canine ventricle. Transmembrane action potentials were recorded simultaneously from three subendocardial sites within the ventricular basis, free wall and apex. At concentrations of 3 x 10(-6) and 2.4 x 10(-5) M, lorcainide caused a dose-dependent decrease in maximum rates of rise and in amplitude of the action potential; 0.6 x 10(-6) M had no significant effect, resting potential and action potential duration remained unchanged with 0.6 x 10(-6) M and 3 x 10(-6) M. The most prominent effect of 2.4 x 10(-6) M lorcainide was the appearance of an increasing notch resulting in clear separation of the action potential in an initial short spike depolarization (50-120 msec) with or without a subsequent plateau depolarization 280-370 msec). Both components demonstrated an independent and inhomogeneous conduction through functionally different pathways. Changes in stimulation rate or premature stimuli resulted in nonstimulated reexcitations resembling bigemini, ventricular tachycardia or regional ventricular fibrillation. The results indicate that dissociation of the action potential in two components is due to toxic alterations of ionic channels of the fiber membrane and that nonstimulated reexcitations are due to reentry via functionally fast and slow pathways.

By means of Langendorff method and standard microelectrode techniques the effects of Ciwujia on reperfusion induced arrhythmias and action potential alterations were studied in isolated rat heart with transient coronary occlusion. Inclusion of Ciwujia extract (equivalent to 1.2 and 2.4 mg crude drug/ml) was found helpful in reducing reperfusion induced ventricular fibrillation and ventricular tachycardia. Associated with this reduction in rhythm disturbances was an increase in the total duration of normal sinus rhythm during the 3 min reperfusion period. With the administration of Ciwujia the number of cells with abnormal action potential configurations was significantly reduced. This confirms that Ciwujia can protect myocardium from electrophysiological abnormalities, and therefore reduces the incidence of malignant arrhythmias.