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Arsenic trioxide (As₂O₃, ATO) is a very efficacious, clinically established agent for the treatment of acute promyelocytic leukaemia, and also potentially useful against other haematological and non-haematological malignancies. Nonetheless, the relative resistance of many tumour cell types requires the generation of sensitizing strategies. One of the properties of ATO which might be exploited for therapeutic purposes is its sensitivity to the intracellular oxidant state, as revealed by increased apoptosis production under conditions of reduced glutathione (GSH) depletion and/or elevated reactive oxygen species (ROS) content. This review summarizes some studies from our laboratory demonstrating that experimental modulation of protein kinase activities (PI3K/Akt, JNK, MEK/ERK) potentiates ATO-provoked apoptosis in relatively resistant human acute myeloid leukaemia (U937, HL60) cell lines by mechanisms involving GSH depletion and/or increased ROS content. In a similar manner, co-treatment with dietary flavonoides such as genistein, normally considered as anti-oxidants, may potentiate apoptosis via generation of moderate oxidative stress and activation of ROS-inducible protein kinases. Finally, co-treatment with ATO may sensitize otherwise refractory leukaemia cells to TNFα-family cytokine-produced apoptosis, by mechanisms involving the interplay between the "intrinsic" (mitochondrial) and "extrinsic" (death receptor-mediated) pathways.

During the outbreak of methanol poisonings in the Czech Republic 2012, we studied the clinical effectiveness of folate therapy in preventing visual damage. Data were obtained from a combined prospective and retrospective study on 79 patients: folinic acid was administered in 28, folic acid in 35; 16 patients received no folates. The groups were comparable by age, time to treatment, laboratory findings, symptoms, and treatment. The number of patients with visual sequelae differed neither between the groups treated with folinic/folic acid, nor between the groups with/without folate administration. The patients with visual sequelae were more acidotic and differed in pH, HCO₃^-, base deficit, anion gap, but not in methanol, ethanol, osmolal gap, formate, and pCO₂. Serum lactate, but not formate differed significantly. The higher serum glucose on admission was in the patients with visual sequelae. Regardless the rationale for folate administration in acute methanol poisoning, its clinical effectiveness in preventing visual damage was not demonstrated in our study. The detoxifying effect of the pathway of tetrahydrofolate-mediated formate conversion is secondary to the formate elimination by haemodialysis. The results of our study cannot promote folinic acid as more efficient than folic acid, but also cannot discount the possible utility of adjunct folate therapy.

Silibinin is known to display high efficacy against cancer cells and for hepatic protection. Metformin, a well-known antidiabetic agent, has recently been reported to inhibit cancer. In the present study, we investigated the effect of metformin on silibinin-induced programmed cell death in cervical cancer cells (C-33A). MTT assay and Western blot assays were performed to quantify cell viability and the expression of signaling proteins, respectively. Combined treatment with metformin and silibinin decreased cell survival in synergistic manner in C-33A cells at a dose that did not affect nonmalignant cells (HUVECs). Silibinin and metformin increased PTEN and AMPK expression in C-33A cells, respectively. Combined treatment caused a greater increase in the expression of activated caspase-3 or AIF, indicating apoptosis. Combined treatment with silibinin and metformin may induce programmed cell death of human cervical cancer cells at a dose that does not affect HUVECs. This finding reveals a potential therapeutic strategy of cervical cancer.

Neutrophils play an important role as the central mediators of the innate immune defence response, providing the first line of host protection. It was shown that these cells can trap and kill various microorganisms through different ways. One of them is a release of neutrophil extracellular traps (NETs) composed of chromatin fibrils and antimicrobial proteins. There is the evidence that the release of NETs does not have only a beneficial effect. NETs can trap and kill microorganisms and pathogens, however on the other hand the same pathway can also cause the damage of the organism by various mechanisms. NETs participate in the pathogenesis of a lot of inflammatory and autoimmune disorders, such as thrombosis, atherosclerosis, cystic fibrosis, periodontitis, lupus, rheumatoid arthritis and others. The aim of this review is to summarize information about the release of NETs and their beneficial, but also detrimental effect during various diseases. The better characterization and understanding of the dual role of NETosis during these diseases is necessary for the early diagnosis and more effective treatment.

The present study was designed to examine effects of Sinomenine (SM) on glioma cells growth in vivo and in vitro. Cells growth and apoptosis were detected by MTT assay, TUNEL assay and flow cytometric analysis. In the study, SM treatment led to growth inhibition on a series of glioma cell lines, including U87, U373, U251, Hs683 and T98G. SM prevented U87 growth in the nude mice as well. Inhibitory effects of SM on U87 cells proliferation in vitro and in vivo were more effective than that of temozolomide (TMZ), and SM has synergistic effects with TMZ in the glioma therapy. SM induced apoptotic death in U87 cells via activation of caspase-3, caspase-8 and caspase-9, and down-regulation of HIAP, Bcl-2 and survivin. Moreover, we observed SM decreased the expression of phosphorylated STAT3 (p-STAT3) both in vivo and in vitro. Interestingly, using a specific activator of STAT3, we demonstrated overexpression of p-STAT3 impaired, SM mediated growth inhibition and apoptosis induction in the U87 cells. In summary, our results indicate SM induced growth suppression of human glioma cells through inhibiting phosphorylation of STAT3.

Non-small-cell lung cancer (NSCLC), the most common type of lung cancer, remains the leading cause of cancer death worldwide. Blocking vascular endothelial growth factor (VEGF) signalling is an effective approach to the treatment of NSCLC. Small molecules have been proven to be good resource for discovery of inhibitors of VEGF signalling. DMH4 is a small molecule that we previously developed and demonstrated to have the property of selectively inhibiting VEGF signalling by targeting VEGF receptor 2 (VEGFR2). In this study, we reported that DMH4 can effectively block phosphorylation of VEGFR2 in both H460 and A549 NSCLC cells, which resulted in significant reduction of NSCLC cell viability in a dose-dependent manner, and the growth inhibition (GI50) of DMH4 against H460 and A549 cell lines were 13.27 and 2.75 mm respectively at 24 h. Our further studies demonstrated that DMH4 significantly suppressed migration and invasion of A549 and H460 cells, and induced apoptosis in those cells. Therefore, DMH4 as a small molecular VEGFR2 inhibitor may represent a new valuable drug lead for NSCLC treatment.

Herein, we report a facile route to synthesize palladium nanoparticles (CGPdNPs) using the aqueous fruit extract of C. guianensis Aubl. as a potent biological reducing agent. Reduction of PdCl₂ solution into their nano scale was confirmed with the formation of a black precipitate which gives a reduced absorbance in UV-vis spectroscopy. Fourier transform infrared spectroscopy (FTIR) reveals the active role of phenolic constituents from C. guianensis in reduction and surface functionalization of nanoparticles (NPs). Dynamic light scattering (DLS) and zeta potential analysis confirms the generation of polydispersed highly stable NPs with large negative zeta value (-17.7 mV). Interestingly, X-ray Diffraction (XRD) pattern shows that the synthesized CGPdNPs were face centered cubic crystalline in nature. The HRTEM micrographs of CGPdNPs displays well-dispersed, spherical NPs in the size ranges between 5 and 15 nm with an average of 6 nm. It was also noticed that the synthesized CGPdNPs possess an effective antimicrobial activity against different bacterial pathogens. On the other hand, in vitro cell viability (MTT) assays reveals that the synthesized CGPdNPs exhibited an extraordinary anticancer properties. Eventually, hemocompatibility assay depicts the safe nature of synthesized NPs for biomedical application.

Helicobacter pylori (H. pylori), which is found in the stomach of approximately 50% of humans, remains there for almost the entire lifetime of the infected individual, leading to various gastrointestinal tract-associated disorders following full-blown infection. Due to the emergence of antibiotic resistance, recurrence and high cost of therapy, most antibiotic-based treatment strategies are not very effective in eradicating H. pylori infections. The quest for an alternative treatment free of these inconveniences is currently in demand. One of the important alternatives is propolis, produced by the honeybee Apis mellifera, which has been used to treat different diseases since it possesses a wide range of biochemical properties. Propolis has been reported as a useful therapeutic regimen against H. pylori, which is an important cause of gastric inflammation, peptic ulcer, gastric cancer, and lymphomas of mucosa-associated lymphoid tissues. Apart from propolis, various active compounds of other natural products have also been confirmed to be effective. This review compiles the scientific evidence of the role of propolis and other natural products against H. pylori-associated gastrointestinal tract-related health complexities by acing as an anti-angiogenic, anti-inflammatory, and antioxidant factor as well as via modulation of enzymatic activities.

An increased number of sulfate-reducing bacteria is often isolated from faeces of patients with gastrointestinal diseases, which can be the cause of the development of bowel inflammation. Frequent use of antibiotics causes the resistance of intestinal microorganisms and ineffective treatment of these diseases. The antimicrobial activity and biological properties of the selected ring-substituted 8-hydroxyquinoline-2-carboxanilides against Desulfovibrio piger Vib-7 were studied. The addition of these compounds in the cultivation medium inhibited the bacterial growth and the process of sulfate reduction dose-dependently. A significant cytotoxic activity under the influence of ring-substituted 8-hydroxyquinoline-2-carboxanilides was determined. The strongest cytotoxic effect of the derivatives was observed for compounds 8-hydroxy-N-(3-methoxyphenyl)quinoline-2-carboxamide and 8-hydroxy-N-(3-trifluoromethylphenyl)quinoline-2-carboxamide that caused a low survival of D. piger Vib-7 in concentration 17 μM and high toxicity rates.

As a common complication of diabetes mellitus (DM), diabetic cardiomyopathy (DCM) is considered to be one of the major causes of mortality and morbidity. The therapeutic effects of naringenin have been verified in the treatment of various human diseases. However, the application of naringenin in the treatment of DCM still has not been reported. In this study, human AC16 cardiac cells were treated with normal d-glucose and high d-glucose (HG). After transfection with miR-30d-5p inhibitor, Cell Counting Kit-8 (CCK-8) method was used to measure cell viability. Hoechst 33258 staining was performed to observe the morphological changes of nucleus. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the activity of caspase-3. Cell apoptosis was detected by Annexin V-FITC/propidium iodide (PI) staining. Levels of light chain 3 (LC3) including LC3-I and LC3-II as well as nucleoporin p62 (P62) were detected by Western blot. We found that Naringenin treatment increased the reduced cell variability caused by HG treatment. Naringenin also increased expression level of miR-30d-5p in human AC16 cardiac cells after HG treatment. Treatment with miR-30d-5p inhibitor reduced the effect of miR-30d-5p in increasing cell variability and reducing cell apoptosis. Naringenin treatment reduced the increased levels of LC-I, LC-II and P62, but miR-30d-5p inhibitor reduced those changes. Therefore we concluded that naringenin could alleviate HG-induced injuries through the upregulation of microRNA-30d-5p level in human AC16 cardiac cells.

Aim
The current study was designed to investigate the effect of berbamine (BBM) on isoproterenol (ISO) induced changes in cardiac marker enzymes, myocardial oxidative stress, lipid profile and expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in male Wistar rats. Rats were pretreated with BBM (25 mg/kg) through intraperitoneal injection for 7 days followed by induction of myocardial infarction (MI) by subcutaneous injection of ISO (85 mg/kg) for last two days. Key findings: In the present study, the histopathological findings of the heart tissue showed that BBM treatment significantly minimized the damage induced by ISO. BBM pretreatment showed a significant decrease in heart weight, serum marker enzymes, lipid peroxidation and significant increase in cardiac endogenous enzymatic and non-enzymatic antioxidants compared to the ISO-treated group. In addition, we observed significantly upregulated eNOS expression and downregulated iNOS expression in BBM pretreated group. Thus, BBM protected the rat's heart from ISO-induced myocardial infarction by its antioxidant, and antilipidemic properties. Significance: The results of the present investigation suggested that BBM efficiently ameliorated the ISO-induced myocardial infarction in rats.

Non-steroidal anti-inflammatory drugs (NSAIDs) play an effective chemopreventive action against a variety of cancers. The present study aimed at targeting pro-inflammatory cyclooxygenase (COX) and NF-kB mediated inflammatory pathways in 9,10-dimethylbenzanthracene (DMBA) induced lung cancer in BALB/C mice and chemoprotective action of NSAIDs. Animals were divided into five groups and treated with NSAIDs, intratracheally, daily for a period of 18 weeks. Group 1 as control, received vehicle treatment; Group 2 received single dose of DMBA (10 mg/kg bw); Group 3, 4 and 5 besides DMBA treatment, also received Aspirin (60 mg/kg bw), Celecoxib (6.0 mg/kg bw) and Etoricoxib (0.6 mg/kg bw), respectively. DMBA induce DNA damage, apoptosis and expression of COX-1, COX-2 and NF-κB using immunofluorescence and blot analysis were done. The present study demonstrated the formation of micronuclei, over-expression of COX-2 and NF-κB in DMBA induced lung tumorigenesis and thereby suggesting a marked role of inflammation in the tumour progression. Results indicate the formation of micronuclei in DMBA group, which were significantly reduced in aspirin treated group, and totally absent in the celecoxib and etoricoxib groups. In conclusion, co-administration of etoricoxib and celecoxib has significantly reduced the inflammatory potential of the growing neoplasm in DMBA induced lung cancer in male BALB/C mice.

This report investigates the positive association between curve progression of Southeast European population and one of the most significant polymorphisms of idiopathic scoliosis (IS). The association between rs11190870 near the ladybird homeobox 1 (LBX1) gene, the curve severity (case-control study) and the curve pattern (case-only study) was explored among 155 IS Caucasian patients and 254 unrelated controls. The genotyping of rs11190870 was carried out by the TaqMan real-time amplification technology. The results revealed the existence of a statistically significant association between rs11190870, downstream of the LBX1 gene and IS predisposition and progression in the population sample. The case-only analysis indicated also that the genetic variant rs11190870 is not correlated to a certain idiopathic curve pattern. Based on the obtained data, rs11190870 could be regarded as a predisposing and modifying genetic factor for IS in patients of Southeast European descent. In addition, replication studies are necessary to investigate the possible relationship between the LBX1 locus and certain subtypes of IS in specific population groups. Clinical relevance should be pursued further, together with the molecular genetic identification of prognostic markers, as a contemporary approach that would make an early treatment including minimally invasive procedures.

Tibial pseudarthrosis often features deficient bone formation, excessive bone resorption, and extensive pathological fibrosis, particularly in individuals with Neurofibromatosis type I (NF1). It was hypothesized that overactive NF1-Ras-JNK signalling may underlie the pathological fibrosis, and that this could be treated via a JNK antagonist. CC-930, a small molecule JNK inhibitor, was trialed in closed fractures in wild type mice CC-930 (25 mg/kg/twice daily) was dosed throughout fracture healing (D2-21) and during the latter stages of repair (D11-21). All fractures healed by D21, regardless of treatment, with some of the CC-930 (D11-21) treatment group showing early bridging. CC-930 (D11-21) was tested in an Nf1-null fracture model where Nf1 was inactivated by Ad-Cre virus injection in Nf1^flox/flox mice; these mice also possessed a Cre-responsive tdTomato transgene. CC-930 resulted in a significant decrease in non-unions (93% vehicle vs. 64% CC-930, p < 0.01). Local treatment with the bone anabolic rhBMP-2 (10 μg) increased union and callus bone volume, but also increased the fibrotic tissue at the fracture site. Fractures treated with a combination of rhBMP-2 (10 μg) and CC-930 were all partially or fully bridged by D21 (p < 0.01 vs. vehicle) and there was a significant decrease in fibrosis vs. rhBMP-2 alone (p < 0.01). In untreated Nf1-null fractures, the tdTomato transgene was expressed in fibrous tissue at the fracture site, but not in the newly forming bone. These data suggest that JNK inhibition may be an effective therapeutic approach for reducing pathological fibrosis in NF1 tibial pseudarthrosis, however other adjunctive strategies may be required to augment bone formation.

Malaria is a serious global health challenge, and it has infected millions of people worldwide. There is an urgent need for new antimalarial drugs and drug targets for both prophylaxis and chemotherapy. In the present study, we biosynthesized TiO₂ nanoparticles (NPs) using the Momordica charantia leaf aqueous extract as a reducing and stabilizing agent. TiO₂ NPs were characterized by UV, XRD, FTIR, HRTEM, EDX, DLS and Zeta-potential. The maximum activity of mosquitocidal was observed in the synthesized TiO₂ NPs against Anopheles stephensi Liston (Diptera: Culicidae) larvae and pupae, LC₅₀ were 2.50 mg/l (I instar), 2.86 mg/l (II), 3.29 mg/l (III), 3.43 mg/l (IV), and 5.04 mg/l (pupa). The antimalarial activity of M. charantia leaf aqueous extract and TiO₂ NPs were evaluated against CQ-resistant (CQ-r) and CQ sensitive (CQ-s) strains of Plasmodium falciparum. IC₅₀ of M. charantia leaf aqueous extract were 83.64 μg/ml (CQ-s) and 88.14 μg/ml (CQ-r). Synthesized TiO₂ NPs achieved IC₅₀ of 53.42 μg/ml (CQ-s) and 59.71 μg/ml (CQ-r). The TiO₂ NPs did not exhibit any noticeable toxicity on Poecilia reticulata after 24 h of exposure. Overall, our results suggest that the synthesized TiO₂ NPs may be employed to develop newer and safer agents for malaria control.

Toxins are produced by bacteria, plants and animals for defense or for predation. Most of the toxins specifically affect the mammalian nervous system by interfering with the transmission of nerve impulses, and such toxins have the potential for misuse by the military or terrorist organizations. This review discusses the origin, structure, toxicity and symptoms, transmission, mechanism(s) of action, symptomatic treatment of the most important toxins and venoms derived from fungi, plants, marine animals, and microorganisms, along with their potential for use in bioweapons and/or biocrime. Fungal trichothecenes and aflatoxins are potent inhibitors of protein synthesis in most eukaryotes and have been used as biological warfare agents. Ricin and abrin are plant-derived toxins that prevent the elongation of polypeptide chains. Saxitoxin, anatoxin, and tetrodotoxin are marine-derived toxins that bind to sodium channels in nerve and muscle tissue and cause muscle paralysis. Most bacterial toxins, such as botulinum and Shiga affect either the nervous system (neurotoxins) or damage cell membranes. Batrachotoxins, which are secreted by poison-dart frogs are extremely potent cardiotoxic and neurotoxic steroidal alkaloids. The aim of this review is to provide basic information to enable further understanding of these toxins and their potential military uses.

Biogenic metal nanoparticles owing to elimination of hazardous chemicals are beneficial for human healthy and biomedical applications. Considerable properties of these particles have motivated researchers to develop of the biosynthesized nanomaterials. In this study, the gold nanoparticles using Dracocephalum kotschyi leaf extract (d-GNPs) were synthesized and characterized by TEM-SEAD, SEM-EDAX, XRD, Zeta potential, DLS, and FT-IR analysis. TEM photograph showed spherical morphologies with an average size of 11 nm. SEAD pattern authorized fcc structure of these particles. The average zeta value of -29.3 mV revealed the surface charge of green synthesized GNPs. We studied the influence of different parameters such as reaction temperature, contact time, and pH on the synthesis of d-GNPs by UV-vis spectroscopy. Moreover, the obtained nanoparticles were evaluated regarding their biological activity (anti-cholinesterase and anticancer), as well as their influence on both the Gram classes of bacteria. The AuNPs showed an excellent inhibitory efficacy against AChE and BChE. Biological results exhibited that these particles displayed a dose-dependent cytotoxicity with IC₅₀: 196.32 and 152.16 μg/ml against K562 and HeLa cell lines as well. These metal nanoparticles were found to show no activity toward tested bacteria.

The present study was performed to assess and compare the therapeutic efficacy of various oximes (methoxime, BI-6, HI-6) combined with benactyzine (BNZ) in cyclosarin (GF-agent)-poisoned mice and to evaluate the influence of pretreatment with PANPAL (pyridostigmine, benactyzine and trihexyphenidyl) on the effect of antidotal treatment in mice poisoned with the GF-agent. In the first part of our experiment, methoxime, BI-6 or HI-6 in combination with benactyzine were used for the treatment of GF-poisoned mice. In the second part of the experiment the animals were pretreated with PANPAL 60 min before the GF-agent challenge and then the oxime therapy was applied in the same time scheme as before. All the therapeutic regimens showed a protective ratio higher than 2 and significantly increased the LD₅₀ of GF-agent. The most efficacious oxime in decreasing of GF-agent toxicity was HI-6. PANPAL increased the protective ratios of all therapeutic regimens in comparison with administration of the oxime and BNZ alone. From the results obtained, the combination of pretreatment with PANPAL and following therapy with BNZ and HI-6 seems to be the most efficacious therapeutic regimen for treatment of GF-agent-poisoned mice.

Current medicine uses a variety of high-tech devices to obtain maximum results with minimally invasive procedures. Our goal was to determine the benefits of laser medicine in tonsillectomy in comparison with traditional tonsillectomy, harmonic scalpel and radio frequency scalpel. Forty adult patients with chronic tonsillitis, scheduled for bilateral tonsillectomy, were divided into four groups in a prospective study. The left side tonsillectomy was performed using a traditional technique. The right side tonsillectomy was performed using four different methods: Ho:YAG laser, Er,Cr:YSGG laser, radiofrequency scalpel and harmonic scalpel. Peroperative bleeding and operation time were evaluated by the surgeon, development of pain during the healing period was evaluated by the patients and also histological examination of the resecates was performed. The results showed a significant increase of postoperative pain after the Ho:YAG and Er,Cr:YSGG laser procedure in comparison to traditional tonsillectomy. No significant differences in postoperative pain were found after the use of radiofrequency scalpel and harmonic scalpel. Average operation time and peroperative bleeding differed partially in all methods. In conclusion, all the tested methods offer a safe, uncomplicated alternative to traditional tonsillectomy; however, they do not bring any substantial benefit for the patient in reduction of pain during the postoperative period.

The reactivating and therapeutic efficacy of two newly developed oximes (K305, K307) was compared with the oxime K203 and trimedoxime using in vivo methods The study determining percentage of reactivation of tabun-inhibited acetylcholinesterase in the peripheral as well as central nervous system (diaphragm, brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While the ability of the oxime K305 to reduce acute toxicity of tabun in mice is approaching to the therapeutic efficacy of trimedoxime, the ability of another novel bispyridinium oxime K307 to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and the oxime K203. Thus, the reactivating and therapeutic efficacy of both examined newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

The temporo-mandibular joint is a characteristic feature of mammalian development, and essential to mastication and speech, yet it causes more problems than any other joint in the body and remains the least understood. While it is generally accepted that the normal joint is loaded under compression, the problems and controversies surrounding this view remain unresolved and the disparity in opinion over its treatment continues. Although difficulties in the acquisition of reliable information have undoubtedly contributed to this situation, it is now considered that deficits in neural control and shortcomings in the underlying biomechanical theory and analysis have also played a part, and that a re-assessment from a different perspective could resolve these.
Biotensegrity considers the TMJ from this position, where the mandible is suspended within a tensioned network that extends over a much wider anatomical field than is generally recognized and significant motion control is contained within the structure itself. It is an evolutionary-conserved arrangement that enables the system to rapidly respond to changing functional demands and provides a more complete model of joint physiology that can be used to guide further research.

Previous studies have indicated that polyphenol-rich Chrysanthemum morifolium extract (CME) may inhibit the formation of hyperlipidemic fatty liver in mice. But there has been no report about therapeutic effect on diabetes mellitus. In the present study, we investigated the action of CME and its potential mechanisms. A mouse model with diabetes mellitus was induced by alloxan. The results showed that after treatment of diabetic mice with polyphenol-rich CME 150 and 300 mg/kg for 6 weeks, the levels of fasting blood glucose (FBG) as well as water and food consumption were decreased (P < 0.05 or P < 0.01), the content of hepatic glycogen was increased, especially in the 300 mg/kg group (P < 0.05), but no significant variations in the body-weight gain, fasting serum insulin, and muscular glycogen were observed. Importantly, toxic alloxan treatment might decrease the protein expressions of hepatic peroxisome proliferator-activated receptor (PPAR) α/γ, glycogen synthase (GS), and glucose transporter-2 (Glut-2) (P < 0.05 or P < 0.01), while CME might reverse the changes (P < 0.01). These findings demonstrate that the reduction of PPARα/γ-mediated hepatic glycogen synthesis may involve in the alloxan-induced hyperglycemia, and the hypoglycemic mechanisms of CME may be mainly associated with the increment of hepatic glycogen synthesis via upregulation of PPARα/γ-mediated GS and Glut-2 protein expressions.

This study investigated the FSH influence on maturation rates of oocytes in vitro maturation (IVM), and expression levels of the follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR) and gonadotropin releasing hormone receptor (GnRHR) of cumulus-oocyte complexes (COCs) response to FSH treatment. 1686 COCs were harvested from 1063 ovaries of sheep. COCs were cultured 26 h at 38.5 °C and 5.0% CO₂ in IVM media supplemented with 0, 5, 10, 20 and 30 IU/ml FSH. They were allocated in to FSH-1 (basal line), FSH-2, FSH-3, FSH-4 and FSH-5 groups. The apoptosis of COCs was assessed by Tunel assay. Expression levels of mRNA and protein for FSHR, LHR and GnRHR in sheep COCs were detected using real time RT-PCR and Western blotting respectively. The results showed that the maturation rates of oocytes were improved gradually when FSH supplement increased from 0 to 10 μg/ml. FSH-3 group showed the highest maturation rate. Apoptosis rates of FSH-treated groups were less than that of FSH-1 group with a minimum of FSH-3 group. Expression levels of FSHR and LHR mRNAs in FSH-3 and FSH-4 were significantly higher than in FSH-1. Expression level of GnRHR mRNA in FSH-3 was higher than in FSH-1 (P < 0.05). Expression levels of FSHR proteins in FSH-3 and FSH-4 groups were higher than that of FSH-1 group. Expression levels of GnRHR proteins increased gradually with a maximal increment of FSH-5. Maturation rates of COCs had significant positive correlations with mRNA and protein levels of FSHR, LHR and GnRHR. In conclusion, FSH could accelerate the maturation rate of sheep oocytes and reduce their apoptosis rate, also increase the expression levels of FSHR, LHR and GnRHR mRNAs, and strengthen expressions of FSHR and GnRHR proteins. 10 IU/ml FSH additions were the optimal dose for IVM of sheep oocytes.

The natural products and conventional chemotherapeutic drugs combination can increase the efficacy of anticancer treatment through their potential synergistic effects and reduce its toxicity. The current study investigates the effect of methanolic extract from aerial parts of Juniperus excelsa on cell death activities induced by vincristine in acute lymphoblastic leukemia cells.
Cytotoxic activity of J. excelsa extract and vincristine in Nalm-6 and Reh cells was determined using MTT assay and synergism was evaluated using the CompuSyn software. Apoptosis was assessed by caspase 3 activity assay and flow cytometry. The expression levels of some apoptosis-related genes, Caspase 3, BAX and BCL-2 were determined by Real-time PCR. Statistical analysis was assessed by one-way ANOVA and Tukey's tests.
The combined treatment of VCR and J. excelsa extract showed a synergistic cytotoxic effect on both Nalm-6 and Reh cells at low doses of vincristine (CI < 1). J. excelsa extract also significantly increased VCR-induced apoptosis (P < 0.001). Expression of CASP3 and BAX genes were upregulated, while BCL-2 gene was downregulated in both cells (P < 0.05).
Our study suggested the combined use of lower doses of VCR and J. excelsa extract promote its effects by apoptosis induction and this combination could potentially decrease the side effects of the drug.

This study investigated the effect of hormonal changes on semen quality, chromatin status, and assisted reproductive outcomes (intracytoplasmic sperm injection), among infertile men. In this research, 219 infertile men undergoing assisted reproductive treatment were evaluated with reproductive hormone levels (including follicle-stimulating hormone, luteinizing hormone and testosterone), semen parameters, and sperm chromatin integrity and condensation, between 2012 and 2014. Finally, the assisted reproductive outcomes in these infertile men were studied. The low rate of total sperm count, motility and morphology, fertilization and the high percentage of DNA damage, the poor zygote (Z4 grade) and embryo quality (grade D), and spontaneous miscarriage was recorded in men with high levels of follicle-stimulating hormone and luteinizing hormone. In conclusion, the changes in the follicle-stimulating hormone, luteinizing hormone, and testosterone by changes in the sperm quality, and DNA damage may have the effects on assisted reproductive outcomes (e.g., low fertilization, poor zygote and embryo quality, and high miscarriage).

The effect of hydro-alcoholic extract of Curculigo orchoides on hexavalent chromium (Cr VI) induced toxicity in rats was investigated. Sub-acute toxicity studies were performed by OECD guidelines. K₂Cr₂O₇ (30 mg/kg) was administered to all groups except control group for a period of 28 days by oral gavage. Control group received distilled water; treatment groups received C. orchoides (25, 50 and 100 mg/kg). Cr(VI) administration resulted in up-regulation of serum biochemical parameters such as alanine transaminase, aspartate transaminase, alkaline phosphatase, and tissue biochemical markers viz. lipid peroxidation and protein carbonyl content. C. orchioides (100 mg/kg) significantly decreased these enzyme levels. The activities of anti-oxidant enzymes like superoxide dismutase, catalase and glutathione S-transferase were significantly decreased by Cr(VI) administration (50.7%, 43.7% and 37.9%, respectively). Further, mRNA expression studies and histopathology studies confirmed Cr(VI) toxicity. In all cases, C. orchioides promoted significant restoration of enzyme levels in a dose dependent manner. These results suggest the ameliorating effect of C. orchoides on Cr(VI) induced oxidative stress is probably via, modulation of cytokines, transcription factors and apoptotic genes.

Objective
The aim of this study was to determine the effects of Shen-Fu injection treatment on skin flap survival in an experimental random pattern skin flap model in rats.
Materials and methods
Ninety male Sprague-Dawley (SD) rats were randomly assigned to the SFI-treated groups and normal saline-treated (control) group. SFI (10 or 20 ml/kg) or normal saline (10 ml/kg) were administered intraperitoneally once daily. On postoperative day 2, malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor α (TNF-α) and IL-6 were evaluated. Besides, flap survival rate, tissue edema, mean vessel densities, number of neutrophil, flap angiography and vascular endothelial growth factor (VEGF) expression were examined on day 7.
Results
Compared with the control group, the mean survival area in SFI groups were significantly larger showing a possible dose-dependent effect of SFI. SOD activity was increased significantly, as well as the VEGF expression. MDA level, in the test group, however, was decreased. The hematoxylin and eosin (H&E) stained slices revealed that SFI had the angiogenesis promotion effect, meantime inflammation was clearly inhibited in the SFI groups.
Conclusion
This study showed that intraperitoneally administered SFI significantly improved random skin flap survival in rats.

The aim of this experimental in vivo study was to examine the effect of topically-used gentamicin bound to microdispersed oxidized cellulose (MDOC) in nanofibre form in the treatment of deep surgical site infections and to compare it with Garamycin Schwamm®. Twelve domestic swine were used in a model of a full-thickness infected dermal wound. The effectiveness of both forms of gentamicin were tested in wound infections caused by Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The effectiveness of gentamicin-MDOC and Garamycin Schwamm® were comparable according to microbiological culture findings, with no statistically significant differences. When macroscopically assessed, 100% of the infected wounds treated by gentamicin-MDOC were without signs of infection, compared with only 16.7% when Garamycin Schwamm® was used and this was of statistical significance. Therefore when combined with a nanofibre MDOC carrier, topically-used gentamicin is rendered more effective for the treatment of full-thickness skin infections.

Cannabinoids have been indicated for the treatment of glaucoma in humans. However, pharmacological studies in other species are lacking. Healthy Beagle dogs were treated with 0.1% cannabinoid eyedrops for 3 or 7 days. Intraocular pressure (IOP) and pupillary diameter (PD) were measured. To evaluate whether the topical cannabinoid formulation affects the motor and central nervous systems, a parallel study was performed. Male Swiss mice received ocular or intraperitoneal (i.p.) cannabinoid solution for 1 day (acute) or 7 days (subacute) and were tested in the open field (OF), elevated plus maze (EPM), open field habituation test (HT), and marble burying test (MBT). The treated dogs exhibited a significant reduction of IOP and PD. Acute i.p. cannabinoid administration reduced locomotion in mice in the OF and increased the number of entries into the open arms of the EPM. Subacute ocular cannabinoid administration increased the time spent on the closed arms and reduced the time spent on the open arms of the EPM. The cannabinoid i.p. and ocular did not exert anxiogenic effects in the MBT. These results indicate that the cannabinoid reduced IOP when used topically, and psychotropic effects occurred only with systemic administration.

The study investigated comparatively the effects of active immunization of Cetrorelix and Triptorelin on the follicle development, histological structures, and expressions of FSHR and LHR proteins in the ovary. One hundred and five female mice, 35 days old, and body weight of 26.56 ± 2.89 g, were randomly assigned into Cetrorelix (CET), Triptorelin (TRI) and control groups (CG). Mice in CET-1, CET-2 and CET-3 (n = 15) were subcutaneously injected with 0.1, 0.2 and 0.4 mL Cetrorelix antigen (100 μg/mL) for seven days, respectively. Mice in TRI-1, TRI-2 and TRI-3 were injected with 0.1, 0.2 and 0.4 mL Triptorelin antigen (100 μg/mL) for seven days. Mice in CG (n = 15) were injected with 0.2 mL saline for seven days. Western blotting was utilized to determine the expressions of follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) proteins. ELISA was used to measure the serum FSH and LH concentrations. The ovarian slices were observed under optical microscopy. The results showed that the ovarian weights of CET and TRI groups increased slightly with a maximum increment of 27.02% of CET-1 mice on day 35. Ovarian weights in TRI group increased dose-dependently with a maximum increment of 45.77% in TRI-3 on day 35. The numbers of the primordial follicle (POF), primary follicle (PF), secondary follicle (SF) and mature follicle (MF) of CET and TRI groups increased at different degrees when compared to CG. The granular layer in SF was arranged tightly and zona pellucida (ZP) was thickened. Follicles developed fully. Follicle longitudinal diameter (FLD), follicle transverse diameter (FTD) and follicle wall thickness (FWT) in CET and TRI groups increased as compared to CG. FLD, FTD and FWT of TRI-3 had a larger increment than CG and CET-1 on days 21 and 35. Expression levels of FSHR and LHR proteins in TRI group increased when compared to CG. Expression levels of FSHR and LHR proteins of CET group decreased. Serum FSH of TRI group was slightly higher than the CG and CET group on day 21. On day 35, serum FSH levels of CET-1 and TRI-1 were greater than CG and the rest of the subgroups. Serum FSH levels had no significant differences among all groups. Expression levels of LHR and FSHR proteins in CET group had obvious negative correlations to FLD, FTD and FWT. However, in the TRI group, these correlations were positive. In conclusion, Cetrorelix and Triptorelin immunization could improve ovarian growth, increase the follicle numbers, enhance dose-dependently the FLD, FTD and FWT, and eventually promote the ovary and follicle development. Cetrorelix decreased expression levels of FSHR and LHR proteins in the ovaries of mice. Triptorelin enhanced expression levels of FSHR and LHR proteins. Triptorelin treatment had more obvious effects than Cetrorelix treatment.