A review of the studies on food-derived factors which regulate energy metabolism via the modulation of lipid-sensing nuclear receptors.

Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.

Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents.

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE2-, PGF2α-, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE2-induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies.

[TREATMENT OF PATIENTS WITH CHRONIC RECURRENT HERPES VIRUS INFECTION OF GENITAL LOCALIZATION: A CLINICAL STUDY OF FORTEPREN PREPARATION].

AIM: Selection of optimal dosage regimen, length of treatment course (frequency of administration), safety, tolerance and clinical effectiveness evaluation of the medical preparation fortepren in patients with chronical recurrent herpes virus infection of genital localization. MATERIALS AND METHODS: The medical product of antiviral and immune modulating effect--fortepren (sodium polyprenyl phosphate) as a 4 mg/ml solution for injections combined with the base course of acyclic nucleoside acyclovir, 400 mg tablets, held studies. 40 male and female patients participated in the study. After a 10-day acyclovir course (400 mg x 3 times a day) for removing the acute phase, 4 groups of 10 individuals were formed: 1--5 ml (20 mg) of fortepren i/m once at day 13 ± 2 after the start of the study after the completion of the treatment of the acute phase of the disease; 2--5 ml (20 mg) fortepren i/m 3 times at an interval of 21 days; 3--2 ml (8 mg) fortepren i/m 3 times at an interval of 21 days; 4 (control)--5 ml of placebo i/m at remission stage 3 times at an interval of 21 days. Increase of the duration of inter-recurrence period, decrease of the severity of the recurrences, state of skin and mucous damage elements, improvements of immunologic parameters were considered during effectiveness evaluation. RESULTS: Significant differences in the frequency of recurrences of genital herpes were shown for 3 months of observation in experimental and control groups. A significant reduction of genital herpes recurrence frequency from 3.52 ± 0.09 (before treatment) to 2.89 ± 0.08 (after treatment) was noted in patients of group 3 (p < 0.001). The frequency of recurrences in the control group was 3.84 ± 0.10, that was higher than the parameters in all the experimental groups. A significant reduction of the rash area was noted in group 3, moreover, a redution of frequency of detection of clinical manifestations of genital herpes in the form of vesicle elements after treatment in groups 2 (p = 0.02) and 3 (p = 0.005) was found. Evaluation of local symptoms has established that burning have caused minimal discomfort for patients of groups 3 and 4 and itch and soreness--of groups 1 and 3. The least pronounced exacerbations were noted in patients of group 3. Intramuscular administration of fortepren preparation was established to result in the increase of titers of leukocyte virus-induced interferon for the whole duration of treatment. CONCLUSION: An intramuscular dose of 2 ml (8 mg) at recurrence stage 3 times at an interval of 21 days after the completion of the 10-day base course of treatment of the acute phase of chronical recurrent herpes virus infection of genital localization using acyclovir was accepted as an optimal dosage regimen. Analysis of the obtained results has shown an acceptable safety profile and a good level of tolerance for fortepren preparation.

Simvastatin downregulates expression of TGF-ßRII and inhibits proliferation of A549 cells via ERK.

Lung cancer is the leading cause of cancer-related death worldwide. Transforming growth factor-ß receptor II (TGF-ßRII) plays an important role in the regulation of proliferation and progression in cancer. Statins have been documented to exhibit anticancer and cancer chemopreventive properties. However, the effects and mechanisms of simvastatin on the development of lung cancer are still unclear. In the present study, quiescent A549 cells were treated in vitro with fetal bovine serum (FBS) in the presence or absence of simvastatin. MTT, Western blot, and real-time qPCR were used to detect cell viability, activation of ERK, and expression of TGF-ßRII at the protein and RNA level. Our results demonstrated that simvastatin inhibited activation of ERK, downregulated expression of TGF-ßRII, and suppressed A549 cell proliferation. Furthermore, the effects of simvastatin can be reversed by farnesyl pyrophosphate (FPP). Therefore, these results suggest that simvastatin may inhibit A549 cell proliferation and downregulate TGF-ßRII expression by inhibiting activation of ERK. Our findings may advance the current understanding of the effects of simvastatin on cancer progression and contribute to the study of cancer treatment.

Intrathecal delivery of farnesyl thiosalicylic acid and GW 5074 attenuates hyperalgesia and allodynia in chronic constriction injury-induced neuropathic pain in rats.

The role of mitogen-activated protein kinase (MAPK) family has been well defined in neuropathic pain. Ras and c-Raf constitute an important part of MAP kinase family as Ras/Raf/MEK/ERK2 signaling cascade. The present study was designed to investigate the analgesic potential of farnesyl thiosalicylic acid, a novel Ras inhibitor, and GW 5074, a selective c-Raf1 inhibitor, in chronic constriction-induced injury (CCI)-induced peripheral neuropathic pain. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. The development of pain was assessed on 14th day in terms of cold allodynia; mechanical hyperalgesia and mechanical allodynia by performing acetone test, pinprick and Von Frey tests, respectively. Farnesyl thiosalicylic acid (2.5, 5 and 10 µg) and GW 5074 (1, 2 and 4 µg) were injected intrathecally on 14th day following nerve ligature to assess their analgesic potential in CCI model. Nerve ligature-induced CCI produced significant neuropathic pain manifestations in terms of cold and mechanical allodynia, and mechanical hyperalgesia. Single intrathecal administration of farnesyl thiosalicylic acid (5 and 10 µg) as well as GW 5074 (2 and 4 µg) significantly attenuated CCI-induced hyperalgesia and allodynia. The analgesic effects of farnesyl thiosalicylic acid and GW 5074 in CCI model suggests that pharmacological inhibition of Ras and c-Raf-1 signaling may be potentially useful for managing neuropathic pain.

[Multidirectional effect of MIF and sodium polyprenyl phosphate on the course of experimental flavivirus infection in mice].

AIM: Study of macrophage migration inhibiting factor (MIF) effect after intracerebral administration on the course of experimental infection induced in mice by tick borne encephalitis virus (TEV), and study of sodium polyprenyl phosphate (PPP) and/or antibodies against MIF on the course of this infection against the background of MIF administration. MATERIALS AND METHODS: Phosprenil preparation was used as a source of PPP. PPP was administered intracerebrally. MIF--human recombinant (R&D, USA), mice--Balb/c line. RESULTS: In the sera of mice infected with TEV, MIF production stimulation was detected at days 8 through 10 after the infection--against the background of clinical signs presentation of tick borne encephalitis (TE). Administration of PPP to infected mice, on the contrary, resulted in MIF production suppression at the specified period. After administration of 20 ng of MIF to mice, lethality increased by 40% and average life span decreased by 2.3 days. Thus, MIF at high doses caused an increase of infection course severity, induced by TEV in mice, and administration of 60 microg of PPP resulted in the protection from infection in 100% of cases. Intracerebral administrationto mice of antibodies against MIF resulted in a decrease of lethality indicator up to 26% as compared with control and an increase of averagelife span by 5.5 days. During simultaneous administration into the brain of infected mice of MIF, PPP and antibodies against MIF, prevention of MIF-induced increase of TE course severity was registered. CONCLUSION: The data obtained allow to conclude that MIF may serve as an indicator of TE course severity, and possible prognostic indicator of meningo-encephalitic form development in humans.

Effect of Polyprenyl Immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis.

Feline infectious peritonitis (FIP) is considered a fatal disease. Three cats with dry form FIP were treated with Polyprenyl Immunostimulant. Two of the three cats are still on treatment and are alive and well 2 years after diagnosis. The third cat survived 14 months but was treated for only 4.5 months. Further studies are necessary to assess the potential of the Polyprenyl Immunostimulant.

[The correction action of Phosprenyl and Gamavit on the functional activity of mouse peritoneal macrophages in response to high doses of Staphylococcus aureus alpha-toxin].

The study of the functional activity of peritoneal macrophages of BALB/c mice at different stages of the toxic action caused by S. aureus alpha-toxin (ST) was carried out. The analysis of the dynamics of toxic reaction revealed the main critical points of triggering necrotic processes: the first hour and day 2. One hour after the injection of large doses of ST a sharp increase in the process of antigen binding with its subsequent sharp decrease. Simultaneously, a decrease in the activity of the lysosomal enzymes cathepsin D and acidic phosphatase was established, which was indicative of the destabilization of both lysosomal and cellular macrophage membranes. The increase of oxygen metabolism on day 2, together with the release of lysosomal proteases into the extracellular area, correlated with the maximum death rate of mice and served as the main index of the development of necrosis. The prophylactic and therapeutic use of the preparations Gamavit and Phosprenyl revealed their antitoxic activity and capacityfor stimulating the level of natural body resistance.

[Protective effect of a new antiviral preparation of phosprenyl in experimental tick-borne encephalitis]. / Zashchitnoe deistvie novogo protivovirusnogo preparata fosprenil pri éksperimental'nom kleshchevom éntsefalite.

Antiviral activity of phosprenyl was studied in BALB/c mice infected with tick-borne encephalitis (TBE) virus. Up to 60% animals infected with TBE virus survived after 1-3 intramuscular injections of phosprenyl. The mortality in the untreated group infected with the virus was 100%. Direct antiviral effect of phosprenyl was studied in sensitive SPEV cells infected with TBE virus. The titer of the virus decreased 10-fold in the cells treated with the drug vs. untreated control cells. Phosprenyl stimulates some interleukins: gamma-interferon, tumor necrosis factor-alpha, and interleukin-6. The stimulating effect of the drug manifests in intact animals and in those infected with TBE virus and treated with phosprenyl. The prospects of further trials of the drug as a therapeutic and prophylactic agent in TBE are discussed.

Inhibition of growth and pulmonary metastasis of B16-F10 murine melanoma by N-1554, a polyprenyl phosphate.

Antitumor effect of N-1554 (alpha-dihydrodecaprenyl phosphate containing eight trans internal isoprene residues) against B16-F10 melanoma in syngeneic C57BL/6 mice was examined. B16-F10 cells were inoculated into the footpad of mice and N-1554 was intraperitoneally administered after the inoculation. The drug significantly inhibited the tumor growth in the footpad and dramatically reduced the pulmonary metastasis from the tumor. The antitumor effect of N-1554 was almost abolished when the immunosuppressant carrageenan or anti-asialo GM1 antibody was administered to mice. In addition, pretreatment of host mice with N-1554 reduced the growth of subcutaneously inoculated B16-F10 melanoma. These results suggest that enhancement of host immune system may be involved in the antitumor effect of N-1554.

Synergistic effect of dolichyl phosphate and human recombinant granulocyte colony-stimulating factor on recovery from neutropenia in mice treated with anti-cancer drugs.

Severe hematopoietic injury in mice was induced by using either 5-fluorouracil, adriamycin, mitomycin C, or vinblastine. Daily subcutaneous administration of purified human recombinant granulocyte colony-stimulating factor (rG-CSF; 0.3-10.0 micrograms/day) markedly accelerated recovery from the drug-induced granulocytopenia in a dose-dependent manner, as reported previously. On the other hand, daily intraperitoneal administration of dolichyl phosphate (Dol-P) also enhanced granulopoiesis to accelerate recovery from granulocytopenia, although the effect of Dol-P was relatively moderate as compared with that of rG-CSF. A synergistic recovery of granulopoiesis was observed when Dol-P was administered together with rG-CSF to the mice treated with anti-cancer drugs. Joint use of Dol-P (1 mg/day) and rG-CSF (0.3 micrograms/day) was as effective as a higher dose of rG-CSF (3 micrograms/day). Joint use of Dol-P (1 mg/day) and rG-CSF (3 micrograms/day) was sometimes more effective.