Role of T lymphocytes in adjuvant arthritis. II. Different subpopulations of T lymphocytes functioning in the development of the disease.

The effects of treatments with cyclophosphamide (CY), hydrocortisone and anti-thymocyte sera (ATS) on the development of adjuvant arthritis (AA) were examined in WKA rats inoculated with wax D to induce AA. A single injection of 25 to 50 mg/kg of CY given 2 to 3 days before wax D inoculation caused severe arthritis with high incidence, whereas larger doses of CY were less efficient. Furthermore, the enhancing effect of CY pretreatment was abolished by passively transferred normal syngeneic thymocyreated with ATS and guinea pig C. On the basis of these results and the previous observations on the effect of adult thymectomy and low-dose irradiation, we concluded that this enhancing effect of CY pretreatment was caused by selective depletion of suppressor T lymphocytes. Pretreatment with 12.5 mg of hydrocortisone also caused severe arthritis. This enhancing effect of hydrocortisone could also be due to the elimination of those suppressor cells. In contrast, in vivo pretreatment with ATS showed striking inhibition on the development of AA, suggesting that ATS could eliminate T lymphocytes that were responsible for eliciting this disease. Thus it appears that at least two T cell subpopulations are involved in the development of AA, one is an ATS-sensitive T2 subpopulation that is effective for induction of AA and the other is a T1 subpopulation that regulates this disease process.     

Treatment of experimental adjuvant arthritis with the combination of methotrexate and lyophilized Enterococcus faecium enriched with organic selenium

The efficacy of combination therapy with methotrexate (MTX) and probiotic bacteriaEnterococcus faecium enriched with organic selenium (EFSe) in rats with adjuvant arthritis was determined. Rats with adjuvant arthritis were given MTX (0.3 mg/kg 2-times weekly, orally); lyophilizedE. faecium enriched with Se (15 mg/kg, 5 d per week, orally); and a combination of MTX plus EFSe for a period of 50 d from the immunization. Levels of serum albumin, serum nitrite/nitrate concentrations, changes in hind paw swellling, arthrogram score, bone erosions, whole body bone mineral density (BMD) and bone mineral content (BMC) were assayed in the rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX and with the combination MTX+EFSe significantly inhibited markers of both inflammation and arthritis. Significant differences in favor of combination therapy with MTX+EFSe as compared to MTX alone were seen in serum albumin concentration, hind paw swelling and arthrogram score. Reductions in radiographic scores were also more pronounced in the combination therapy group. Combination therapy, but not MTX alone, inhibited the reduction of BMD and BMC; treatment with lyophilized EFSe alone had no significant effect on adjuvant arthritis in rats. The potent therapeutic effect of low dosage MTX therapy in combination with lyophilized EFSe on adjuvant arthritis in rats was shown.     

The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks

We describe the effects of nitric oxide (NO) agonists and antagonists and the influence of a novel organoprotective pentadecapeptide BPC 157, on the development of pulmonary hypertension syndrome and tissue lesions in chicks. Acute toxicity, which includes single dose application of saline (1 mL intraperitoneally (ip)), BPC 157 (10 μg/kg bw), L-NAME (NO antagonist, doses 50, 100, 150 mg/kg bw) and L-arginine (NO agonist/100 mg/kg bw with their combination L-NAME + BPC 157; L-NAME + L-arginine) was investigated. In this experiment pathohistological examination of the spleen, heart, liver and lungs and hematological analysis was conducted. In the chronic toxicity experiment, the animals were treated daily for 5 weeks with L-NAME (10 mg/kg bw), L-arginine (100 mg/kg bw), BPC 157 (10 μg/kg bw) and their combinations (L-NAME + BPC 157; L-NAME + L-arginine) ip. Seven animals from each group, including controls (saline 1 mL ip) were killed every week. Application of L-NAME caused pulmonary hypertension syndrome (PHS) in the treated chicks, which was prevented by the simultaneous application of L-arginine and BPC 157. Pathohistological examination of both acute and chronic toxicity revealed that L-NAME caused severe tissue damage (myocardial and hepatic cell necrosis, necrosis of the lymphoid cells in the spleen) while L-arginine provoked predominantly congestion, edema and hemorrhages in all organs. The effect of L-NAME was successfully inhibited by the application of L-arginine and BPC 157 but the latter substance did not cause any tissue or organ damage. Hematological analysis shows significant hemoglobin and leukocyte number decrease in the L-NAME-treated groups of chicks.     

Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria <Emphasis Type="Italic">Escherichia coli</Emphasis> O83 (Colinfant®)

A certain relationship was observed between the gastrointestinal system, arthritis and immune system. Patients with rheumatoid arthritis have an altered microflora composition and disturbed intestinal defensive barrier. Effect of probiotic bacteria (Colinfant®; COL) with known favorable effect on intestinal microflora was determined on the methotrexate (MTX) treatment of adjuvant arthritis. Rats with adjuvant arthritis were administered methotrexate 0.5 mg/kg body mass 2-times weekly per os, COL 1 mL/kg body mass every second day per os, and a combination of MTX+COL for a period of 28 d from the immunization. Levels of serum albumin, body mass, changes in hind paw swelling, and arthrogram score were estimated in rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX, as well as with the combination treatment with MTX+COL significantly inhibited both inflammation and destructive arthritis-associated changes. The combination treatment inhibited both the hind paw swelling and arthrogram score more remarkably than MTX alone; on the other hand, the difference between combination treatment and MTX alone was not significant. Treatment with COL alone had no effect on adjuvant arthritis in rats. Colinfant® can increase the preventive effect of MTX treatment in rat adjuvant arthritis by improving its antiarthritic effects.     

Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats

The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg), boswellic acids (250 mg/kg), glucosamine (250 mg/kg) and a combination of boswellic acids (125 mg/kg) and glucosamine (125 mg/kg). BA when administered at 250 mg/kg in rats, carrageenan-induced paw edema and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic acids, glucosamine when administered at 250 mg/kg showed a mild effect in carrageenan-induced edema and moderate inhibition of paw swelling against developing arthritis. Although the combination of boswellic acids and glucosamine did not affect the acute inflammation to a greater extent yet a significant anti-arthritic activity was observed in rats. In conclusion, a synergistic effect was observed in chronic inflammatory conditions when two chemical entities were administered in combination in preclinical study.     

Effect of gentamycin in combination with prodigiozan on the immunological reactivity of the body

The effect of gentamicin sulphate and its combination will prodigiozan on antibody formation in experiments and the levels of the immunobiologic reactivity of patients with purulent inflammatory processes was studied with a purpose of developing rational schemes of antibiotic therapy of infectious diseases. A decrease in the titers of the antibodies to Aeromonas and the number of antibody-forming cells in the spleen was noted on repeated administration of gentamicin to albino mice in a dose of 20 mg/kg. This was prevented by the use of prodigiozan in a dose of 500 micrograms/kg once every 4 days. The use of gentamicin in patients with purulent inflammatory diseases in doses of 40 or 80 mg twice a day for 7--10 days had no significant effect on the titers of IgA, IgG, IgM, lysozyme blood serum levels, serum bactericidal activity and absorption activity of the peripheral blood neutrophils. Still, it induced a marked suppression of the neutrophil digestive capacity as compared to the initial levels, especially on administration of gentamicin in a dose of 40 mg twice a day. An increase in the level of IgM and no suppression of the neutrophil digestive capacity were noted after completion of the therapy in the patients treated with gentamicin administered in a dose of 40 mg twice a day and prodigiozan administered in a dose of 50 micrograms once every 4 days. It is recommended to use prodigiozan in combinaed therapy with gentamicin for correction of the changes in the specific and nonspecific protective forces of the host.     

Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats

Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg sc), aspirin (400 mg/kg ig) and diclofenac (125 mg/kg ip) studies, BPC 157 (10 μg or 10 ng/kg ip) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 μg or 10 ng/kg ip), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0–14th day, 14–30th day, 14th day–1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect.     

Pathological evaluation of anti-rheumatic drugs on type II collagen-induced arthritis in DBA/1J mouse

The effects of anti-rheumatic drugs (lobenzarit (CCA); 10 and 50mg/kg, cyclophosphamide (CP); 5 mg/kg and dexamethasone (DM); 0.25mg/kg) were evaluated immunologically and histopathologically on DBA/1J mice that develop polyarthritis after immunization by the intradermal injection of type II collagen. Serum anti-type II collagen IgG levels in the groups treated with CP and DM were significantly suppressed to 1/2 and 1/10 as compared to those of the positive control group, respectively. Those of both groups treated with CCA were not different from those of the positive control group. Histopathological examination revealed that treatment with CP and DM markedly reduced or suppressed inflammatory changes and resulted in low incidence of arthritis. From the standpoint mentioned above, treatment with anti-rheumatic drugs suppressed the development of arthritis in this model, and we could confirm that this model was useful for evaluation of the effect of anti-rheumatic drugs.     

Effect of flumecinol (Zixoryn) on the cytochrome P450 and cytochrome P448 dependent hepatic microsomal monooxygenase activities in male rats.

The effect of three-day oral administration of 50 mg/kg bw. and 100 mg/kg bw. flumecinol (Zixoryn, Gedeon Richter Chemical Works Ltd., Budapest, Hungary) and intraperitoneal administration of 50 mg/kg bw. phenobarbital as well as the single intraperitoneal administration of 20 mg/kg bw. 3-methylcholanthrene on various cytochrome P450 and P448 dependent hepatic microsomal enzyme activities was studied in male albino Wistar rats. 50 mg/kg bw. flumecinol had no significant effect. 100 mg/kg bw. flumecinol had an inducing effect comparable to the one of phenobarbital. The activity of the cytochrome P448 dependent 7-ethoxyresorufin O-deethylase was enhanced by all three substances, but flumecinol's effect was by far behind that of 3-methylcholanthrene, so the carcinogenic promoter effect of flumecinol can be questioned.     

Protection by interleukin 1 against lung toxicity caused by cyclophosphamide and irradiation

Interleukin 1 has been shown to provide protection against the toxic effects of cyclophosphamide given in combination with localized irradiation of the lung. A single dose of 15 micrograms/kg interleukin 1 was given 24 h before cyclophosphamide (25-125 mg/kg) which was followed 1 day later by five daily exposures of 4.5 or 5.0 Gy, localized to the lung. Interleukin 1 significantly reduced early measurements of breathing rate for mice treated with high cyclophosphamide doses and irradiation, and at cyclophosphamide doses above 50 mg/kg, there was a significant reduction in the lethality from the combined treatment. At lower levels of cyclophosphamide, however, there seemed to be no effect.     

Chemoprotective effects of carnosine against genotoxicity induced by cyclophosphamide in mice bone marrow cells

The protective effects of carnosine as a natural dipeptide were investigated in mouse bone marrow cells against genotoxicity induced by cyclophosphamide. Mice were injected with solutions of carnosine at three different doses (10, 50 and 100?mg kg(-1) bw) for five consecutive days. On the fifth day of treatment, mice were injected cyclophosphamide and killed after 24?h. The frequency of micronuclei in polychromatic erythrocytes and the ratio of polychromatic erythrocyte/polychromatic erythrocyte?+?normochromatic erythrocyte [PCE/(PCE?+?NCE)] were evaluated by May-Grunwald/Giemsa staining. Histopathology of bone marrow was examined in mice treated with cyclophosphamide and carnosine. Carnosine significantly reduced micronucleated polychromatic erythrocytes (MnPCEs) induced by cyclophosphamide at all three doses. Carnosine at dose of 100?mg kg(-1) bw reduced MnPCEs 3.76-fold and completely normalized the PCE/(PCE?+?NCE) ratio. Administration of carnosine inhibited bone marrow toxicity induced by cyclophosphamide. It appeared that carnosine with protective activity reduced the oxidative stress and genotoxicity induced by cyclophosphamide in bone marrow cells of mice. Copyright ? 2012 John Wiley & Sons, Ltd.     

Modification of the adjuvans arthritis by carrageenin, compound 48/80, histamine- and serotonin antagonists, non-steroid antiphlogistics as well as protease inhibitors and their possible relations to inflammation mediators]

1. Injections of carrageenin (1,25 mg/kg i.v.) from the 1st to the 3rd day and then each 2nd or 3rd day inhibited paw swelling in adjuvant arthritis of the rat during the time of treatment. Injections from the 11th to the 15th day were ineffective. The level of plasma kininogen was slightly decreased but the total complement serum level was significantly lowered. 2,5 and 3 mg carrageenin/kg respectively were toxic after repeated injections. After a single administration the levels of plasma kininogen and of total serum complement were decreased by 50% although paw swelling was not affected. 2. Pentosane polysulfoester (25 mg/kg i.v.) did not influence paw swelling despite daily administration from the 1st to the 17th day. Heparin (10 000 IE/kg i.v.) was likewise ineffective. 3. Single or repeated injections of compound 48/80 (0,125-0,5 mg/kg i.v.; 1-5 mg/kg i.p.; 3-6 mg/kg s.c.), reserpine (0,2 mg/kg i.p.), cyproheptadine (5 mg/kg i.v.), bromolysergic acid diethylamide (2 x 2 mg/kg i.v.) or metiamide (10 mg/kg i.v.) were without effect on paw swelling. Neither did compound 48/80 effect the complement serum level. 4. Daily administration of chloropromazine (4-10 mg/kg p.o.) or of promethazine (10-15 mg/kg s.c. or p.o.) inhibited paw swelling in the first phase of adjuvant arthritis but not in the second one. 5. The soybean trypsin inhibitor (15 mg/kg i.v.) inhibited paw swelling significantly up to the 4th day, the Kunitz inhibitor (25 000 E/kg i.v.) was ineffective. 6. The content of prostaglandin E of the inflamed paws was increased threefold in both phases of arthritis. The results are discussed with regard to the putative role of mediators of inflammation (histamine, serotonin, kinins, prostaglandins, lysosomal enzymes, lymphokines, complement).     

Studies on anticonvulsant actions of L-deprenyl

L-Deprenyl (Selegeline) introduced for use in parkinson's disease, is implicated to show beneficial effects in epilepsy, alzheimer's disease, cognition, depression and other age related neurological diseases. In this study, we investigated the CNS effects of L-deprenyl with special reference to epilepsy, anxiety and cognition and memory in mice. L-deprenyl (10, 20 and 40 mg/kg) showed a significant anticonvulsant activity against pentylenetetrazole (PTZ)-induced convulsions. Combination of L-deprenyl (10 mg/kg) with the sub-protective dose of diazepam (1 mg/kg) showed potentiation of the anticonvulsant effect. In the maximal-electroshock (MES)-induced convulsions, L-deprenyl (10 mg/kg) significantly delayed the onset and decreased the duration of extensor phase. Its combination with the lower dose of phenytoin (10 mg/kg) showed potentiation in response compared to the per se effect of both the drugs. However, L-deprenyl did not show any protective effect in lithium-pilocarpine induced status epilepticus. Acute treatment with L-deprenyl had no effect on learning and memory. In chronic treatment, L-deprenyl per se showed no effect on learning and memory but did improve the condition in mice with scopolamine induced memory deficit. L-Deprenyl per se was anxiogenic though in combination with diazepam (1 mg/kg) it potentiated the antianxiety effect of the latter. The above observations suggest that in epilepsy, L-deprenyl might be acting partially by influencing the GABAA/benzodiazepine mechanism in the brain (similar to diazepam and phenytoin), and in cognition enhancing effect, the cholinergic system might be playing a role. Thus, L-deprenyl could prove to be an adjuvant in the antiepileptic therapy and beneficial in dementia associated with epilepsy.     

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline,a Monoamine Oxidase-A Inhibitor

We evaluated the effects of pretreatment with clorgyline, an irreversible monoamine oxidase (MAO)-A inhibitor, on morphine-induced hyperlocomotion and antinociception. A single administration of morphine (30 mg/kg, i.p.) to male ICR mice induced a hyperlocomotion. ANOVA analysis revealed the statistical significance of the morphine effect on horizontal locomotion and of the clorgyline pretreatment × morphine interaction effect, but not of the effect of clorgyline pretreatment. The initial (5 min after challenge) phase of morphine actions vs. saline challenge appeared as if morphine had a strong inhibitory effect on locomotor activity in combination with different doses of clorgyline. The mice administered with morphine in combination of clorgyline (1 and 10 mg/kg) did not show any stereotypic behaviors. Clorgyline at a dose of 0.1 mg/kg but not other doses tested significantly potentiated morphine-induced antinociception evaluated by tail flick but not hot plate test. During the measurements of locomotor activity and antinociception, clorgyline at doses of 1 and 10 mg/kg significantly inhibited monoamine metabolism through MAO. These results suggest that clorgyline showed an inhibitory effect on morphine-induced hyperlocomotion, but not antinociception, through MAO inhibition. There is not a possibility that clorgyline pretreatment enhanced morphine action on motor activity, resulting in the abnormal behavior from hyperlocomotion to stereotypic movements.     

Combination of Omega-3 Fatty Acids,Lithium, and Aripiprazole Reduces Oxidative Stress in Brain of Mice with Mania

Manic episode in bipolar disorder (BD) was evaluated in the present study with supplementation of omega-3 fatty acids in combination with aripiprazole and lithium on methylphenidate (MPD)-induced manic mice model. Administration of MPD 5 mg/kg bw intraperitoneally (i.p.) caused increase in oxidative stress in mice brain. To retract this effect, supplementation of omega-3 fatty acids 1.5 ml/kg (p.o.), aripiprazole 1.5 mg/kg bw (i.p.), and lithium 50 mg/kg bw (p.o) were given to mice. Omega-3 fatty acids alone and in combination with aripiprazole- and lithium-treated groups significantly reduced the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation products (thiobarbituric acid reactive substances) in the brain. MPD treatment significantly decreased the reduced glutathione (GSH) level and glutathione peroxidase (GPx) activity, and they were restored by supplementation of omega-3 fatty acids with aripiprazole and lithium. There is no remarkable difference in the effect of creatine kinase (CK) activity between MPD-induced manic model and the treatment groups. Therefore, our results demonstrate that oxidative stress imbalance and mild insignificant CK alterations induced by administration of MPD can be restored back to normal physiological levels through omega-3 fatty acids combined with lithium and aripiprazole that attributes to effective prevention against mania in adult male Swiss albino mice.     

Effects of beta 2-adrenergic stimulants on the progesterone and oestradiol-17 beta serum levels in pseudopregnant rats.

In CFY rats pseudopregnancy (PSP) was induced by mechanical stimulation of cervix uteri. On the days 1 or 7 of PSP indvelling catheter was built in one of the jugular veins and blood was collected daily until 7th or 14th days of PSP respectively, meanwhile the animals were daily injected with clenbuterol (0.1 mg/kg bw), fenoterol (0.5 mg/kg bw), ritodrin (1.0 mg/kg bw), propranolol (2.0 mg/kg bw) or 1.0 ml/kg bw 0.9% NaCl subcutaneously. From the blood samples progesterone (P) and oestradiol-17 beta (E2) were determined by RIA. beta 2-adrenergic agonists did not influence the serum levels of P either in the first or in the second half of PSP and the propranolol failed to alter also the serum levels of P during the PSP. Clenbuterol and ritodrin, however, decreased the serum levels of E2 in the first half of PSP, while in the second half of PSP fenoterol and ritodrin elevated, the propranolol diminished it. It was supposed that in PSP rats beta 2-adrenergic mechanism has a more pronounced effects on the theca-interstitial cells than that of the luteal cells.     

Combined action of X-rays and nonylphenol on mouse sperm

The aim of this study was to assess the effects of 2-weeks’ X-ray and/or nonylphenol (NP) exposure on male mice’s sperm count and quality. Pzh:SFIS mice were exposed to X-rays (0.05 Gy, 0.10 Gy, 0.20 Gy) or to nonylphenol (25 mg/kg bw, 50 mg/kg bw, 100 mg/kg bw) or to both agents (0.05 Gy + 25 mg/kg bw NP, 0.10 Gy + 50 mg/kg bw NP). At 24 h and 5 weeks after the end of exposure the sperm count, morphology and frequency of DNA damage in the male germ cells were estimated. Each agent alone diminished sperm count and morphology. The dose of 0.05 Gy of X-rays decreased the frequency of DNA damage. Combined exposure to lower doses of both agents significantly improved sperm morphology and decreased the level of DNA damage compared to one agent alone. Combined exposure to higher doses reduced the frequency of DNA damage compared to the effect of the appropriate dose of NP. Results of combined exposure to low doses of both agents suggest that 0.05 Gy of X-rays stimulate the DNA damagecontrol system and in consequence repair of DNA caused by X-rays and NP. It may be correlated with increased antioxidant capacity.     

In vivo antimutagenic effect of vitamins C and E against rifampicin-induced chromosome aberrations in mouse bone-marrow cells

-The genotoxic effect of rifampicin (RMP), one of the most active antituberculosis agents is studied. Also, the possible protection provided by the natural antioxidant vitamins C (VC) and E (VE) against the genotoxic effect of RMP is assessed.Mice were orally treated by gavage with 10, 50, 150 and 300 mg RMP kg(-1) body weight (bw). Also, oral treatment was conducted with RMP plus the vitamins. Mice received 300 mg RMP kg(-1) bw plus 100, 200 and 400mg VC or VE kg(-1) bw. Samples were taken 24h after the treatment. Repeated treatments with: (1) the therapeutic dose of RMP (10 mg kg(-1) bw); (2) RMP plus a dose of 25, 50 and 75 mg VC kg(-1); (3) RMP plus 10, 20 and 40 mg VE kg(-1) bw for 30 consecutive days were conducted.The tested doses of RMP induced a significant increase in the percentage of chromosome aberrations. However, a lower percentage of chromosome aberrations was observed when animals were treated with the therapeutic dose for 30 consecutive days.The obtained results revealed that chromosome aberrations induced by RMP decreased to a significant extent when mice were treated with RMP plus VC. The repeated doses of VC reduced the percentage of chromosome aberrations induced by RMP in a significant and dose-dependent manner. On the other hand, repeated doses of VE were not very effective in reducing the percentage of chromosome aberrations induced by RMP. Only the highest dose (3 x 40 mg kg(-1) bw) showed a significant effect (P<0.01).The results on the induction of chromosome damage clearly show that only VC appears able to efficiently protect the bone-marrow cells when given together with RMP, while no significant reduction in the yield of chromosome aberrations was observed for VE in combination with the antituberculosis drug.     

Allylpyrocatechol attenuates methotrexate-induced hepatotoxicity in a collagen-induced model of arthritis

The cornerstone of treatment for rheumatoid arthritis is low dose methotrexate (MTX), but its use is limited by concerns regarding its potential for hepatotoxicity. Allylpyrocatechol (APC), a phytoconstituent sourced from leaves of Piper betle demonstrated antioxidant, anti-inflammatory, and antiarthritic properties. The present study aimed to evaluate the combined effect of APC and MTX on limiting progression of lipopolysaccharide accelerated collagen-induced arthritis, along with reduction of MTX-induced hepatic damage. A collagen-induced arthritis (CIA) model was established by immunising Sprague-Dawley rats with bovine collagen type II (CII) and lipopolysaccharide, followed by a booster dose of CII on day 15. Rats from days 11–27 were administered APC (20?mg/kg), methotrexate (1.5?mg/kg), or a combination of MTX and APC. The combinatorial therapy of APC and MTX significantly improved the parameters of arthritis as evident from the reduction in paw oedema and arthritic score and was endorsed by radiological and histopathological changes. This combination prevented the rise in levels of proinflammatory cytokines, tumour necrosis factor (TNF-α), and interleukin 6 (IL-6). Furthermore, unlike MTX-monotherapy, the APC-MTX combination decreased the associated cachexia, splenomegaly, and oxidative stress. Importantly, the hepatic damage mediated by MTX monotherapy was effectively attenuated by the inclusion of APC. Taken together, antioxidants such as APC when combined with MTX not only potentiated the antiarthritic effect but importantly alleviated the MTX-induced hepatic damage, thus endorsing its effectiveness in preventing progression of articular diseases such as rheumatoid arthritis.     

Therapeutic Potential of Riboflavin,Niacin and Ascorbic Acid on Carbohydrate Metabolizing Enzymes in Secondary Endometrial Carcinoma Bearing Rats

Curative potential of riboflavin, niacin and ascorbic acid against tamoxifen mediated endometrial carcinoma was established by studies on carbohydrate metabolizing enzymes. The enzymes investigated were glycolytic enzymes namely, hexokinase; aldolase; phosphoglucoisomerase and the gluconeogenic enzymes namely, glucose-6-phosphatase and fructose-1, 6-biphosphatase in endometrial carcinoma bearing rats. A significant increase in glycolytic enzymes and a subsequent decrease in gluconeogenic enzymes were observed in plasma, liver and kidney of endometrial carcinoma animals. The administration of riboflavin (45 mg/kg bw/day), niacin (100 mg/kg bw/day) and ascorbic acid (200 mg/kg bw/day) along with tamoxifen (45 mg/kg bw/day) caused a significant decrease in the activity of glycolytic enzymes and a significant increase in the activities of gluconeogenic enzymes to near normal levels in experimental animals. Our results suggest that riboflavin, niacin and ascorbic acid have potential combination therapy against tamoxifen mediated secondary endometrial carcinoma in experimental rats. However, there were no deleterious side effects observed in combinants alone treated animals.