Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression

One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.     

(-)-Epigallocatechin-3-gallate prevents photocarcinogenesis in mice through interleukin-12-dependent DNA repair

We have shown previously that topical application of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, prevents photocarcinogenesis in mice. EGCG prevents UVB-induced immunosuppression by inducing interleukin-12 (IL-12). As immunosuppression is a risk factor for photocarcinogenesis, we investigated the possibility that EGCG also prevents UVB-induced photocarcinogenesis through an IL-12-dependent DNA repair mechanism. To investigate this possibility, we determined the effects of EGCG on photocarcinogenesis in IL-12 knockout (KO) mice using the formation of cyclobutane pyrimidine dimers (CPD) as an indicator of the extent of UVB-induced DNA damage. Topical application of EGCG (1 mg/cm(2) skin) prevented photocarcinogenesis in wild-type (C3H/HeN) mice in terms of tumor incidence and tumor multiplicity but did not prevent photocarcinogenesis in IL-12 KO mice. UVB-induced DNA damage, as determined by the formation of CPDs and the number of sunburn cells, was resolved more rapidly in the skin of wild-type mice treated with EGCG than untreated control mice. In contrast, the extent of UVB-induced DNA damage and the numbers of sunburn cells were not significantly different in the EGCG-treated IL-12 KO mice and untreated control mice. In addition, treatment of XPA-proficient human fibroblast cells with EGCG promoted repair of UVB-induced CPDs in a dose-dependent manner but not in an XPA-deficient cells, indicating that the nucleotide excision repair mechanism is involved in EGCG-mediated DNA repair. Taken together, these results indicate for the first time that EGCG can prevent photocarcinogenesis through an EGCG-induced IL-12-dependent DNA repair mechanism.     

Revisiting curcumin chemistry part I: a new strategy for the synthesis of curcuminoids

A new strategy for the synthesis of curcuminoids is described involving the reaction of acetylacetone difluroboronite with an aromatic aldehyde in the presence of n-butylamine as catalyst. The new intermediate products, curcuminoid difluroboronites, of symmetrically substituted curcuminoids like curcumin and bisdemethoxycurcumin are stable, can be isolated and hydrolysed with aq. methanol at pH 5.8 to get the curcuminoids of high purity. The method is applicable for unsymmetrical curcuminoids like demethoxycurcumin also with some modification involving column chromatography. The intermediate curcuminoid difluroboronites, as also the natural β-diketone pongamol difluroboronite, prepared for the first time were characterized on the basis of physical and chemical properties and spectroscopic data. The advantage of using borontrifluoride to protect the enol group in acetylacetone over the generally used boric oxide is brought out. The importance of conducting biological activity studies using pure curcuminoids is explained.     

Tonic Pupil in Cytomegalovirus Anterior Uveitis in an Immunocompetent Adult Male – A Case Report

Purpose: To report an interesting case of development of tonic pupil in an immunocompetent male with cytomegalovirus (CMV) anterior uveitis.

Methods: Retrospective case report

Results: A 30-year-old Iranian healthy male was diagnosed to have Posner–Schlossman syndrome (OS). Aqueous tap was positive for CMV by multiplex Polymerase chain reaction (PCR). Adequate control of inflammation and Intraocular pressures (IOP) were achieved with topical steroids, ganciclovir gel, and antiglaucoma medications. On a follow-up visit, he complained of recent onset of blurring of vision (OS) despite appropriate refractive correction, quiet anterior chamber, and normal IOP. Pupillary examination showed anisocoria (larger pupil in OS). Pupillary constriction (OS) on instillation of 0.125% pilocarpine drops confirmed the diagnosis of a tonic pupil.

Conclusion: We describe a unique finding of tonic pupil on a follow-up examination in an immunocompetent adult male with CMV anterior uveitis. A prior association has not been described in literature (Medline Search).     

Naringin and naringenin inhibit nitrite-induced methemoglobin formation

Naringin and naringenin protect hemoglobin from nitrite-induced oxidation to methemoglobin. The protection is not observed when naringin and naringenin are added after the autocatalytic stage of the oxidation of hemoglobin by nitrite. The ability of naringin and naringenin to scavenge oxygen free radicals may be responsible for the action because superoxide, hydroxyl and other free radicals are implicated in promoting the autocatalytic stage of oxidation of hemoglobin by nitrite. Both compounds showed less ability to protect intact erythrocytes suggesting that they may not cross the erythrocyte membrane in sufficient amounts. Naringenin was more effective than naringin, probably because of the extra phenolic group in the aglycone.     

Cefoperazone-sulbactam for treatment of intra-abdominal infections: results from a randomized, parallel group study in India

BACKGROUND: Combinations of a third-generation cephalosporin and metronidazole, with or without an aminoglycoside, often are used for the treatment of intra-abdominal infections in surgical settings. Simpler regimens that preserve an adequate spectrum of coverage, but allow easier administration and have fewer side effects, may be a more desirable option. METHODS: This randomized, open-label, active comparator study evaluated the effectiveness (non-inferiority hypothesis) of the beta-lactam/beta-lactamase inhibitor combination cefoperazone-sulbactam (2-8 g/day), compared with ceftazidime (2-6 g/day)-amikacin (15 mg/kg/day)-metronidazole (500 mg three times daily) in 154 and 152 subjects, respectively, having intra-abdominal infections. The study was conducted at 17 centers in India. RESULTS: Non-inferiority of cefoperazone-sulbactam (91.9%) compared with ceftazidime-amikacin-metronidazole (81.8%) was demonstrated for continued resolution of clinical signs and symptoms at the 30-day follow-up (primary endpoint) with a treatment difference of 10.1% (95% confidence interval 2.1%, 18.1%; pre-defined non-inferiority limit > -12.5%). Superiority of cefoperazone-sulbactam also was demonstrated for this endpoint, with significantly more subjects achieving continued resolution at the 30-day follow-up than in the comparator group (p = 0.015). On microbiologic outcomes, cefoperazone-sulbactam had higher success rates than ceftazidime-amikacin-metronidazole (92.9% vs. 80.0%). The pathogens (202 isolated) isolated most commonly were Escherichia coli (38.6%) and Klebsiella spp. (12.9%). The incidence of treatment-related adverse events was 6.5% and 16.4% in the cefoperazone-sulbactam and ceftazidime-amikacin-metronidazole groups, respectively, with more discontinuations due to treatment-related adverse events in the comparator arm (3.2% vs. 9.9%). CONCLUSION: Empirical cefoperazone-sulbactam monotherapy could be a useful adjunct to surgical intervention for intra-abdominal infections.     

Brahmarasayana protects against Ethyl methanesulfonate or Methyl methanesulfonate induced chromosomal aberrations in mouse bone marrow cells

ABSTRACT: BACKGROUND: Ayurveda, the traditional Indian system of medicine has given great emphasis to the promotion of health. Rasayana is one of the eight branches of Ayurveda which refers to rejuvenant therapy. It has been reported that rasayanas have immuno-modulatory, antioxidant and antitumor functions, however, the genotoxic potential and modulation of DNA repair of many rasayanas have not been evaluated. METHODS: The present study assessed the role of Brahmarasayana (BR) on Ethyl methanesulfonate (EMS)- and Methyl methanesulfonate (MMS)-induced genotoxicity and DNA repair in in vivo mouse test system. The mice were orally fed with BR (5g or 8 mg / day) for two months and 24 h later EMS or MMS was given intraperitoneally. The genotoxicity was analyzed by chromosomal aberrations, sperm count, and sperm abnormalities. RESULTS: The results have revealed that BR did not induce significant chromosomal aberrations when compared to that of the control animals (p > 0.05). On the other hand, the frequencies of chromosomal aberrations induced by EMS (240 mg / kg body weight) or MMS (125 mg/kg body weight) were significantly higher (p < 0.05) to that of the control group. The treatment of BR for 60 days and single dose of EMS or MMS on day 61, resulted in significant (p < 0.05) reduction in the frequency of chromosomal aberrations in comparison to EMS or MMS treatments alone, indicating a protective effect of BR. Constitutive base excision repair capacity was also increased in BR treated animals. CONCLUSION: The effect of BR, as it relates to antioxidant activity was not evident in liver tissue however rasayana treatment was observed to increase constitutive DNA base excision repair and reduce clastogenicity. Whilst, the molecular mechanisms of such repair need further exploration, this is the first report to demonstrate these effects and provides further evidence for the role of brahmarasayana in the possible improvement of quality of life.