Anticlastogenic activity of morin against whole body gamma irradiation in Swiss albino mice

Anticlastogenic activity of morin was explored against whole body gamma radiation, at a dose rate of 1.66 Gy/min in Swiss albino mice pretreated intraperitoneal or orally. Pretreatment with morin 10, 25, 50, 75, 100, 125, and 150 mg/kg, i.p. delayed and reduced percentage mortality and increased mean survival times in mice irradiated with 10 Gy gamma radiation. Intraperitoneal route was found superior to oral route. An i.p. dose of 100 mg/kg was found to be the most effective dose in preventing radiation-induced weight loss, increasing the mean survival times and reducing percentage mortality. Morin (100 mg/kg) pretreatment effectively maintained spleen index (spleen weight/body weight x 100) and stimulated endogenous spleen colony forming units. Pretreatment with morin (100 mg/kg) significantly reduced dead, inflammatory, and mitotic cells in irradiated mice jejunum along with a significant increase in goblet cells and rapidly multiplying crypt cells. Morin (100 mg/kg) also maintained the villus height close to normal, prevented mucosal erosion and basement membrane damage in irradiated jejunum. Nuclear enlargement in epithelial cells of jejunum was lower in morin treated mice compared to radiation control. Morin (100 mg/kg) also significantly elevated the endogenous antioxidant enzymes viz. glutathione S transferase (GST), superoxide dismutase (SOD) and reduced glutathione (GSH), in normal mice at 2, 4 and 8 h post treatment. Drastic decrease in endogenous enzymes (GSH, GST, catalase and SOD) and total thiols was observed in irradiated mice at 2, 4 and 8 h post irradiation, while pretreatment with morin (100 mg/kg) prevented this decrease. Morin (100 mg/kg) also elevated radiation LD(50) from 9.2 to 10.1 Gy, indicating a dose modifying factor (DMF) of 1.11.     

2-cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor gamma in colon and pancreatic cancer cells

Betulinic acid (BA) is a phytochemical triterpenoid acid from bark extracts and is cytotoxic to cancer cells and tumors. We modified the A-ring of BA to give a 2-cyano-1-en-3-one moiety and the effects of the 2-cyano-lup-1-en-3-oxo-20-oic acid (CN-BA), 2-cyano derivative of BA, and its methyl ester (CN-BA-Me) were investigated in colon and pancreatic cancer cells. Both CN-BA and CN-BA-Me were highly cytotoxic to Panc-28 pancreatic and SW480 colon cancer cells. CN-BA and CN-BA-Me also induced differentiation in 3T3-L1 adipocytes, which exhibited a characteristic fat droplet accumulation induced by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Based on these results, we investigated the activities of CN-BA and CN-BA-Me as PPARgamma agonists using several receptor-mediated responses including activation of transfected PPARgamma-responsive constructs, induction of p21 in Panc-28 cells and induction of caveolin-1 and Krüppel-like factor 4 in colon cancer cells. The results clearly demonstrated that both CN-BA and CN-BA-Me activated PPARgamma-dependent responses in colon (caveolin-1) and pancreatic (p21) cancer cells, whereas induction of KLF4 by these compounds in colon cancer cells was PPARgamma independent and also dependent on cell context. The PPARgamma agonist activities of CN-BA and CN-BA-Me were structure-, response/gene- and cell context-dependent suggesting that these compounds are a novel class of selective PPARgamma modulators with potential for clinical treatment of colon and pancreatic cancer.     

Aberrant Huntingtin interacting protein 1 in lymphoid malignancies

Huntingtin interacting protein 1 (HIP1) is an inositol lipid, clathrin, and actin binding protein that is overexpressed in a variety of epithelial malignancies. Here, we report for the first time that HIP1 is elevated in non-Hodgkin's and Hodgkin's lymphomas and that patients with lymphoid malignancies frequently had anti-HIP1 antibodies in their serum. Moreover, p53-deficient mice with B-cell lymphomas were 13 times more likely to have anti-HIP1 antibodies in their serum than control mice. Furthermore, transgenic overexpression of HIP1 was associated with the development of lymphoid neoplasms. The HIP1 protein was induced by activation of the nuclear factor-kappaB pathway, which is frequently activated in lymphoid malignancies. These data identify HIP1 as a new marker of lymphoid malignancies that contributes to the transformation of lymphoid cells in vivo.     

Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.     

Discovery of Novel Allosteric Eg5 Inhibitors Through Structure‐Based Virtual Screening

Mitotic kinesin Eg5 is an attractive anticancer drug target. Discovery of Eg5 inhibitors has been focused on targeting the ‘monastrol‐binding site’. However, acquired drug resistance has been reported for such inhibitors. Therefore, identifying new Eg5 inhibitors which function through a different mechanism(s) could complement current drug candidates and improve drug efficacy. In this study, we explored a novel allosteric site of Eg5 and identified new Eg5 inhibitors through structure‐based virtual screening. Experiments with the saturation‐transfer difference NMR demonstrated that the identified Eg5 inhibitor SRI35566 binds directly to Eg5 without involving microtubules. Moreover, SRI35566 and its two analogs significantly induced monopolar spindle formation in colorectal cancer HCT116 cells and suppressed cancer cell viability and colony formation. Together, our findings reveal a new allosteric regulation mechanism of Eg5 and a novel drug targeting site for cancer therapy.     

In Vivo Evaluation of Guar Gum-based Colon-targeted Drug Delivery Systems of Ornidazole in Healthy Human Volunteers

The aim of the present study was to find the in vivo performance of guar gum-based colon-targeted tablets of ornidazole (dose 250 mg) in comparison with an immediate release tablet of ornidazole (250 mg) in human volunteers. Six healthy volunteers participated in the study, and a cross over design was followed. The plasma concentration of ornidazole was estimated by HPLC. The immediate release tablets of ornidazole produced peak plasma concentration (C max of 2171.33 ± 278.15 ng/ml) at 2.91 ± 0.14 h (T max) whereas colon-targeted tablets produced peak plasma concentration (C max of 1716.66 ± 125.83 ng/ml) at 11.91 ± 0.14 h. The delayed T max, decreased C max, and decreased k a of ornidazole from guar gum-based colon-targeted ornidazole tablets, in comparison with the immediate tablets, indicated that the drug was not released in stomach and small intestine, but targeted to colon. Slow absorption of ornidazole from the less absorptive colon might result in the availability of drug for local action in the colon.     

CT patterns and differential criteria for acute eosinophilic pneumonia and COVID‐19 pneumonia

Difficulties encountered in diagnosing and treating COVID‐19 pneumonia and acute eosinophilic pneumonia during the pandemic from 2019 to 2021 led to the identification and study of the differential features of the two conditions.     

ATP-induced chondrocalcinosis

Objective. To determine whether adult articular cartilage mineralizes in the presence of ATP. Methods. Intact adult porcine articular cartilage and monolayers of chondrocytes were cultured in physiologic media containing ATP, and mineralization was measured as retention of ⁴⁵Ca. Cartilage was analyzed by electron microscopy. Results. Articular cartilage sequestered ⁴⁵Ca when incubated with 100 γM ATP. Use of the ATP analog α,β-methylene ATP did not promote mineralization and addition of pyrophosphatase inhibited mineralization, indicating that hydrolysis of ATP to AMP and inorganic pyrophosphate is necessary for the process to occur. Mineral was concentrated in articular cartilage vesicles in the perichondral area. Conclusion. Adult articular cartilage mineralizes in the presence of ATP, in a manner similar to that found with isolated matrix or articular cartilage vesicles. This supports the notion that these structures have a role in chondrocalcinosis.     

Impact evaluation of a community nutrition and livelihood program on child nutrition in rural Bangladesh

Given the high prevalence of child undernutrition in Bangladesh, multi-sectoral approaches involving livelihood promotion have potential to mitigate the burden of undernutrition. This study examined the impact of an economic development (ED) program providing poultry assets, gardening skills and saving training added to the Positive Deviant (PD)/Hearth program (PDH/ED), compared to PD/Hearth only (PDH). A total of 1029 children who attended PD/Hearth sessions in September–November 2018 at 6–13 months of age were enrolled in the cohort study in July–August 2019. The cohort, comprised of 532 children in the PDH/ED group and 593 children in the PDH group, was reassessed in November 2020. The program impact on child nutrition, food security, crop production, dietary quality and household income was estimated using a difference-in-differences approach accounting for the sociodemographic differences between PDH/ED and PDH groups. Compared to the PDH group, the PDH/ED group showed increases in child dietary diversity score (DDS) (+0.32), child minimum dietary diversity (13.7 percentage points [pp]), and maternal DDS (+0.28) (all p < 0.05). From 2019 to 2020, the PDH/ED households improved food security by 12.6 pp and diversified crop production (bananas (9.7 pp), papaya (11.1 pp), carrots (3.8 pp) and lemons (5.9 pp)), and increased the proportion of annual income ≥60,000 Taka by 12.4 pp and last month income ≥5000 Taka by 7.8 pp, compared to PDH group (all p < 0.05). However, there was no impact on child nutritional status, morbidity, livestock ownership and total annual/last income. Incorporating an ED program into nutrition programming could benefit food security and dietary diversity in rural Bangladesh.