Alternating Magnetic Field Induced Membrane Permeability in Erythromycin Magneto-Liposomes A Potential Solution to Antibiotic Resistance

Biophysics - Antibiotic resistance is a serious problem facing the world; it is increasing every year due to over or misuse of antibiotics that led to developing new mechanisms of drug resistance...     

A cluster of Ankyrin and Ankyrin-TPR repeat genes is associated with panicle branching diversity in rice

The number of grains per panicle is an important yield-related trait in cereals which depends in part on panicle branching complexity. One component of this complexity is the number of secondary branches per panicle. Previously, a GWAS site associated with secondary branch and spikelet numbers per panicle in rice was identified. Here we combined gene capture, bi-parental genetic population analysis, expression profiling and transgenic approaches in order to investigate the functional significance of a cluster of 6 ANK and ANK-TPR genes within the QTL. Four of the ANK and ANK-TPR genes present a differential expression associated with panicle secondary branch number in contrasted accessions. These differential expression patterns correlate in the different alleles of these genes with specific deletions of potential cis-regulatory sequences in their promoters. Two of these genes were confirmed through functional analysis as playing a role in the control of panicle architecture. Our findings indicate that secondary branching diversity in the rice panicle is governed in part by differentially expressed genes within this cluster encoding ANK and ANK-TPR domain proteins that may act as positive or negative regulators of panicle meristem’s identity transition from indeterminate to determinate state.     

N-type Calcium Channel in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

One of the family of voltage-gated calcium channels (VGCC), the N-type Ca²⁺ channel, is located predominantly in neurons and is associated with a variety of neuronal responses, including neurodegeneration. A precise mechanism for how the N-type Ca²⁺ channel plays a role in neurodegenerative disease, however, is unknown. In this study, we immunized N-type Ca²⁺ channel α_1B-deficient (α_1B^−/−) mice and their wild type (WT) littermates with myelin oligodendrocyte glycoprotein 35–55 and analyzed the progression of experimental autoimmune encephalomyelitis (EAE). The neurological symptoms of EAE in the α_1B^−/− mice were less severe than in the WT mice. In conjunction with these results, sections of the spinal cord (SC) from α_1B^−/− mice revealed a reduction in both leukocytic infiltration and demyelination compared with WT mice. No differences were observed in the delayed-type hypersensitivity response, spleen cell proliferation, or cytokine production from splenocytes between the two genotypes. On the other hand, Western blot array analysis and RT-PCR revealed that a typical increase in the expression of MCP-1 in the SC showed a good correlation with the infiltration of leukocytes into the SC. Likewise, immunohistochemical analysis showed that the predominant source of MCP-1 was activated microglia. The cytokine-induced production of MCP-1 in primary cultured microglia from WT mice was significantly higher than that from α_1B^−/− mice and was significantly inhibited by a selective N-type Ca²⁺ channel antagonist, ω-conotoxin GVIA or a withdrawal of extracellular Ca²⁺. These results suggest that the N-type Ca²⁺ channel is involved in the pathogenesis of EAE at least in part by regulating MCP-1 production by microglia.     

Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)–negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.     

Mercury (Hg) Exposure in Breast-Fed Infants and Their Mothers and the Evidence of Oxidative Stress

The objective of this work was to assess exposure to mercury (Hg) and its induction of oxidative stress in 155 healthy lactating Saudi mothers and their infants. Samples of breast milk and blood were collected from the mothers, while urine was taken from both infants and mothers. Both urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured in mothers and infants as biomarkers of oxidative stress. The mean concentration of Hg in breast milk was 1.19 μg/L (range 0.012–6.44 μg/L) with only one mother having Hg >4 μg/L, the upper limit established by the US Agency for Toxic Substance and Disease Registry. However, 57.4 % had Hg ≥1 μg/L, the background level for Hg in human milk. The mean urinary Hg corrected for creatinine (Hg-C) in mothers and infants was 1.47 and 7.90 μg/g creatinine, respectively, with a significant correlation between the two (p?<?0.001). Urinary Hg levels over 5 μg/g creatinine (the background level in an unexposed population) were found in 3.3 % of mothers and 50.1 % of infants. None of the mothers had total blood Hg above the US Environmental Protection Agency’s maximum reference dose of 5.8 μg/L. No correlation was noted between urinary Hg in infants and Hg in breast milk (p?>?0.05). Hg in breast milk, though, was associated with Hg in blood (p?<?0.001), suggesting the efficient transfer of Hg from blood to milk. Hg in the breast milk of mothers and in the urine of infants affected the excretion of urinary MDA and 8-OHdG, respectively, in a dose-related manner. These findings reveal for the first time lactational exposure to Hg-induced oxidative stress in breast-fed infants, which may play a role in pathogenesis, particularly during neurodevelopment. This will also contribute to the debate over the benefits of breast milk versus the adverse effects of exposure to pollutants. Nevertheless, breastfeeding should not be discouraged, but efforts should be made to identify and eliminate the source of Hg exposure in the population.     

Angiotensin II Receptor Blocker Attenuates Intrarenal Renin-Angiotensin-System and Podocyte Injury in Rats with Myocardial Infarction

The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague–Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16^ink4a, decreased immunostaining for Wilms’ tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2’-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16^ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.