Novel green-based polyglycerol polymeric nanoparticles loaded with ferulic acid: A promising approach for hepatoprotection.

In the pursuit of eco-friendly and sustainable materials, polyglycerol diacid polymers hold immense promise for drug delivery compared to those derived from fossil fuels. Harnessing this potential, we aimed to prepare nanoparticles (NPs) derived from sustainable polymers, loaded with ferulic acid (FA), a natural polyphenolic compound known for its shielding effect against liver-damaging agents, including carbon tetrachloride (CCl4). Glycerol was esterified with renewable monomers, such as succinic acid, adipic acid, and/or FA, resulting in the creation of a novel class of polyglycerol diacid polymers. Characterization via Fourier-transform infrared spectroscopy and nuclear magnetic resonance confirmed the successful synthesis of these polymers with <7 % residual monomers. FA-loaded NPs were fabricated using the newly synthesized polymers. To further augment their potential, the NPs were coated with chitosan. The chitosan-coated NPs boasted an optimal PS of 290 ± 5.03 nm, showing superior physical stability, and a commendable EE% of 58.79 ± 0.43%w/v. The cytotoxicity was examined on fibroblast cells using the SRB assay. In-vivo experiments employing a CCl4-induced liver injury model yielded compelling evidence of the heightened hepatoprotective effects conferred by chitosan-coated particles. This demonstrates the benefits of incorporating sustainable polymers into innovative composites for efficient drug delivery, indicating their potential for creating versatile platforms for various therapeutic applications.

Association between sarcoidosis and diabetes mellitus: a systematic review and meta-analysis.

Background: Sarcoidosis is multisystem inflammatory granulomatosis that can potentially affect any organ of the human body. We aimed to estimate the prevalence of diabetes mellitus (DM) in sarcoidosis patients and determine the association between sarcoidosis and DM.Method: All relevant articles reporting the prevalence of DM in sarcoidosis published until September 19th, 2020, were retrieved from ten electronic databases. We used the random effect model to perform the meta-analysis.Results: After screening 2,122 records, we included 19 studies (n = 18,686,162). The prevalence of DM in sarcoidosis patients was 12.7% (95% CI 10-16.1). The prevalence was highest in North America with 21.3% (13.5-31.8), followed by Europe 10.4 (7.9-13.7) and Asia 10% (1.8-39.7). Sarcoidosis patients had higher rates of DM compared to controls (OR 1.75; 95% CI 1.49-2.05). Sensitivity analysis, after removing the largest weighted study, did not reveal any effect on the significance of the results (OR 1.73; 95% CI 1.33-2.25).Conclusion: The prevalence of DM in sarcoidosis is considerably high, with increased odds of DM in sarcoidosis compared to healthy controls. Further research with a wide range of confounders is required to confirm the association of sarcoidosis with DM.

Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells.

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.

Using single-molecule FRET to probe the nucleotide-dependent conformational landscape of polymerase ß-DNA complexes.

Eukaryotic DNA polymerase ß (Pol ß) plays an important role in cellular DNA repair, as it fills short gaps in dsDNA that result from removal of damaged bases. Since defects in DNA repair may lead to cancer and genetic instabilities, Pol ß has been extensively studied, especially its mechanisms for substrate binding and a fidelity-related conformational change referred to as "fingers closing." Here, we applied single-molecule FRET to measure distance changes associated with DNA binding and prechemistry fingers movement of human Pol ß. First, using a doubly labeled DNA construct, we show that Pol ß bends the gapped DNA substrate less than indicated by previously reported crystal structures. Second, using acceptor-labeled Pol ß and donor-labeled DNA, we visualized dynamic fingers closing in single Pol ß-DNA complexes upon addition of complementary nucleotides and derived rates of conformational changes. We further found that, while incorrect nucleotides are quickly rejected, they nonetheless stabilize the polymerase-DNA complex, suggesting that Pol ß, when bound to a lesion, has a strong commitment to nucleotide incorporation and thus repair. In summary, the observation and quantification of fingers movement in human Pol ß reported here provide new insights into the delicate mechanisms of prechemistry nucleotide selection.

A pre-catalytic non-covalent step governs DNA polymerase ß fidelity.

DNA polymerase ß (pol ß) selects the correct deoxyribonucleoside triphosphate for incorporation into the DNA polymer. Mistakes made by pol ß lead to mutations, some of which occur within specific sequence contexts to generate mutation hotspots. The adenomatous polyposis coli (APC) gene is mutated within specific sequence contexts in colorectal carcinomas but the underlying mechanism is not fully understood. In previous work, we demonstrated that a somatic colon cancer variant of pol ß, K289M, misincorporates deoxynucleotides at significantly increased frequencies over wild-type pol ß within a mutation hotspot that is present several times within the APC gene. Kinetic studies provide evidence that the rate-determining step of pol ß catalysis is phosphodiester bond formation and suggest that substrate selection is governed at this step. Remarkably, we show that, unlike WT, a pre-catalytic step in the K289M pol ß kinetic pathway becomes slower than phosphodiester bond formation with the APC DNA sequence but not with a different DNA substrate. Based on our studies, we propose that pre-catalytic conformational changes are of critical importance for DNA polymerase fidelity within specific DNA sequence contexts.

Defective Nucleotide Release by DNA Polymerase ß Mutator Variant E288K Is the Basis of Its Low Fidelity.

DNA polymerases synthesize new DNA during DNA replication and repair, and their ability to do so faithfully is essential to maintaining genomic integrity. DNA polymerase ß (Pol ß) functions in base excision repair to fill in single-nucleotide gaps, and variants of Pol ß have been associated with cancer. Specifically, the E288K Pol ß variant has been found in colon tumors and has been shown to display sequence-specific mutator activity. To probe the mechanism that may underlie E288K's loss of fidelity, a fluorescence resonance energy transfer system that utilizes a fluorophore on the fingers domain of Pol ß and a quencher on the DNA substrate was employed. Our results show that E288K utilizes an overall mechanism similar to that of wild type (WT) Pol ß when incorporating correct dNTP. However, when inserting the correct dNTP, E288K exhibits a faster rate of closing of the fingers domain combined with a slower rate of nucleotide release compared to those of WT Pol ß. We also detect enzyme closure upon mixing with the incorrect dNTP for E288K but not WT Pol ß. Taken together, our results suggest that E288K Pol ß incorporates all dNTPs more readily than WT because of an inherent defect that results in rapid isomerization of dNTPs within its active site. Structural modeling implies that this inherent defect is due to interaction of E288K with DNA, resulting in a stable closed enzyme structure.

Knowledge and attitude toward HIV voluntary counseling and testing services among pregnant women attending an antenatal clinic in Sudan.

Human immunodeficiency virus (HIV) infection and the development of the acquired immunodeficiency syndrome (AIDS) are increasing at an alarming rate especially in the sub-Saharan region. Pregnant women susceptible to HIV and its transmission to the fetus provide a unique opportunity for implementing preventive strategy against HIV infection of newborn babies. During the period of August-December 2005 a cross-sectional study was conducted at the Fath-Elrahman Elbashir antenatal clinic, Khartoum Teaching Hospital, to investigate pregnant women's basic knowledge and attitude toward HIV and mother to child transmission as well as voluntary counseling and testing. Pre-tested structured questionnaires were given to antenatal attendants by professional counselors. Their basic socio-demographic and obstetric characteristics were obtained. Respondents' knowledge about HIV and mother to child transmission were tested. In addition, their willingness toward HIV testing was also reported. Out of the 1,005 women investigated, 79% had basic knowledge about HIV. Those who were resident in Khartoum and whose age was > or =26.1 years and their education level was secondary and above were found to be more knowledgeable about HIV. More than half of respondents were aware of mother to child transmission. Older (> or =26.1 years), educated, and working mothers were found to be more knowledgeable about mother to child transmission. Willingness to undergo the test was demonstrated in 72.8% of respondents. However, only 30.3% had the test done. Older women, primigravidae, and Muslims have higher acceptance of voluntary counseling and testing. There is a need to extend the voluntary counseling and testing program in all antenatal clinics. In addition, there is a need to increase the level of education and raise health awareness about HIV and mother to child transmission.