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Marine Drugs May 2024Deep seawater (DS), obtained from a depth over 200 m, has health benefits due to its rich nutrients and minerals, and intake of DS has shown diverse immunomodulatory...
Deep seawater (DS), obtained from a depth over 200 m, has health benefits due to its rich nutrients and minerals, and intake of DS has shown diverse immunomodulatory effects in allergies and cancer. Therefore, the immunostimulatory effects of Korean mineral-rich seawaters were examined in a cyclophosphamide (CPA)-induced immunosuppression model. Three samples of Korean seawater, namely DS from the East Sea off the coasts of Pohang (PDS) and Uljin (UDS), and seawater from the West Sea off the coast of Boryeong (BS), were collected. The seawaters were abundant in several minerals (calcium, iron, zinc, selenium, etc.). Mice were orally administered the seawaters for 42 days, followed by CPA-induced immunosuppression. The CPA induction reduced the weight of the spleen and lymph nodes; however, the administration of seawaters increased the weight of the lymphoid organs, accompanied by stimulation of natural killer cells' activity and NF-kB-mediated cytokine production (IFNγ, TNFα, IL1β, IL6, and IL12). The mouse-derived splenocytes showed lymphoproliferation without cytotoxicity in the seawater groups. Histopathological analysis revealed that the seawaters improved the CPA-induced atrophic changes by promoting lymphoproliferation in the spleen and lymph nodes. These results provide useful information for the use of Korean mineral-rich seawaters, particularly PDS and UDS, as alternative immunostimulants under immunosuppressive conditions.
Topics: Animals; Cyclophosphamide; Mice; Seawater; Minerals; Cytokines; Republic of Korea; Immunosuppression Therapy; Spleen; Killer Cells, Natural; Male; Adjuvants, Immunologic; Lymph Nodes; Immunosuppressive Agents; Mice, Inbred BALB C
PubMed: 38921545
DOI: 10.3390/md22060234 -
Biosensors Jun 2024Agricultural products are vitally important for sustaining life on earth and their production has notably grown over the years worldwide in general and in Brazil...
Agricultural products are vitally important for sustaining life on earth and their production has notably grown over the years worldwide in general and in Brazil particularly. Elevating agricultural practices consequently leads to a proportionate increase in the usage of pesticides that are crucially important for enhanced crop yield and protection. These compounds have been employed excessively in alarming concentrations, causing the contamination of soil, water, and air. Additionally, they pose serious threats to human health. The current study introduces an innovative tool for producing appropriate materials coupled with an electrochemical sensor designed to measure carbendazim levels. The sensor is developed using a molecularly imprinted polymer (MIP) mounted on a glassy carbon electrode. This electrode is equipped with multi-walled carbon nanotubes (MWCNTs) for improved performance. The combined system demonstrates promising potential for accurately quantifying carbendazim. The morphological characteristics of the synthesized materials were investigated using field emission scanning electron microscopy (FESEM) and the Fourier-transform infrared (FTIR) technique. The analytical curve was drawn using the electrochemical method in the range of 2 to 20 ppm while for HPLC 2-12 ppm; the results are presented as the maximum adsorption capacity of the MIP (82.4%) when compared with NIP (41%) using the HPLC method. The analysis conducted using differential pulse voltammetry (DPV) yielded a limit of detection (LOD) of 1.0 ppm and a repeatability of 5.08% ( = 10). The results obtained from the analysis of selectivity demonstrated that the proposed electrochemical sensor is remarkably efficient for the quantitative assessment of carbendazim, even in the presence of another interferent. The sensor was successfully tested for river water samples for carbendazim detection, and recovery rates ranging from 94 to 101% were obtained for HPLC and 94 to 104% for the electrochemical method. The results obtained show that the proposed electrochemical technique is viable for the application and quantitative determination of carbendazim in any medium.
Topics: Carbamates; Benzimidazoles; Pesticides; Nanotubes, Carbon; Electrochemical Techniques; Biosensing Techniques; Electrodes; Biomimetic Materials; Limit of Detection
PubMed: 38920608
DOI: 10.3390/bios14060304 -
Acta Dermatovenerologica Alpina,... Jun 2024Melasma, a chronic acquired skin pigmentation disorder, is characterized by the presence of irregular-edged brown to gray-brown patches with a symmetrical distribution,... (Randomized Controlled Trial)
Randomized Controlled Trial
The effectiveness and safety of 3% tranexamic acid cream vs. 4% hydroquinone cream for mixed-type melasma in skin of color: a double-blind, split-face, randomized controlled trial.
INTRODUCTION
Melasma, a chronic acquired skin pigmentation disorder, is characterized by the presence of irregular-edged brown to gray-brown patches with a symmetrical distribution, primarily on sun-exposed areas such as the face. Topical hydroquinone (HQ) is the gold standard for melasma treatment but has numerous side effects. This study assesses the effectiveness of topical tranexamic acid (TA) as an alternative for melasma treatment.
METHODS
In a double-blind, split-face, randomized controlled trial involving 20 subjects, the effectiveness of 3% TA versus 4% HQ cream was evaluated over 8 weeks. The modified melasma area and severity index (mMASI), melanin index, erythema index, and side effects were assessed. Subjective improvement was measured using the patient global assessment (PtGA).
RESULTS
A significant decline in the mMASI score was observed at weeks 4 and 8 in both groups compared to baseline. There were no statistically significant differences in PtGA scores between the 3% TA group and the 4% HQ group.
CONCLUSIONS
Topical 3% TA is as effective and safe as 4% HQ for treating melasma in the Indonesian population, with potential advantages in terms of side-effect profiles.
Topics: Adult; Female; Humans; Male; Middle Aged; Administration, Cutaneous; Double-Blind Method; Hydroquinones; Melanosis; Severity of Illness Index; Skin Cream; Tranexamic Acid; Treatment Outcome
PubMed: 38918942
DOI: No ID Found -
Asian Pacific Journal of Cancer... Jun 2024This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9,...
OBJECTIVE
This study examined the morphological changes in the colonic mucosa and the presence of inflammation in rats induced with 1,2-dimethylhydrazine (DMH) 30 mg/kg BW over 9, 11, and 13 weeks without a latency period.
METHODS
Hematoxylin and eosin staining was performed to assess the morphology and characteristic alteration of the epitheliocytes in the colon. Immunohistochemistry was employed to assess the expression of tumor necrosis factor (TNF)-α and cyclooxygenase-2 (COX-2). The difference in the severity of inflammation and COX-2 expression was examined using one-way analysis of variance. The correlation of COX-2 expression with the severity of inflammation was analyzed using Spearman's rank correlation test.
RESULT
Until week 13, chronic inflammation and non-hyperplastic and hyperplastic aberrant crypt foci occurred. The severity of inflammation gradually shifted from high moderate to low moderate. TNF-α expression was high in all groups; however, COX-2 expression was gradually lower with longer duration of induction, which corresponded with the severity of inflammation.
CONCLUSION
DMH induction until week 13 without a latency period caused chronic inflammation without the formation of adenoma or adenocarcinoma. A very strong correlation was established between COX-2 expression and inflammation.
Topics: Animals; 1,2-Dimethylhydrazine; Rats; Colorectal Neoplasms; Cyclooxygenase 2; Inflammation; Male; Tumor Necrosis Factor-alpha; Intestinal Mucosa; Carcinogens; Rats, Sprague-Dawley; Aberrant Crypt Foci; Colon; Adenocarcinoma
PubMed: 38918668
DOI: 10.31557/APJCP.2024.25.6.2059 -
BioRxiv : the Preprint Server For... Jun 2024Stalled replication forks can be processed by several distinct mechanisms collectively called post-replication repair which includes homologous recombination, fork...
Stalled replication forks can be processed by several distinct mechanisms collectively called post-replication repair which includes homologous recombination, fork regression, and translesion DNA synthesis. However, the regulation of the usage between these pathways is not fully understood. The Rad51 protein plays a pivotal role in maintaining genomic stability through its roles in HR and in protecting stalled replication forks from degradation. We report the isolation of separation-of-function mutations in Rad51 that retain their recombination function but display a defect in fork protection leading to a shift in post-replication repair pathway usage from HR to alternate pathways including mutagenic translesion synthesis. Rad51-E135D and Rad51-K305N show normal and recombination despite changes in their DNA binding profiles, in particular to dsDNA, with a resulting effect on their ATPase activities. The mutants lead to a defect in Rad51 recruitment to stalled forks as well as a defect in the protection of dsDNA from degradation by Dna2-Sgs1 and Exo1 . A high-resolution cryo-electron microscopy structure of the Rad51-ssDNA filament at 2.4 Å resolution provides a structural basis for a mechanistic understanding of the mutant phenotypes. Together, the evidence suggests a model in which Rad51 binding to duplex DNA is critical to control pathway usage at stalled replication forks.
PubMed: 38915629
DOI: 10.1101/2024.06.14.599120 -
BioRxiv : the Preprint Server For... Jun 2024Understanding how the number, placement and affinity of transcription factor binding sites dictates gene regulatory programs remains a major unsolved challenge in...
Understanding how the number, placement and affinity of transcription factor binding sites dictates gene regulatory programs remains a major unsolved challenge in biology, particularly in the context of multicellular organisms. To uncover these rules, it is first necessary to find the binding sites within a regulatory region with high precision, and then to systematically modulate this binding site arrangement while simultaneously measuring the effect of this modulation on output gene expression. Massively parallel reporter assays (MPRAs), where the gene expression stemming from 10,000s of in vitro-generated regulatory sequences is measured, have made this feat possible in high-throughput in single cells in culture. However, because of lack of technologies to incorporate DNA libraries, MPRAs are limited in whole organisms. To enable MPRAs in multicellular organisms, we generated tools to create a high degree of mutagenesis in specific genomic loci using base editing. Targeting GFP integrated in genome of cell culture and whole animals as a case study, we show that the base editor AID stemming from sea lamprey fused to nCas9 is highly mutagenic. Surprisingly, longer gRNAs increase mutation efficiency and expand the mutating window, which can allow the introduction of mutations in previously untargetable sequences. Finally, we demonstrate arrays of >20 gRNAs that can efficiently introduce mutations along a 200bp sequence, making it a promising tool to test enhancer function in a high throughput manner.
PubMed: 38915503
DOI: 10.1101/2024.06.10.598328 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2024α-arbutin has important applications in cosmetics and medicine. However, the extraction yield from plant tissues is relatively low, which restricts its application...
α-arbutin has important applications in cosmetics and medicine. However, the extraction yield from plant tissues is relatively low, which restricts its application value. In this study, we investigated the synthesis of α-arbutin using maltodextrin as the donor and hydroquinone as the acceptor, using a cyclodextrin glucosyltransferase (CGTase) from . We performed site-saturated and site-directed mutagenesis on CGTase. The activity of the variant CGTase-F235G-N166H was 3.48 times higher than that of the wild type. Moreover, we achieved a conversion rate of 63% by optimizing the reaction pH, temperature, and hydroquinone addition amount. Overall, this study successfully constructed a strain with improved conversion rate for the synthetic production of α-arbutin and hydroquinone. These findings have significant implications for reducing the industrial production cost of α-arbutin and enhancing the conversion rate of the product.
Topics: Glucosyltransferases; Arbutin; Hydroquinones; Mutagenesis, Site-Directed; Polysaccharides
PubMed: 38914495
DOI: 10.13345/j.cjb.230693 -
Integrative Medicine (Encinitas, Calif.) May 2024Tumor microenvironment infiltration by cells of the T helper cell type 1 (T1) system, including T1 cells, M1 macrophages, natural killer cells, and CD8 T cells, is...
Tumor microenvironment infiltration by cells of the T helper cell type 1 (T1) system, including T1 cells, M1 macrophages, natural killer cells, and CD8 T cells, is associated with better cancer prognosis. In contrast, tumor microenvironment infiltration by cells of the T2 system, including T2 cells, M2 macrophages, and innate lymphoid cells type 2, as well as immune suppressive myeloid-derived suppressor cells and regulatory T cells, is associated with poorer cancer prognosis. Beyond the tumor itself and a myriad of other modifying factors, such as genetic and epigenetic influences on tumorigenesis, the overall immune state of the patient, termed the macroenvironment, has also been shown to significantly influence cancer outcomes. Alterations in the tricarboxylic acid (TCA) cycle (TCA cycle breaks) involving loss of function of succinate dehydrogenase, isocitrate dehydrogenase, and fumarate hydratase have been shown to be associated with an intracellular metabolic shift away from oxidative phosphorylation and into glycolysis in cells that are transforming into cancer cells. The same loss of function of succinate dehydrogenase and isocitrate dehydrogenase has also been identified as inducing a shift in macrophages toward glycolysis that is associated with M1 macrophage polarization. M1 macrophages make interleukin 12, which stimulates T1 cells and natural killer cells to produce interferon gamma (IFN-γ), which in turn stimulates M1 macrophage activity, forming an activation loop. IFN-γ also drives activation of CD8 T cells. Thus, M1 macrophage activation initiates and sustains activation of the T1 system of cells. In this fashion, TCA cycle breaks at succinate dehydrogenase and isocitrate dehydrogenase that promote cellular transformation into cancer cells are also associated with upregulation of the T1 system that provides anti-cancer immune surveillance. The T1 and T2 systems are known to inhibit each other's activation. It is this author's hypothesis that, in patients whose macroenvironment is sufficiently T2-dominant, the metabolic shift toward glycolysis induced by TCA cycle breaks that gives rise to mutagenic changes in tissue parenchymal cells is not counterbalanced by adequate activation of M1 macrophages, thus giving rise to cancer cell development. For instance, the atopic T2-high asthma phenotype, a T2 dominance-based comorbidity, is associated with a more than doubled incidence of colon, breast, lung, and prostate cancer, compared with non-asthmatics. Failure of TCA cycle breaks to induce M1 polarization of tissue-resident macrophages yields a tissue environment in which the tissue-resident macrophages fail to routinely perform M1-associated functions such as phagocytizing newly developing cancer cells. Failure of M1 phenotypic expression in both tissue-resident macrophages and monocyte-derived macrophages recruited to the tumor microenvironment yields both a loss of direct antitumor M1 macrophage actions and failure of T1 system activation in general, including failure of CD8 T cell activation, yielding a cancer-permissive tumor microenvironment and a poorer prognosis in patients with existing cancers. This paper proposes a conceptual framework that connects established elements in the existing research and points to the utility of a patient profiling process, aimed at personalization of treatment through identification and targeting of elements in each patient's tumor microenvironment and macroenvironment that contribute to unfavorable prognosis.
PubMed: 38911450
DOI: No ID Found -
NAR Molecular Medicine Jan 2024Antibiotic resistance rapidly develops against almost all available therapeutics. Therefore, searching for new antibiotics to overcome the problem of antibiotic...
Antibiotic resistance rapidly develops against almost all available therapeutics. Therefore, searching for new antibiotics to overcome the problem of antibiotic resistance alone is insufficient. Given that antibiotic resistance can be driven by mutagenesis, an avenue for preventing it is the inhibition of mutagenic processes. We previously showed that the DNA translocase Mfd is mutagenic and accelerates antibiotic resistance development. Here, we present our discovery of a small molecule that inhibits Mfd-dependent mutagenesis, ARM-1 (anti-resistance molecule 1). We found ARM-1 using a high-throughput, small molecule, screen. Using biochemical assays, we characterized the mechanism by which ARM-1 inhibits Mfd. Critically, we found that ARM-1 reduces mutagenesis and significantly delays antibiotic resistance development across highly divergent bacterial pathogens. These results demonstrate that the mutagenic proteins accelerating evolution can be directly inhibited. Furthermore, our findings suggest that Mfd inhibition, alongside antibiotics, is a potentially effective approach for prevention of antibiotic resistance development during treatment of infections.
PubMed: 38911259
DOI: 10.1093/narmme/ugae001 -
Biomedicine & Pharmacotherapy =... Jun 2024Cannabidiol (CBD), a naturally occurring cyclic terpenoid found in Cannabis sativa L., is renowned for its diverse pharmacological benefits. Marketed as a remedy for...
Exploring the safety of cannabidiol (CBD): A comprehensive in vitro evaluation of the genotoxic and mutagenic potential of a CBD isolate and extract from Cannabis sativa L.
Cannabidiol (CBD), a naturally occurring cyclic terpenoid found in Cannabis sativa L., is renowned for its diverse pharmacological benefits. Marketed as a remedy for various health issues, CBD products are utilized by patients as a supplementary therapy or post-treatment failure, as well as by healthy individuals seeking promised advantages. Despite its widespread use, information regarding potential adverse effects, especially genotoxic properties, is limited. The present study is focused on the mutagenic and genotoxic activity of a CBD isolate (99.4 % CBD content) and CBD-rich Cannabis sativa L extract (63.6 % CBD content) in vitro. Both CBD samples were non-mutagenic, as determined by the AMES test (OECD 471) but exhibited cytotoxicity for HepG2 cells (∼IC 26 µg/ml, ∼IC 6-8 µg/ml, MTT assay). Noncytotoxic concentrations induced upregulation of genes encoding metabolic enzymes involved in CBD metabolism, and CBD oxidative as well as glucuronide metabolites were found in cell culture media, demonstrating the ability of HepG2 cells to metabolize CBD. In this study, the CBD samples were found non-genotoxic. No DNA damage was observed with the comet assay, and no influence on genomic instability was observed with the cytokinesis block micronucleus and the γH2AX and p-H3 assays. Furthermore, no changes in the expression of genes involved in genotoxic stress response were detected in the toxicogenomic analysis, after 4 and 24 h of exposure. Our comprehensive study contributes valuable insights into CBD's safety profile, paving the way for further exploration of CBD's therapeutic applications and potential adverse effects.
PubMed: 38908200
DOI: 10.1016/j.biopha.2024.116969