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Viruses May 2024The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the most significant...
The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the most significant global health crises in recent history. The clinical characteristics of COVID-19 patients have revealed the possibility of immune activity changes contributing to disease severity. Nevertheless, limited information is available regarding the immune response in human lung tissue, which is the primary site of infection. In this study, we conducted an extensive analysis of lung tissue to screen for differentially expressed miRNAs and mRNAs in five individuals who died due to COVID-19 and underwent a rapid autopsy, as well as seven control individuals who died of other causes unrelated to COVID-19. To analyze the host response gene expression, miRNA microarray and Nanostring's nCounter XT gene expression assay were performed. Our study identified 37 downregulated and 77 upregulated miRNAs in COVID-19 lung biopsy samples compared to the controls. A total of 653 mRNA transcripts were differentially expressed between the two sample types, with most transcripts (472) being downregulated in COVID-19-positive specimens. Hierarchical and PCA K-means clustering analysis showed distinct clustering between COVID-19 and control samples. Enrichment and network analyses revealed differentially expressed genes important for innate immunity and inflammatory response in COVID-19 lung biopsies. The interferon-signaling pathway was highly upregulated in COVID-19 specimens while genes involved in interleukin-17 signaling were downregulated. These findings shed light on the mechanisms of host cellular responses to COVID-19 infection in lung tissues and could help identify new targets for the prevention and treatment of COVID-19 infection.
Topics: Humans; COVID-19; Lung; Gene Regulatory Networks; MicroRNAs; Autopsy; SARS-CoV-2; Male; Female; Middle Aged; Aged; Gene Expression Profiling; RNA, Messenger; Adult
PubMed: 38932146
DOI: 10.3390/v16060853 -
Pharmaceutics May 2024Nanoparticles conjugated with fluorescent probes have versatile applications, serving not only for targeted fluorescent imaging but also for evaluating the in vivo...
Nanoparticles conjugated with fluorescent probes have versatile applications, serving not only for targeted fluorescent imaging but also for evaluating the in vivo profiles of designed nanoparticles. However, the relationship between fluorophore density and nanoparticle behavior remains unexplored. The IR783-modified liposomes (IR783-sLip) were prepared through a modified ethanol injection and extrusion method. The cellular uptake efficiency of IR783-sLip was characterized by flow cytometry and fluorescence microscope imaging. The effects of IR783 density on liposomal in vivo behavior were investigated by pharmacokinetic studies, biodistribution studies, and in vivo imaging. The constitution of protein corona was analyzed by the Western blot assay. Dense IR783 modification improved cellular uptake of liposomes in vitro but hindered their blood retention and tumor imaging performance in vivo. We found a correlation between IR783 density and protein corona absorption, particularly IgM, which significantly impacted the liposome performance. Meanwhile, we observed that increasing IR783 density did not consistently improve the effectiveness of tumor imaging. Increasing the density of modified IR783 on liposomes is not always beneficial for tumor near-infrared (NIR) imaging yield. It is not advisable to prematurely evaluate novel nanomaterials through fluorescence dye conjugation without carefully optimizing the density of the modifications.
PubMed: 38931866
DOI: 10.3390/pharmaceutics16060744 -
Pharmaceutics May 2024(1) Background: Antimicrobial resistance is growing at an extreme pace and has proven to be an urgent topic, for research into alternative treatments. Such a prospective...
(1) Background: Antimicrobial resistance is growing at an extreme pace and has proven to be an urgent topic, for research into alternative treatments. Such a prospective possibility is hidden in antimicrobial peptides because of their low to no toxicity, effectiveness at low concentrations, and most importantly their ability to be used for multiple treatments. This work was focused on the study of the effect of the modification in position 7 of Temporin A on its biological activity; (2) Methods: The targeted peptides were synthesized using Fmoc/O-Bu SPPS. The antibacterial activity of the analogs was determined using the broth microdilution method and disk-diffusion method. In vitro tests were performed to determine the cytotoxicity, phototoxicity, and antiproliferative activity of the peptide analogs on a panel of tumor and normal cell lines; (3) Results: All analogs except DTCit showed good antibacterial activity, with DTDab having the best activity according to the disk-diffusion method. However, DTCit had an acceptable cytotoxicity, combined with good selectivity against the test MCF-7 cell line; (4) Conclusions: The obtained results revealed the importance of the basicity and length of the side chain at position 7 in the Temporin A sequence for both tested activities.
PubMed: 38931840
DOI: 10.3390/pharmaceutics16060716 -
Sensors (Basel, Switzerland) Jun 2024Breast cancer is the second most common cancer worldwide, primarily affecting women, while histopathological image analysis is one of the possibile methods used to...
Breast cancer is the second most common cancer worldwide, primarily affecting women, while histopathological image analysis is one of the possibile methods used to determine tumor malignancy. Regarding image analysis, the application of deep learning has become increasingly prevalent in recent years. However, a significant issue is the unbalanced nature of available datasets, with some classes having more images than others, which may impact the performance of the models due to poorer generalizability. A possible strategy to avoid this problem is downsampling the class with the most images to create a balanced dataset. Nevertheless, this approach is not recommended for small datasets as it can lead to poor model performance. Instead, techniques such as data augmentation are traditionally used to address this issue. These techniques apply simple transformations such as translation or rotation to the images to increase variability in the dataset. Another possibility is using generative adversarial networks (GANs), which can generate images from a relatively small training set. This work aims to enhance model performance in classifying histopathological images by applying data augmentation using GANs instead of traditional techniques.
Topics: Humans; Neural Networks, Computer; Breast Neoplasms; Image Processing, Computer-Assisted; Deep Learning; Female; Algorithms; Image Interpretation, Computer-Assisted
PubMed: 38931561
DOI: 10.3390/s24123777 -
Pharmaceuticals (Basel, Switzerland) Jun 2024In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine,...
Pharmacokinetics, Dose-Proportionality, and Tolerability of Intravenous Tanespimycin (17-AAG) in Single and Multiple Doses in Dogs: A Potential Novel Treatment for Canine Visceral Leishmaniasis.
In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m) of 17-AAG or a placebo ( = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m. After single doses of 17-AAG (50-250 mg/m), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.
PubMed: 38931434
DOI: 10.3390/ph17060767 -
Pharmaceuticals (Basel, Switzerland) May 2024For developing novel photosensitizers with therapeutic potential in non-malignant and malignant cutaneous disorders, the unsymmetrical porphyrin,...
For developing novel photosensitizers with therapeutic potential in non-malignant and malignant cutaneous disorders, the unsymmetrical porphyrin, 5-(2-hydroxy-3-methoxyphenyl)-10, 15, 20--(4-carboxymethylphenyl) porphyrin, was evaluated and The cellular uptake of the investigated porphyrin and its ability to perform photodynamic therapy were investigated in terms of the viability, proliferation, and necrosis of human HaCaT keratinocytes and human Hs27 skin fibroblasts, in correlation with the predictions regarding diffusion through cell membranes, ADMET profile (absorption, distribution, metabolism, elimination, toxicity), and potential pharmacological mechanism. Molecular docking and 250 ns molecular dynamics simulations revealed that P5.2 has the potential to form a relatively stable complex with the carbonic anhydrase IX catalytic site, the lowest predicted free energy of binding (MM/PBSA) being -39.097 kcal/mol. The results of the in vitro study showed that P5.2 is incorporated within 24 h in the investigated cells, especially in HaCaT keratinocytes, indicating its photosensitizing ability. Nevertheless, P5.2 does not exert significant cytotoxicity in "dark" conditions. In turn, PDT induced a decrease in the number of metabolically active HaCaT keratinocytes within 24 h, accompanied by a 4-fold increase in lactate dehydrogenase release, indicating its ability to perform PDT in human skin cells. The experimental results suggest that the asymmetrical porphyrin is a promising candidate theranostics agent for skin disorders.
PubMed: 38931355
DOI: 10.3390/ph17060688 -
Nutrients Jun 2024Free radicals and reactive oxygen species initiate when the oxidative stress arises. (1) Background: The effect of natural molecules on oxidative stress in...
Free radicals and reactive oxygen species initiate when the oxidative stress arises. (1) Background: The effect of natural molecules on oxidative stress in hyperlipidemic rats, taking statins, was observed. (2) Methods: One hundred and twelve white Wistar rats, males and females, were divided into seven: Group I received 20 mg of atorvastatin while groups II and III received a combination of 20 mg of atorvastatin and 100 mg of Sea buckthorn and grape extract. Groups IV and V received 100 mg of Sea buckthorn and grape extract, while groups VI and VII received only high-fat diet (HFD) and normal rodents' fodder. After two and six months, rats were euthanized, and blood was gathered to measure the main paraclinical values and total antioxidant capacity (TAC). Also, the liver and kidney were stored for the organs' cytoarchitecture. For statistics, two-way analysis of variance (ANOVA), was performed. (3) Results: HFD produced hyperlipidemia, accompanied by augmented serum and hepatic oxidative stress markers, in addition to a reduction in antioxidant enzyme activities and glutathione levels. Polyphenolic substances proven efficient against HFD caused oxidative stress. (4) Conclusions: Atorvastatin heightened the histological injuries caused by the fatty diet, but these were diminished by taking atorvastatin in combination with 100 mg/kg of plant extracts.
Topics: Animals; Atorvastatin; Oxidative Stress; Rats, Wistar; Hyperlipidemias; Male; Hippophae; Vitis; Plant Extracts; Female; Antioxidants; Diet, High-Fat; Liver; Rats; Biomarkers; Kidney
PubMed: 38931308
DOI: 10.3390/nu16121954 -
Plants (Basel, Switzerland) Jun 2024The present study was performed to investigate the negative impact of salinity on the growth of Chinese flowering cabbage ( ssp. var. ) and the ameliorative effects of...
The present study was performed to investigate the negative impact of salinity on the growth of Chinese flowering cabbage ( ssp. var. ) and the ameliorative effects of quercetin dihydrate on the plant along with the elucidation of underlying mechanisms. The tolerable NaCl stress level was initially screened for the Chinese flowering cabbage plants during a preliminary pot trial by exposing the plants to salinity levels (0, 50, 100, 150, 200, 250, 300, 350, and 400 mM) and 250 mM was adopted for further experimentation based on the findings. The greenhouse experiment was performed by adopting a completely randomized design using three different doses of quercetin dihydrate (50, 100, 150 µM) applied as a foliar treatment. The findings showed that the exposure salinity significantly reduced shoot length (46.5%), root length (21.2%), and dry biomass (32.1%) of Chinese flowering cabbage plants. Whereas, quercetin dihydrate applied at concentrations of 100, and 150 µM significantly diminished the effect of salinity stress by increasing shoot length (36.8- and 71.3%), root length (36.57- and 56.19%), dry biomass production (51.4- and 78.6%), Chl (69.8- and 95.7%), Chl (35.2- and 87.2%), and carotenoid contents (21.4- and 40.3%), respectively, compared to the plants cultivated in salinized conditions. The data of physiological parameters showed a significant effect of quercetin dihydrate on the activities of peroxidase, superoxide dismutase, and catalase enzymes. Interestingly, quercetin dihydrate increased the production of medicinally important glucosinolate compounds in Chinese flowering cabbage plants. Molecular docking analysis showed a strong affinity of quercetin dihydrate with three different stress-related proteins of plants. Based on the findings, it could be concluded that quercetin dihydrate can increase the growth of Chinese flowering cabbage under both salinity and normal conditions, along with an increase in the medicinal quality of the plants. Further investigations are recommended as future perspectives using other abiotic stresses to declare quercetin dihydrate as an effective remedy to rescue plant growth under prevailing stress conditions.
PubMed: 38931131
DOI: 10.3390/plants13121698 -
Plants (Basel, Switzerland) Jun 2024Vermicompost is applied as a soil amendment to promote plant growth and yield. It also helps to significantly reduce the incidence of soil-borne diseases. However, its...
Vermicompost is applied as a soil amendment to promote plant growth and yield. It also helps to significantly reduce the incidence of soil-borne diseases. However, its efficiency depends on the type of earthworm from which it is formed. The current study aims to compare the effects of two vermicompost types derived from African nightcrawler (AF) and Tiger worm (TG) as a soil amendment to evaluate its potential for suppressing damping-off disease both in vitro and in vivo. It also aims to determine the effects of both vermicompost types on the growth and yield-related traits of potted Thai vegetable soybean [ (L.) Merrill] variety "Chiang Mai 84-2" grown under greenhouse conditions when amended to the soil at various application rates (1%, 2%, 3% /). AF vermicompost exhibited better suppression of damping-off disease than TG vermicompost in vitro and under greenhouse conditions. AF vermicompost performed significantly greater suppressive efficacy on the mycelial growth of in vitro than TG vermicompost, indicated by 50% and 16% inhibition, respectively. Damping-off incidence on vegetable soybean seedlings grown in soil amended with AF vermicompost was significantly lower (21%) than in soil amended with TG vermicompost (32%) under greenhouse conditions. With an increased application rate of 1% to 2% or 3% for each vermicompost type, plant yields significantly enhanced, with no significant variations among the 2% and 3% rates. Applying vermicompost at 2% / through soil amendment was the appropriate rate for promoting the growth and yield of potted vegetable soybeans. The results can be used to guide the application of vermicompost to control soil-borne plant diseases, promote plant growth, and enhance yields, especially in terms of organic crop production. Further research is needed to evaluate its potential for other potted crops and protect against soil-borne diseases.
PubMed: 38931039
DOI: 10.3390/plants13121607 -
Molecules (Basel, Switzerland) Jun 2024This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory...
This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.
Topics: Humans; NF-E2-Related Factor 2; Ferroptosis; Xanthophylls; Heme Oxygenase-1; Cell Line, Tumor; Phospholipid Hydroperoxide Glutathione Peroxidase; Molecular Docking Simulation; Reactive Oxygen Species; Signal Transduction; Tongue Neoplasms; Receptors, Transferrin; Membrane Potential, Mitochondrial; Kelch-Like ECH-Associated Protein 1; Gene Expression Regulation, Neoplastic; Amino Acid Transport System y+; Superoxide Dismutase; Down-Regulation; Antigens, CD
PubMed: 38930897
DOI: 10.3390/molecules29122832