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Multiple myeloma (MM) is an incurable hematological malignancy with increasing incidence and mortality rates, with a worldwide incidence of 160,000 cases per year. Currently approved treatments, including bortezomib treatment, have adverse effects that ultimately lead to the development of resistance. Inadequate vitamin D (VD) levels are frequently observed in patients with MM, and its supplementation has anti-proliferative effects on different MM phenotypes. However, the risk of hypercalcemia restricts the application of VD in cancer therapy; therefore, we analyzed truncated VD analogs with anticancer effects but no calcemic activity. We previously identified a derivative of the C/D ring fragment of vitamin D2 (VD2) against cervical cancer, lung cancer, and MM. Herein, we conducted a structure–activity relationship study by introducing more derivatives and testing them against different MM cells, including bortezomib-sensitive and bortezomib-resistant phenotypes. VDF-4 exhibited remarkable toxicity against all tested cells, with less of an effect on normal blood cells; this reflects its potentially high selectivity. VDF-4 IC50 values against KMS-12-PE, KMS-11, and KMS-11/BTZ were 19.1 ± 1.0, 19.8 ± 2.5, and 23.3 ± 1.9 µM, respectively. Notably, the KMS-11/BTZ cells were insensitive to VD2. Furthermore, VDF-4 demonstrated moderate activity against other leukemic cell lines, including Jurkat and M8166 cells. Although its mechanism of action has not yet been elucidated, VDF-4 is a promising compound and warrants further investigation. [ABSTRACT FROM AUTHOR]

Chronic inflammation is a common underlying factor in many major diseases, including heart disease, diabetes, cancer, and autoimmune disorders, and is responsible for up to 60% of all deaths worldwide. Metformin, statins, and corticosteroids, and NSAIDs (non-steroidal anti-inflammatory drugs) are often given as anti-inflammatory pharmaceuticals, however, often have even more debilitating side effects than the illness itself. The natural product-based therapy of inflammation-related diseases has no adverse effects and good beneficial results compared to substitute conventional anti-inflammatory medications. In this review article, we provide a concise overview of present pharmacological treatments, the pathophysiology of inflammation, and the signaling pathways that underlie it. In addition, we focus on the most promising natural products identified as potential anti-inflammatory therapeutic agents. Moreover, preclinical studies and clinical trials evaluating the efficacy of natural products as anti-inflammatory therapeutic agents and their pragmatic applications with promising outcomes are reviewed. In addition, the safety, side effects and technical barriers of natural products are discussed. Furthermore, we also summarized the latest technological advances in the discovery and scientific development of natural products-based medicine. [ABSTRACT FROM AUTHOR]

Cerium oxide nanoparticles (CONPs), owing to their radical scavenging property, have recently emerged as a therapeutic candidate for oxidative stress-mediated neurological diseases. However, oral and intravenous administration of CONPs is limited due to their poor physicochemical characteristics, low bioavailability, rapid systemic clearance, poor blood–brain penetration and dose-dependent toxicity. To overcome these challenges, we developed intranasal CONPs and evaluated their potential in the experimental PD model. CONPs were prepared by homogenous precipitation using tween 80 as a stabilizer and methanol/water as solvent. The optimization was done using Central Composite Design (CCD). The CONPs synthesis was confirmed by UV and FTIR. The optimized CONPs were small-sized (105.1 ± 5.78 nm), spherical (TEM), uniform (PDI, 0.119 ± 0.006) and stable (ZP, –22.7 ± 1.02 mV). Energy‐dispersive X‐ray analysis showed characteristic signals of Ce in developed CONPs. The X-ray diffraction pattern described the cubic fluorite structure and nano-crystalline nature of CONPs. The CONP anti-oxidant activity was found to be 93.60 ± 0.32% at 25 µg/mL concentration. Finally, motor manifestation studies like the forced swim test, locomotor test, akinesia, catalepsy, and muscle coordination test were conducted to assess the motor dysfunctions and behavioral activity in all four animal groups. Results of the in vivo motor manifestation studies in the haloperidol-induced PD rat model showed that co-administration of intranasal CONPs along with a half dose of levodopa resulted in significant protection, and results were significantly different from the untreated group but not significantly different from the healthy group. In conclusion, intranasal CONPs can be useful in ameliorating oxidative stress through their antioxidant effect and could be prospective therapeutics for the treatment of motor manifestations in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Three concentrations (1.25, 2.5, and 5 × 107 spores ml−1) (of the biocontrol fungus Purpureocillium lilacinum (strain AUMC 10620) were tested on citrus nematode Tylenchulus semipenetrans under in vitro and field conditions. Larvae and eggs were exposed to the fungal spores in vitro for 24, 48, and 72 h, and the findings were recorded at each time point. These results were compared with the application of the nematicide abamectin. Strain AUMC 10620 effectively reduced larval activity and egg hatching of T. semipenetrans under laboratory conditions. The highest concentration (5× 107 spores ml−1) of P. lilacinum, resulted in 89.01% immobility in the larvae, compared to abamectin, which resulted in 65.93% immobility after 48 h of exposure. These percentages of immobility were increased after 72 h of exposure (100 and 85.09%) when P. lilacinum at a concentration of 5 × 107 spores ml−1 and abamectin were used, respectively. On the other hand, the two other P. lilacinum concentrations (1.25, and 2.5 × 107 spores ml−1) affected the T. semipenetrans larvae to a lesser extent. The highest fungal concentration 5× 107 spores ml−1 inhibited the hatching of T. semipenetrans eggs in vitro with 71.34, 80, and 86.67% after 24, 48 and 72 h of treatment compared to the abamectin treatment which showed 76.67, 78, and 87% after the abovementioned periods, respectively. In addition, the application of P. lilacinum (5 × 107 spores ml−1) or abamectin under field conditions significantly (P < 0.05) reduced the population of the major nematode species (T. semipenetrans, Tylenchorhynchus spp., Helicotylenchus spp., and Pratylenchus spp.) infesting citrus after one, two, and three weeks of treatment compared to the control treatment but with no significant (P > 0.05) differences between the two treatments. Three weeks after the field application, the percentage of nematode reduction was significantly (P < 0.05) smaller than the control treatment at concentrations of 5, 2.5, and 1.25 × 107 spores ml−1, respectively, by 78.42, 64.03, and 58.35%. It is evident from these results that the application of P. lilacinum strain (AUMC 10620) can be used in integrated pest management programs to control nematodes infesting citrus trees. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that is usually overexpressed in many types of cancers. In the present study, an effort was done in synthesis of new 3,4-diaminothieno[2,3-b] thiophene-2,5-dicarbonitrile derivatives 2–8, assisted by a microwave device. Different spectroscopic instruments were used for their analysis and confirmed their chemical structures. The antimicrobial properties of the produced compounds were investigated and found to be promising. Next, they were tested for cytotoxicity against MCF-7, HepG-2, HCT-116, and A549 cell lines. Moreover, in vitro cytotoxicity evaluation against well-known standards, namely, gefitinib and erlotinib was achieved using MTT method. The obtained compounds (2–8) were found to be more effective against the two tested cancer cell lines than erlotinib. In MCF-7 and A549 cells, compound 3 was found to be 4.42 and 4.12 times more active than erlotinib, respectively. The activity of radical scavenging was inhibited by 78%. The most cytotoxic compounds were subsequently studied for their kinase inhibitory effect against EGFRWT and EGFRT790M using the HTRF assay. Compound 3 was shown to be the most powerful against both kinds of EGFR, with IC50 values of 0.28 and 5.02. Furthermore, compound 2 demonstrated the highest antioxidant activity as it has a radical scavenging activity of 78%. Compounds 2,6,7 and 8 revealed to be the most safe compounds, none hepatotoxic, none carcinogenic, none immunotoxic, none mutagenic and none cytotoxic. [ABSTRACT FROM AUTHOR]

The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 μM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 μM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 μM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 μM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10–6 cm/s. Both compounds were stabilized in protein–ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of − 74.57 and − 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Evaluating the feasibility of two-step preparation of clotrimazole solid glass solutions for improving its physicochemical properties, intrinsic dissolution, and antifungal activity. Methods: Co-grinding with selected coformers including vitamin C and L-arginine was employed to form co-amorphous dispersions; then, a polymeric carrier was added to form a homogenous glass solution. The solid solutions were converted to nanosuspensions after reconstitution and ultrasonication. The dispersions were characterized for equilibrium solubility, intrinsic dissolution, particle size, and zeta potential. Solid state characterization was carried out using differential scanning calorimetry, X-ray powder diffraction, and Infrared spectroscopy. The antifungal activity was evaluated using candida albicans species. Results: Equilibrium solubility indicated superb increase in clotrimazole solubility (more than 289 times) from glass solutions compared to pure crystalline drug. The intrinsic dissolution data showed 64% ± 0.34 of drug released within 15 min, and complete dissolution was obtained in 45 min. The ideal formula showed nanosized particles after dispersion in water (225 nm), optimum zeta potential (20.20 µV), and polydispersity index (0.35). Solid state characterization showed shortened peaks and diffraction lines of the glass solutions compared to parent components. The biological activity of the reconstituted nanosuspension showed decreased minimum inhibitory concentration by 50% and increased area of growth inhibition zones of candida albicans by more than 28% compared to drug solution. Conclusions: These findings suggest that solid glass solutions and its derived nanosuspensions of clotrimazole with ascorbic acid and polyvinyl pyrrolidone could be a valuable solution for maximizing drug bioavailability. [ABSTRACT FROM AUTHOR]

As a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, Fluvastatin (FLV) is used for reducing low-density lipoprotein (LDL) cholesterol as well as to prevent cardiovascular problems. FLV showed cell line cytotoxicity and antitumor effect. Melittin (MEL) exhibits antineoplastic activity and is known to be promising as a therapeutic option for cancer patients. The aim of this work was to investigate the combination of FLV with MEL loaded hybrid formula of phospholipid (PL) with alpha lipoic acid (ALA) nanoparticles to maximize anticancer tendencies. This study examines the optimization of the prepared formulation in order to minimize nanoparticles size and maximize zeta potential to potentiate cytotoxic potentialities in colon cancer cells (Caco2), cell viability, cell cycle analysis and annexin V were tested. In addition to biological markers as P53, Bax, bcl2 and Caspase 3 evaluation The combination involving FLV PL ALA MEL showed enhanced cytotoxic potentiality (IC50 = 9.242 ± 0.35 µg/mL), about twofold lower, compared to the raw FLV (IC50 = 21.74 ± 0.82 µg/mL). According to studies analyzing cell cycle, optimized FLV PL ALA MEL was found to inhibit Caco2 colon cancer cells more significantly than other therapeutic treatments, wherein a higher number of cells were found to accumulate over G2/M and pre-G1 phases, whereas G0/G1/S phases witnessed the accumulation of a lower number of cells. The optimized formulation may pave the way for a novel and more efficacious treatment for colon cancer. [ABSTRACT FROM AUTHOR]

Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO2 was studied as function of pressure and temperature to assess the feasibility of that for production of nanomedicine to enhance the solubility. The data was collected for solubility optimization of Decitabine at the temperature 308–338 K, and pressure 120–400 bar used as the inputs to the machine learning models. A dataset of 32 data points and two inputs (P and T) have been applied to optimize the solubility. The only output is Y = solubility, which is Decitabine mole fraction solubility in the solvent. The developed models are three models including Kernel Ridge Regression (KRR), Decision tree Regression (DTR), and Gaussian process (GPR), which are used for the first time as a novel model. These models are optimized using their hyper-parameters tuning and then assessed using standard metrics, which shows R2-score, KRR, DTR, and GPR equal to 0.806, 0.891, and 0.998. Also, the MAE metric shows 1.08E−04, 7.40E−05, and 9.73E−06 error rates in the same order. The other metric is MAPE, in which the KRR error rate is 4.64E−01, DTR shows an error rate equal to 1.63E−01, and GPR as the best mode illustrates 5.06E−02. Finally, analysis using the best model (GPR) reveals that increasing both inputs results in an increase in the solubility of Decitabine. The optimal values are (P = 400, T = 3.38E + 02, Y = 1.07E−03). [ABSTRACT FROM AUTHOR]

Accurate specification of the drugs' solubility is known as an important activity to appropriately manage the supercritical impregnation process. Over the last decades, the application of supercritical fluids (SCFs), mainly CO2, has found great interest as a promising solution to dominate the limitations of traditional methods including high toxicity, difficulty of control, high expense and low stability. Oxaprozin is an efficient off-patent nonsteroidal anti-inflammatory drug (NSAID), which is being extensively used for the pain management of patients suffering from chronic musculoskeletal disorders such as rheumatoid arthritis. In this paper, the prominent purpose of the authors is to predict and consequently optimize the solubility of Oxaprozin inside the CO2SCF. To do this, the authors employed two basic models and improved them with the Adaboost ensemble method. The base models include Gaussian process regression (GPR) and decision tree (DT). We optimized and evaluated the hyper-parameters of them using standard metrics. Boosted DT has an MAE error rate, an R2-score, and an MAPE of 6.806E-05, 0.980, and 4.511E-01, respectively. Also, boosted GPR has an R2-score of 0.998 and its MAPE error is 3.929E-02, and with MAE it has an error rate of 5.024E-06. So, boosted GPR was chosen as the best model, and the best values were: (T = 3.38E + 02, P = 4.0E + 02, Solubility = 0.001241). [ABSTRACT FROM AUTHOR]

These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO2). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO2 through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E−09, 9.71E−09, and 3.78E−11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility. [ABSTRACT FROM AUTHOR]

Currently, the humanity is in a fierce battle against various health-related challenges especially those associated with human malignancies. This created the urge to develop potent and selective inhibitors for tumor cells through targeting specific oncogenic proteins possessing crucial roles in cancer progression and survive. In this respect, new series of pyrazole-thiazol-4-one hybrids (9a–p) were synthesized as potential anticancer agents. All the synthesized molecules exhibited potent antiproliferative actions against breast cancer (BC) T-47D and MDA-MB-231 cell lines with IC50 ranges 3.14–4.92 and 0.62–58.01, respectively. Moreover, the most potent anti-proliferative counterparts 9g and 9k were assessed against EGFR. They displayed nanomolar inhibitory activity, IC50 267 ± 12 and 395 ± 17 nM, respectively. Worth noting, both compounds 9g and 9k induced apoptosis in MDA-MB-231 cells, and resulted in a cell cycle arrest at G2/M phase. Furthermore, an in silico analysis including docking and molecular dynamic simulations was performed. [ABSTRACT FROM AUTHOR]

New ciprofloxacin/ quaternary ammonium salts 3a–e were designed and synthesized as potential antimicrobial agents. Most of the prepared derivatives showed promising dual antibacterial/antifungal activities. Compound 3e was the most potent and afforded vast spectrum antibacterial activity against S. aureus and most of the tested Gram-negative bacterial strains with MIC values ranging from 1.53–9.54 µg/mL. Moreover, ciprofloxacin and compound 3e induced DNA cleavage in S. aureus DNA gyrase and S. aureus TOPO IV DNA by 1 and 10 µM, respectively. In addition, docking study results agreed with results of DNA cleavage assays where all the tested compounds showed no additional significant interactions over the parent ciprofloxacin. On the other side, compounds 3e and 3f exhibited outstanding antifungal activity better than the reference itraconazole with MICs of 1.87, 4.67, and 11.22 µg/mL, respectively, against Candida. albicans. These data suggest the prevalence of another mechanism in addition to DNA gyrase circumvention, like metal chelation, antibiofilm, and/or improvement of lipophilicity and subsequent penetration. [ABSTRACT FROM AUTHOR]

Abstract: In modern industrial processes, various types of soft sensors are used in process monitoring, control, and optimization, and the soft sensors designed to maintain or update these models are highly desirable in the industry. This paper proposes a novel technique for monitoring and control optimization of soft sensors in automation industry for fault detection. The fault detection has been carried out using probabilistic multi-layer Fourier transform perceptron (PMLFTP), and the input data has been pre-processed for removal of samples containing null values for fault detection and diagnosis process through Fourier transform–based detection and multi-layer perceptron–based diagnosis in the manufacturing process. The controlling of data in soft sensors has been optimized using auto-regression-based ant colony optimization (AR_ACO), and the experimental results have been reported in terms of computational rate of 40%, QoS of 78%, RMSE of 45%, fault detection rate of 90%, and control optimization of 93%. [ABSTRACT FROM AUTHOR]