In-vivo Studies Research Articles

Pharmacokinetic and Pharmacodynamic Evaluation of Telmisartan-loaded Novel Curcumin-tagged Solid Nanodispersion for the Treatment of Diabetic Nephropathy in an Animal Model

Aim: This study aimed to evaluate the therapeutic efficacy of telmisartan-loaded novel curcumin-tagged solid nanodispersion in streptozotocin-nicotinamide-induced diabetic nephropathy in Wistar rats. Objective: The objective of this study was to perform a comprehensive pharmacokinetic and pharmacodynamic evaluation of a novel curcumin-tagged solid nanodispersion loaded with telmisartan, with the aim of assessing its potential as a treatment for diabetic nephropathy in an animal model. Specifically, the following objectives will be addressed: formulation and character-ization, in vitro evaluation, pharmacokinetics and pharmacodynamics evaluation, and compara-tive analysis. Materials and Methods: Telmisartan-loaded curcumin-tagged solid nanodispersion was prepared using the emulsion solvent evaporation method. The optimized formulation was evaluated for pharmacokinetic and pharmacodynamic parameters in an animal model. Wistar rats were divided into 5 groups, with 6 animals in each group. Diabetes was induced using nicotinamide (240 mg/kg) and streptozotocin (55 mg/kg, i.p.) injections in the animals. After 30 to 45 days of intro-duction, diabetic nephropathy was manifested. The kidneys and pancreas were used for histological analysis and renal and pancreatic damage assessment. Results: In-vivo studies showed better bioavailability with the t1/2 and Cmax of TLS-15 was 14.92 ± 0.47 hours and 0.32 ± 0.009, respectively, within 2 hours as compared to the t1/2 and Cmax of MP was 4.38 ± 0.19 hours and 0.19 ± 0.008 owing to the better dissolution due to solubility improvement. When compared to the commercially available product, TLS-15 was found to have blood glucose and body weight that were, respectively, 1.01 and 1.03 times higher. Kidney measures, such as serum urea and creatinine, were found to be 0.71 and 1.16 times lower for TLS-15, respectively, and albumin had a value that was 1.13 times higher than for the commercial formulation. Urine indicators, urine albumin, and creatinine estimations, as well as cytokine estimations, revealed that TLS-15 had creatinine levels that were 1.17 times higher and IL-6 lev-els that were 0.77 times higher than those of a commercial batch. Conclusion: The findings strongly support the renoprotective and pancreatic protective effects of TLS and Cur (SND-Solid Nanodispersion) combined by lowering levels of cytokines factor (IL-6), kidney, and lipid parameters. The postulated mechanism might be the combined inhibitory action of TLS and Cur.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and invivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For invivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. Invivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

In vitro PK/PD modeling of tyrosine kinase inhibitors in non-small cell lung cancer cell lines.

Tyrosine kinase inhibitors (TKIs) are routinely prescribed for the treatment of non-small cell lung cancer (NSCLC). As with all medications, patients can experience adverse events due to TKIs. Unfortunately, the relationship between many TKIs and the occurrence of certain adverse events remains unclear. There are limited invivo studies which focus on TKIs and their effects on different regulation pathways. Many invitro studies, however, that investigate the effects of TKIs observe additional changes, such as changes in gene activations or protein expressions. These studies could potentially help to gain greater understanding of the mechanisms for TKI induced adverse events. However, in order to utilize these pathways in a pharmacokinetic/pharmacodynamic (PK/PD) framework, an invitro PK/PD model needs to be developed, in order to characterize the effects of TKIs in NSCLC cell lines. Through the use of ordinary differential equations, cell viability data and nonlinear mixed effects modeling, an invitro TKI PK/PD model was developed with estimated PK and PD parameter values for the TKIs alectinib, crizotinib, erlotinib, and gefitinib. The relative standard errors for the population parameters are all less than 25%. The inclusion of random effects enabled the model to predict individual parameter values which provided a closer fit to the observed response. It is hoped that this model can be extended to include invitro data of certain pathways that may potentially be linked with adverse events and provide a better understanding of TKI-induced adverse events.

Effect of Direct Fed Microbial (DFM) on in-vitro Methanogenesis and Dry Matter Digestibility

The in-vitro rumen fermentation study was conducted to evaluate the effect of supplementation of direct-fed microbial (DFM) in the total mixed ration (TMR) on total gas production, methanogenesis and dry matter digestibility by using rumen liquor of adult Surti buffaloes. DFM was supplemented at 0, 1, 2, 3, 4, 5, 6, 7, and 8% with TMR (65% Straw and 35% concentrate) for in-vitro gas production trials. The result of the in-vitro study revealed significantly (P<0.05) higher IVDMD (57.03%) and lower CH4 production (3.20 ml CH4/100 mg DDM) at a 3% level of DFM supplementation in TMR. Based on the overall results of in-vitro studies 3% level of DFM supplementation was found to be most suitable for further in-vivo studies in adult Surti buffaloes.

In-vivo integration of soft neural probes through high-resolution printing of liquid electronics on the cranium

Current soft neural probes are still operated by bulky, rigid electronics mounted to a body, which deteriorate the integrity of the device to biological systems and restrict the free behavior of a subject. We report a soft, conformable neural interface system that can monitor the single-unit activities of neurons with long-term stability. The system implements soft neural probes in the brain, and their subsidiary electronics which are directly printed on the cranial surface. The high-resolution printing of liquid metals forms soft neural probes with a cellular-scale diameter and adaptable lengths. Also, the printing of liquid metal-based circuits and interconnections along the curvature of the cranium enables the conformal integration of electronics to the body, and the cranial circuit delivers neural signals to a smartphone wirelessly. In the in-vivo studies using mice, the system demonstrates long-term recording (33 weeks) of neural activities in arbitrary brain regions. In T-maze behavioral tests, the system shows the behavior-induced activation of neurons in multiple brain regions.

A mathematical model for predicting the spatiotemporal response of breast cancer cells treated with doxorubicin

ABSTRACT Tumor heterogeneity contributes significantly to chemoresistance, a leading cause of treatment failure. To better personalize therapies, it is essential to develop tools capable of identifying and predicting intra- and inter-tumor heterogeneities. Biology-inspired mathematical models are capable of attacking this problem, but tumor heterogeneity is often overlooked in in-vivo modeling studies, while phenotypic considerations capturing spatial dynamics are not typically included in in-vitro modeling studies. We present a data assimilation-prediction pipeline with a two-phenotype model that includes a spatiotemporal component to characterize and predict the evolution of in-vitro breast cancer cells and their heterogeneous response to chemotherapy. Our model assumes that the cells can be divided into two subpopulations: surviving cells unaffected by the treatment, and irreversibly damaged cells undergoing treatment-induced death. MCF7 breast cancer cells were previously cultivated in wells for up to 1000 hours, treated with various concentrations of doxorubicin and imaged with time-resolved microscopy to record spatiotemporally-resolved cell count data. Images were used to generate cell density maps. Treatment response predictions were initialized by a training set and updated by weekly measurements. Our mathematical model successfully calibrated the spatiotemporal cell growth dynamics, achieving median [range] concordance correlation coefficients of > .99 [.88, >.99] and .73 [.58, .85] across the whole well and individual pixels, respectively. Our proposed data assimilation-prediction approach achieved values of .97 [.44, >.99] and .69 [.35, .79] for the whole well and individual pixels, respectively. Thus, our model can capture and predict the spatiotemporal dynamics of MCF7 cells treated with doxorubicin in an in-vitro setting.

Anti-Müllerian hormone induces autophagy to preserve the primordial follicle pool in mice.

The reserve pool of primordial follicles (PMFs) is finely regulated by molecules implicated in follicular growth or PMF survival. Anti-Müllerian hormone (AMH), produced by granulosa cells of growing follicles, is known for its inhibitory role in the initiation of PMF growth. We observed in a recent invivo study that injection of AMH into mice seemed to induce an activation of autophagy. Furthermore, injection of AMH into mice activates the transcription factor FOXO3A which is also known for its implication in autophagy regulation. Many studies highlighted the key role of autophagy in the ovary at different stages of folliculogenesis, particularly in PMF survival. Through an invitro approach with organotypic cultures of prepubertal mouse ovaries, treated or not with AMH, we aimed to understand the link among AMH, autophagy, and FOXO3A transcription factor. Autophagy and FOXO3A phosphorylation were analyzed by western blot. The expression of genes involved in autophagy was quantified by RT-qPCR. In our invitro model, we confirmed the decrease in FOXO3A phosphorylation and the induction of autophagy in ovaries incubated with AMH. AMH also induces the expression of genes involved in autophagy. Interestingly, most of these genes are known to be FOXO3A target genes. In conclusion, we have identified a new role for AMH, namely the induction of autophagy, probably through FOXO3A activation. Thus, AMH protects the ovarian reserve not only by inhibiting the growth of PMFs but also by enabling their survival through activation of autophagy.

An update on a technical method of cartilage decellularization: (a physical-based protocol)

Introduction: Despite advances in orthopedic surgery, the lack of effective conventional treatment for cartilage defects has led to research in cartilage tissue engineering. One of the interesting topics is the use of decellularized extracellular matrix (ECM) as a suitable natural scaffold that supports the growth and function of cells cultured in it. A concern with decellularization protocols, especially those with high detergent concentrations, is the disruption of native ECM, which has deleterious effects on subsequent scaffold recellularization. Therefore, this study focused on optimizing cartilage decellularization by physical methods without the use of ionic detergents. Methods: The bovine tracheal cartilage fragments were decellularized by a combination of 8 cycles of freeze-thaw and ultrasound techniques. Then, the tissues were immersed and shaken in 0.25% trypsin for 24 hours. Efficient cell removal and preservation of ECM were confirmed by histological and cytocompatibility assessments. The in-vivo studies were performed to evaluate the biocompatibility and bioactivity of the scaffold. Results: The histological assessments indicated the appropriate cytocompatibility and the fibroblast cell culture study demonstrated that cells were able to proliferate and migrate on the decellularized cartilage. In-vivo evaluation also showed a reduced adverse immune response, including leukocyte infiltration into the ECM. Conclusions: These results suggest that a cartilage scaffold created using a physical decellularization protocol that efficiently removes cells while preserving the native ECM can be a suitable scaffold for cartilage reconstruction. The main advantage of this protocol is the absence of potentially toxic chemicals in the tissues.

Screening out molecular pathways and prognostic biomarkers of ultraviolet-mediated melanoma through computational techniques.

Ultraviolet radiation causes skin cancer, but the exact mechanism by which it occurs and the most effective methods of intervention to prevent it are yet unknown. For this purpose, our study will use bioinformatics and systems biology approaches to discover potential biomarkers of skin cancer for early diagnosis and prevention of disease with applicable clinical treatments. This study compared gene expression and protein levels in ultraviolet-mediated cultured keratinocytes and adjacent normal skin tissue using RNA sequencing data from the National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database. Then, pathway analysis was employed with a selection of hub genes from the protein-protein interaction (PPI) network and the survival and expression profiles. Finally, potential clinical biomarkers were validated by receiver operating characteristic (ROC) curve analysis. We identified 32 shared differentially expressed genes (DEGs) by analyzing three different subsets of the GSE85443 dataset. Skin cancer development is related to the control of several DEGs through cyclin-dependent protein serine/threonine kinase activity, cell cycle regulation, and activation of the NIMA kinase pathways. The cytoHubba plugin in Cytoscape identified 12 hub genes from PPI; among these 3 DEGs, namely, AURKA, CDK4, and PLK1 were significantly associated with survival (P < 0.05) and highly expressed in skin cancer tissues. For validation purposes, ROC curve analysis indicated two biomarkers: AURKA (area under the curve (AUC) value = 0.8) and PLK1 (AUC value = 0.7), which were in an acceptable range. Further translational research, including clinical experiments, teratogenicity tests, and in-vitro or in-vivo studies, will be performed to evaluate the expression of these identified biomarkers regarding the prognosis of skin cancer patients.

Evaluation of Probiotic Quality of Lactic Acid Bacteria Isolated from Locally Fermented Palm Wine and Kunu from Sellers in Oluku and Oba Markets in Benin City, Edo State, Nigeria

Commonly used probiotics bacteria are the lactic acid bacteria (LAB) from the gastro intestinal tract. However, other LAB from exogenous origin having similar functional properties can also confer health benefit to the host. The objective of this work is to evaluate the probiotic quality of lactic acid bacteria isolated from locally fermented palm wine and kunu from sellers in Oluku and Oba markets in Benin City, Edo State, Nigeria using standard microbiological methods. Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus casei were isolated from palm wine and kunu, and they were assessed for the following: resistance to simulated gastric and intestinal fluids, resistance to bile salt and low pH, haemolytic activity and their antimicrobial characteristic against some bacteria pathogens, mainly; Staphylococcus aureus, Klebsiella pneumonia, Pseudomonas aeruginosa and Escherichia coli. Results showed resistance/tolerance and cell viability of all LAB isolates to simulated gastric and intestinal fluids, and low pH resistance of all isolates were negative at pH 2 but positive with viable cell growth at pH 3. The L. fermentum, L. plantarum, and L. acidophilus were not haemolytic while L. casei was haemolytic (alpha haemolysis). The LAB isolates were more resistance to bile salt (with viable cell growth) at 0.1% and 0.3% concentration compared to 0.5% concentration. Antibacterial activity testing showed that L. acidophilus and L. casei had antibacterial property against Pseudomonas aeruginosa, while L. plantarum and L. fermentum had antibacterial property against Staphylococcus aureus and Klebsiella pneumonia respectively. While all lactic acid bacteria (Lactobacillus species) isolated from the locally fermented food/product samples demonstrated strong probiotic characteristic properties, further in-vivo study to establish their probiotic potential is recommended.

Microwave-assisted synthesis and 99mTc-radiolabeling of anti-inflammatory active curcumin derivatives for inflammation diagnosis and therapy

AbstractUsing a one-pot cyclo-condensation process under microwave irradiation, derivatives of curcumin have been created. Evaluation their anti-inflammatory efficacy showed that they had stronger properties than curcumin. Additionally, the most active derivative was radiolabeled with the diagnostic radioisotope technetium-99m and prepared with a high radiochemical yield (96.5 ± 0.09%) and in vitro stability of up to 6 h. The in-vivo study in inflamed mice showed that [99mTc]Tc-curcumin derivative accumulated with a high target to non-target ratio. The gathered information confirmed the efficacy of the [99mTc]Tc-curcumin derivative as a novel possible tracer for the identification and localization of inflammation.

Geometric distortion caused by metallic femoral head prosthesis in prostate cancer imaging on an MR Linac: in-vivo measurements of spatial deformation.

Metallic implants cause artefacts and distortion on MRI. To ensure accurate dose delivery and plan adaptation on an MR Linac, there is a need to evaluate distortion caused. Participants were imaged on an MR Linac (Elekta Unity, Elekta AB Stockholm). Three sequences were evaluated. Two vendor supplied (T2W TSE 3D), and one T2W TSE 3D optimized to reduce metal artefact distortions. Images were rigidly registered to CT images by a single observer, using bony anatomy. Three coronal and three axial images were selected, and six paired, adjacent, bony landmarks were identified on each slice. Images bisecting treatment isocentre were included. Difference between landmark coordinates was taken to be measure of distortion. Five observers participated. Thirty six pairs of bony landmarks were identified. Median difference in position of landmarks was ≤3 mm (range 0.3-4.4 mm). One-way analysis of variance (ANOVA) between observer means showed no significant variation between sequences or patients (P = 1.26 in plane, P = 0.11 through plane). Interobserver intra class correlation (ICC) was 0.70 in-plane and 0.78 through-plane. Intra-observer ICC for three observers was 0.76, 0.81, 0.83, showing moderate to good reliability on this small cohort. This in-vivo feasibility study suggests distortion due to metallic hip prosthesis is not an obstacle for pelvic radiotherapy on an MR Linac. Research on the impact on plan quality is warranted. This work supports feasibility of treating patients with metallic hip prosthesis on an MR Linac.

Effectively α-Terpineol Suppresses Glioblastoma Aggressive Behavior and Downregulates KDELC2 Expression

BackgroundGlioblastoma (GBM) is notorious for the aggressive behaviors and easily results in chemo-resistance. Studies have shown that the use of herbal medicines as treatments for GBM as limited by the blood-brain barrier (BBB) and glioma stem cells. PurposeThe aim of this study was to investigate the relationship between GBM suppression and α-terpineol, the monoterpenoid alcohol derived from Eucalyptus glubulus and Pinus merkusii. Study DesignUsing serial in-vitro and in-vivo studies to confirm the mechanism of α-terpineol on down-regulating GBM development. MethodsThe 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate IC50 of α-terpineol to inhibit GBM cell survival. In order to evaluate the impact of GBM aggressive behaviors by α-terpineol, the analysis of cell migration, invasion and colony formation were implemented. In addition, the ability of tumor spheres and WB of CD44 and OCT3/4 were evaluated under the impression of α-terpineol decreased GBM stemness. The regulation of neoangiogenesis by α-terpineol via the WB of angiogenic factors and human umbilical vein endothelial cells (HUVEC) tube assay. To survey the decided factors of α-terpineol downregulating GBM chemoresistance depended on the impact of O6-methylguanine-DNA methyltransferase (MGMT) expression and autophagy-related factors activation. Additionally, WB and quantitative real-time polymerase chain reaction (qRT/PCR) of KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2), endoplasmic reticulum (ER) stress, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) cascade signaling factors were examined to explore the mechanism of α-terpineol inhibiting GBM viability. Finally, the orthotopic GBM mouse model was applied to prove the efficacy and toxicity of α-terpineol on regulating GBM survival. Resultsα-terpineol significantly suppressed GBM growth, migration, invasion, angiogenesis and temozolomide (TMZ) resistance. Furthermore, α-terpineol specifically targeted KDELC2 to downregulate Notch and PI3k/mTOR/MAPK signaling pathway. Finally, we also demonstrated that α-terpineol could penetrate the BBB to inhibit GBM proliferation, which resulted in reduced cytotoxicity to vital organs. ConclusionCompared to published literatures, we firstly proved α-terpineol possessed the capability to inhibit GBM through various mechanisms and potentially decreased the occurrence of chemoresistance, making it a promising alternative therapeutic option for GBM in the future.

Cost-effective 3D lung tissue spheroid as a model for SARS-CoV-2 infection and drug screening.

The SARS-CoV-2 pandemic has spurred an unparalleled scientific endeavor to elucidate the virus' structure, infection mechanisms, and pathogenesis. Two-dimensional culture systems have been instrumental in shedding light on numerous aspects of COVID-19. However, these invitro systems lack the physiological complexity to comprehend the infection process and explore treatment options. Three-dimensional (3D) models have been proposed to fill the gap between 2D cultures and invivo studies. Specifically, spheroids, composed of lung cell types, have been suggested for studying SARS-CoV-2 infection and serving as a drug screening platform. 3D lung spheroids were prepared by coculturing human alveolar or bronchial epithelial cells with human lung stromal cells. The morphology, size, and ultrastructure of spheroids before and after SARS-CoV-2 infection were analyzed using optical and electron microscopy. Immunohistochemistry was used to detect spike protein and, thus, the virus presence in the spheroids. Multiplex analysis elucidated the cytokine release after virus infection. The spheroids were stable and kept their size and morphology after SARS-CoV-2 infection despite the presence of multivesicular bodies, endoplasmic reticulum rearrangement, tubular compartment-enclosed vesicles, and the accumulation of viral particles. The spheroid responded to the infection releasing IL-6 and IL-8 cytokines. This study demonstrates that coculture spheroids of epithelial and stromal cells can serve as a cost-effective infection model for the SARS-CoV-2 virus. We suggest using this 3D spheroid as a drug screening platform to explore new treatments related to the cytokines released during virus infection, especially for long COVID treatment.

The Needle Shield Size and Applied Force of Subcutaneous Autoinjectors Significantly Influence the Injection Depth.

This study examines how shield-triggered autoinjectors (AIs), for subcutaneous drug delivery, affect injection depth. It focuses on shield size and applied force, parameters that could potentially lead to inadvertent intramuscular (IM) injections due to tissue compression. A blinded ex-vivo study was performed to assess the impact of shield size and applied force on injection depth. Shields of 15, 20, and 30 mm diameters and forces from 2 to 10 N were investigated. The study involved 55 injections in three Landrace, Yorkshire, and Duroc (LYD) pigs, with injection depths measured with computed tomography (CT). An in-vivo study, involving 20 injections in three LYD pigs, controlled the findings, using fluoroscopy (FS) videos for depth measurement. The CT study revealed that smaller shield sizes significantly increased injection depth. With a 15 mm diameter shield, 10 N applied force, and 5 mm needle protrusion, the injection depth exceeded the needle length by over 3 mm. Injection depth increased with higher applied forces until a plateau was reached around 8 N. Both applied force and size were significant factors for injection depth (analysis of variance [ANOVA], P < .05) in the CT study. The FS study confirmed the ex-vivo findings in an in-vivo setting. The study demonstrates that shield size has a greater impact on injection depth than the applied force. While conducted in porcine tissue, the study provides useful insights into the relative effects of shield size and applied force. Further investigations in humans are needed to confirm the predicted injection depths for AIs.

Reconstruction of multi-phase parametric maps in 4D-magnetic resonance fingerprinting (4D-MRF) by optimization of local T1 and T2 sensitivities.

Time-resolved magnetic resonance fingerprinting (MRF), or 4D-MRF, has been demonstrated its feasibility in motion management in radiotherapy (RT). However, the prohibitive long acquisition time is one of challenges of the clinical implementation of 4D-MRF. The shortening of acquisition time causes data insufficiency in each respiratory phase, leading to poor accuracies and consistencies of the predicted tissues' properties of each phase. To develop a technique for the reconstruction of multi-phase parametric maps in four-dimensional magnetic resonance fingerprinting (4D-MRF) through the optimization of local T1 and T2 sensitivities. The proposed technique employed an iterative optimization to tailor the data arrangement of each phase by manipulation of inter-phase frames, such that the T1 and T2 sensitivities, which were quantified by the modified Minkowski distance, of the truncated signal evolution curve was maximized. The multi-phase signal evolution curves were modified by sliding window reconstruction and inter-phase frame sharing (SWIFS). Motion correction (MC) and dot product matching were sequentially performed on the modified signal evolution and dictionary to reconstruct the multi-parametric maps. The proposed technique was evaluated by numerical simulations using the extended cardiac-torso (XCAT) phantom with regular and irregular breathing patterns, and by in vivo MRF data of three health volunteers and six liver cancer patients acquired at a 3.0 T scanner. In simulation study, the proposed SWIFS approach achieved the overall mean absolute percentage error (MAPE) of 8.62%±1.59% and 16.2%±3.88% for the eight-phases T1 and T2 maps, respectively, in the sagittal view with irregular breathing patterns. In contrast, the overall MAPE of T1 and T2 maps generated by the conventional approach with multiple MRF repetitions were 22.1%±11.0% and 30.8%±14.9%, respectively. For in-vivo study, the predicted mean T1 and T2 of liver by the proposed SWIFS approach were 795ms±38.9ms and 58.3ms±11.7ms, respectively. Both simulation and in vivo results showed that the approach empowered by T1 and T2 sensitivities optimization and sliding window under the shortened acquisition of MRF had superior performance in the estimation of multi-phase T1 and T2 maps as compared to the conventional approach with oversampling of MRF data.

In-vivo Studies conducted following the success In-vitro and Dissemination of Anticancer Clinical Trials

Since the beginnings of cancer research, phytochemicals have been a focal point because they were some of the first antineoplastic drugs found (e.g., leucovorin in 1950, carzinophilin in 1954, vincristine in 1963, actinomycin D in 1964, etc.). Additionally, their research is still ongoing today. It is crucial to note that natural substances are used both as adjuvants and chemotherapeutic agents in the treatment of cancer. By summarizing the three aspects of natural compounds' anticancer activity, this review offers a fresh perspective on their use in the field of oncology. Chemotherapeutic drugs because of their inherent antitumor effects, chemopreventive drugs, and sensitizers for multi-drug resistance are the first three categories. Numerous active agents are undergoing preclinical and clinical trials right now. It is crucial to draw attention to the important advancements that have been made in this field of study, with some secondary plant metabolites already in use in medicine and others being tested in human clinical trials as anticancer agents. Phytochemicals have numerous positive effects on human health and are crucial in preventing the development and spread of cancer. Through a diet high in fruits and vegetables, as well as with the aid of highly-standardized supplements containing the active compounds, one may achieve the ideal intake of natural chemopreventive agents.

In silico ADME/T Prediction of Steroidal Chalcone derivatives using Swiss ADME and OSIRIS explorer

Cancer is the most devastating and widespread disease all over the globe. To overcome drug resistance, new drugs need to be developed that are target specific. Previously designed ten steroidal chalcone derivatives were assessed for their pharmacokinetic profile and toxicity. The present study describes the evaluation of these derivatives for their ADME profile and toxicity using Swiss ADME and OSIRIS web tools. Structures of designed steroidal chalcone derivatives and progesterone (standard) were converted into canonical SMILES format by using Swiss ADME web tool. These structures were submitted to the Swiss ADME web tool that provided physicochemical and pharmacokinetic properties of the compounds. The OSIRIS web server was mainly used for predicting toxicity properties of all derivatives. OSIRIS results on toxicity showed that all compounds were slightly toxic. Based on Swiss ADME analysis, compounds 4, 9 and 10 have an acceptable bioavailability and comply with Lipinski's rule of five. By evaluating their drug score and ADMET properties, it was concluded that compounds 4, 9 and 10 could potentially have favourable characteristics of oral drugs, and further research could be carried out to evaluate them as anticancer agents by performing in-vitro and in-vivo cytotoxic studies.

METTL3 inhibitor STM2457 impairs tumor progression and enhances sensitivity to anlotinib in OSCC.

To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m6 A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both invitro and invivo. The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would-healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT-PCR, MeRIP-qPCR, immunofluorescence, and immunohistochemistry. STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis invitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial-mesenchymal transition) features of OSCC cells. Remarkably, invivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells. The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti-tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC.

Insilico screening to identify novel inhibitors targeting 30S ribosomal protein S12 in meningitis-causing organism ‘Elizabethkingia meningoseptica’

The current trend in biomedical research is on prioritizing infections based on multidrug resistance. Elizabethkingia meningoseptica, a nosocomial infection-causing organism emerging from Neonatal Intensive Care Units (NICUs), leads to neonatal meningitis and sepsis resulting in severe illness, and, in some cases, fatal. Finding a solution remains challenging due to limited prior work. Translational S12 ribosomal proteins play a crucial role in decoding the codon-anticodon helix, which is essential for the survival of E. meningoseptica. These proteins do not exhibit significant similarity with humans, making them potential drug targets. An in silico study aims to identify specific inhibitors for E. meningoseptica ribosomal proteins among known bioactive compounds targeting prokaryotic 30S ribosomal protein. A 3D model of the 7JIL_h protein from Flavobacterium johnsoniae, showing 90% sequence similarity with the target protein was generated using SWISS-MODEL software. The model was validated through Molprobity v4.4, VERIFY 3D, Errata, and ProSA analysis, confirming conserved residues of the target protein. Insilico screening of known bioactive compounds and their analogs identified potential ligands for the target protein. Molecular Docking and post-docking analysis assessed the stability of the protein-ligand complexes among the shortlisted compounds. The top two compounds with high Gold fitness scores and low predicted binding energy underwent MD simulation and further estimation of free binding energy using the MM_PBSA module. These computationally shortlisted compounds, namely chEMBL 1323619 and chEMBL 312490 may be considered for future in-vivo studies as potential inhibitors against the modeled 30S ribosomal protein S12 of E. meningoseptica. Communicated by Ramaswamy H. Sarma