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Stereolithography (SLA) 3D printing of pharmaceuticals suffers from the problem of light scattering, which leads to over-curing, resulting in the printing of objects that are non-compliant with design dimensions and the overloading of drugs. To minimize this problem, photoabsorbers such as tartrazine (food grade) can be used to absorb the stray light produced by scattering, leading to unintended photopolymerization. Ghost tablets (i.e., non-erodible inert matrices) were additively manufactured using SLA with varying ratios of polyethylene glycol diacrylate (PEGDA): polyethylene glycol (PEG) 300, along with tartrazine concentrations. The 3D printed ghost tablets containing maximum (0.03%) tartrazine were extremely precise in size and adhered to the nominal value of the metformin hydrochloride content. Resolution analysis reinstated the influence of tartrazine in achieving highly precise objects of even 0.07 mm2 area. Furthermore, 3D printed ghost tablets were characterized using analytical means, and swelling studies. Additionally, ghost tablets were tested for their mechanical robustness using dynamic mechanical and texture analysis, and were able to withstand strains of up to 5.0% without structural failure. The printed ghost tablets displayed a fast metformin hydrochloride release profile, with 93.14% release after 12 h when the PEG 300 ratio was at its maximum. Ghost tablets were also subjected to in vivo X-ray imaging, and the tablets remained intact even after four hours of administration and were eventually excreted in an intact form through fecal excretion. [Display omitted] [ABSTRACT FROM AUTHOR]

• Lipid mediated nanostructured lipid carriers, a delivery platform for active plant constituents. • Overcome two potent active plant constituent's solubility/permeability related issues. • Development of Compritol® 888 ATO (solid lipid), and squalene (liquid lipid) based lipid matrix. • Amorphous conversion of active plant constituents after encapsulation inside the lipid matrix. • Safety of NLCs was evidenced through no haemolysis in blood samples. Active plant constituents obtained from edible sources have manifested their pharmacological potential as a therapy against several diseases. But the lack of their desired physicochemical properties such as solubility, permeability ultimately leads to poor bioavailability. Two potent active plant constituents namely, quercetin and piperine having a problem with either solubility or permeability or both, and hence require an advanced lipid-mediated separate formulation system to improve their aforementioned concerns. Concerning advancement in nanoformulations, lipid-based nano-carriers systems have created their mark as a novel drug delivery system. Therefore, an advanced formulation like nanostructured lipid carriers (NLCs) has been formulated individually for both the active plant constituents/drugs through the solvent evaporation technique using high shear homogenization method followed by sonication. Compritol® 888 ATO, a solid lipid, and squalene as liquid lipid was used in their optimized ratios to formulate individual NLCs. Blank and individual drugs loaded NLCs were further characterized for their in vitro physicochemical properties. NLCs showed a negative surface charge with an average particle size below 200 nm. Electron microscopy images showed an anomalous structure of both the formulated NLCs with higher % drug encapsulation efficiency (DEE) with the desired in vitro drug release profile. In the case of quercetin-NLCs, 93.18 ± 5.5 % DEE was observed followed by drug release up to 45.0 ± 1.3 % within 12 h, while piperine-NLCs showed 91.80 ± 2.51 % DEE and drug release up to 38 ± 5.2 % at the same time. XRD and DSC plots showed the conversion of both the drugs into an amorphous structure encapsulated in a lyophilized NLCs matrix. Finally, the safety profile for formulated NLCs was confirmed by haemolysis assay. Hence, the developed active plant constituents enriched NLCs can further be delivered separately and/or in combination, and also may further be evaluated both in vitro and in vivo means. [ABSTRACT FROM AUTHOR]

Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-β1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang–II)–stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-β1/Smad2/3 signaling axis. [Display omitted] • Oxidative stress and deposition of ECM components are key factors in the development of cardiac hypertrophy. • Nrf2 signaling can modulate oxidative damage and adverse myocardial remodeling. • Daphnetin is a plant-derived coumarin derivative that possesses anti-oxidative and anti-inflammatory activity. Daphnetin ameliorates TAC-induced cardiac hypertrophy in vivo and Ang-II induced hypertrophy in H9c2 cardiomyoblast. [ABSTRACT FROM AUTHOR]

This article reports a novel, clean and energy-efficient thermal-plasma assisted synthesis technique, for very high rate production of defective, ferromagnetic, 2D stoichiometric molybdenum-oxide, maximum up to 750 g/h, but without compromising with the sizes of the nanomaterials or their state of aggregation. A collimated, laminar beam of plasma with large cross-section and uniform profile is produced as the jet expands supersonically into a vacuum chamber that engulfs a large molybdenum target plate and heat it up in a controlled manner. The surface of the target is rapidly oxidized into a sublimating vapour, from which nanometric metal-oxides are nucleated through gas phase condensation process. Surface oxygen-defects are introduced into the product, but even without employing an additional step of defect-engineering, which endowed them with robust room-temperature ferromagnetic properties (maximum saturation magnetization = 1.84 emu/g) and easy dispersibility in aqueous solutions. It is further demonstrated that the as-synthesized, phase-pure α-MoO 3 sample with hierarchical morphology can adsorb cationic methylene blue (MB) dyes from an aqueous solution at 94.1 % in 30 min, and the corresponding maximum adsorption capacity is 1045.9 mg/g. The ferromagnetic nanoadsorbents may be separated from wastewater with a simple lab scale magnetic field, to reduce secondary pollution and for reuse of the adsorbents. • Very high rate, energy-efficient production of nanometric 2D α-MoO 3 up to 750 g/h. • Doesn't compromise on particle sizes & their aggregation even at highest production. • O vacancies introduced even without additional step of hazardous defect engineering. • Induced max saturation magnetization is 1.84 emu/g, separable with a small magnet. • Fast MB adsorption kinetics, large capacity (1045.9 mg/g), reusable nanoadsorbents. [ABSTRACT FROM AUTHOR]

[Display omitted] A 3D printed assembly of hollow microneedles (HMNs) array, conjoined with a reservoir void, was designed and additively manufactured using stereolithography (SLA) technology utilizing a proprietary class-I resin. The HMNs array was utilized for transdermal delivery of high molecular weight antibiotics, i.e., rifampicin (M w 822.94 g/mol), which suffers from gastric chemical instability, low bioavailability, and severe hepatotoxicity. HMNs morphology was designed with sub-apical holes present in a quarter of the needle tip to improve its mechanical strength and integrity of the HMNs array. The HMNs array was characterized by optical microscopy and electron microscopy to ascertain the print quality and uniformity across the array. The system was also subjected to mechanical characterization for failure and penetration analyses. The ex vivo permeation and consequent transport of rifampicin across porcine skin were systematically evaluated. Finally, in vivo examinations of rifampicin administration through the microneedle reservoir system in SD rats revealed efficient penetration and desired bioavailability. [ABSTRACT FROM AUTHOR]

Breast cancer treatment with PARP-1 inhibitors remains challenging due to emerging toxicities, drug resistance, and unaffordable costs of treatment options. How do we invent strategies to design better anti-cancer drugs? A part of the answer is in optimized compound properties, desirability functions, and modern computational drug design methods that drive selectivity and toxicity and have not been reviewed for PARP-1 inhibitors. Nonetheless, comparisons of these compound properties for PARP-1 inhibitors are not available in the literature. In this review, we analyze the physchem, PKPD space to identify inherent desirability functions characteristic of approved drugs that can be valuable for the design of better candidates. Recent literature utilizing ligand, structure-based drug design strategies and matched molecular pair analysis (MMPA) for the discovery of novel PARP-1 inhibitors are also reviewed. Thus, this perspective provides valuable insights into the medchem and multiparameter optimization of PARP-1 inhibitors that might be useful to other medicinal chemists. [Display omitted] • Breast cancer treatment with PARP-1 inhibitors is losing effectiveness due to emerging resistance and side effects. • Novel desirability functions have been identified by reviewing compound property parameters. • Computer-Aided Drug Design methods continue to guide the discovery of novel inhibitors. • MMPA leads to the identification of statistically meaningful structural transformation (substitution) rules. [ABSTRACT FROM AUTHOR]

Tubulointerstitial fibrosis, a frequent complication of chronic kidney disease (CKD) is a major public health issue. Biochanin A (BCA), an isoflavone, has numerous pharmacological activities. However, its effect on renal fibrosis and underlying molecular mechanism has not yet been clarified. This study explored the effect of BCA on renal tubulointerstitial fibrosis and inflammation in mice. The mouse model of unilateral ureteral obstruction (UUO) in vivo and transforming growth factor (TGF)-β1 activated renal fibroblast (NRK 49F) cells in vitro model were used to assess the antifibrotic effect of BCA. Biochemical analysis, histopathology, western blotting, and immunofluorescent staining methods were performed to elucidate the mechanism of BCA. In vitro, BCA suppressed the expression of fibrogenic proteins in TGF-β1-activated renal fibroblasts. The treatment with BCA displayed less tubular injury, prevented the aberrant accumulation of extracellular matrix (ECM) components, and inhibited the TGF-β1/Smad2/3 signaling axis in the kidneys. Furthermore, BCA impeded the phosphorylation of NF-kB(p65) and blunted the expression of inflammatory genes in the obstructed kidneys. The UUO induced expressions of nod-like receptor protein 3 (NLRP3), active caspase 1, interleukin(IL)-18, and IL-1β proteins were decreased in the BCA treated groups. We also found the increased expression of redox-sensitive nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins in BCA treated groups compared to the UUO control. These findings indicate that BCA has a therapeutic benefit against renal fibrosis, and the ameliorative effect is mediated via inhibiting the TGF-β1/Smad2/3 and NF-kB/NLRP3 signaling axis. [Display omitted] [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats. Cardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated. Aloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-β (TGF-β) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro. Our findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-β/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Analytical sample preparation techniques are regarded as crucial steps for analyzing compounds from different biological matrices. The development of new extraction techniques is a modern trend in the bioanalytical sciences. 3D printed techniques have emerged as a valuable technology for prototyping devices in customized shapes for a cost-effective way to advance analytical sample preparation techniques. The present study aims to fabricate customized filaments through the hot-melt extrusion (HME) technique followed by fused deposition modeling mediated 3D printing process for rapid prototyping of 3D printed sorbents to extract a sample from human plasma. Thus, we fabricated our own indigenous filament using poly (vinyl alcohol), Eudragit® RSPO, and tri-ethyl citrate through HME to prototype the fabricated filament into a 3D printed sorbent for the extraction of small molecules. The 3D sorbent was applied to extract hydrocortisone from human plasma and analyzed using a validated LC-MS/MS method. The extraction procedure was optimized, and the parameters influencing the sorbent extraction were systematically investigated. The extraction recovery of hydrocortisone was found to be >82% at low, medium, and high quality control samples, with a relative standard deviation of <2%. The intra-and inter-day precisions for hydrocortisone ranged from 1.0% to 12% and 2.0%–10.0%, respectively, whereas the intra-and inter-day accuracy for hydrocortisone ranged from 93.0% to 111.0% and 92.0% to 110.0%, respectively. The newly customizable size and shape of the 3D printed sorbent opens new possibilities for extracting small molecules from human plasma. [Display omitted] • Developed indigenous filaments through hot-melt-extrusion technique followed by 3D printed sorbent. • 3D printed sorbents used for sample extraction of molecule. • The extraction recovery of hydrocortisone was found to be >82% with <2% relative standard deviation. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) with underlying interstitial fibrosis is often associated with end-stage renal disease (ESRD). In the present study, we investigated the renoprotective and antifibrotic potential of nootkatone (NTK), a bioactive sesquiterpene, in an experimental model of renal fibrosis. Unilateral ureteral obstruction (UUO) model was performed to induce renal fibrosis in Balb/C mice. The animals were randomly assigned into 5 groups: sham, NTK control, UUO control, UUO and NTK 5 mg/kg, and UUO and NTK 10 mg/kg. Animals received NTK at a dose of 5 mg/kg and 10 mg/kg orally for the next 14 consecutive days. UUO induced histological alterations, accumulation of extracellular matrix (ECM) components including collagens, fibronectin, and alpha-smooth muscle actin (α-SMA), activation of the transforming growth factor-β (TGF-β)/Smad signaling and oxidative damage in the obstructed kidneys. Our study revealed that NTK (10 mg/kg) inhibits UUO mediated kidney fibrosis in vivo. Administration of NTK (10 mg/kg) prevented the activation of the TGF-β/Smad signaling, expression of ECM components, markedly attenuated the renal tubular injury and fibrosis area (% area: 6.66 ± 1.45% vs UUO: 26.33 ± 2.90%). Administration of NTK at 10 mg/kg significantly restored the endogenous antioxidants and prevented the reactive oxygen species generation (25.31 ± 1.65% vs UUO: 45.01 ± 4.85%) and reduced the level of tumor necrosis factor (TNF)-α (95.22 ± 12.39 vs UUO: 215.57 ± 60.45 pg/mg protein) in the kidneys. Altogether, our findings suggest that NTK might be a budding therapeutic candidate for renal fibrosis. [ABSTRACT FROM AUTHOR]

Oral squamous cellular carcinoma (OSCC) is considered a life-threatening disease with detection in late stages, which forces us to opt for dangerous treatment with a combination of chemotherapy and radiotherapy. Herbal components such as piperine and quercetin are derived from edible sources, proving their anticancer potential against oral cancer cells in vitro. Encapsulation into lipid matrix-mediated nanostructured lipid carriers (NLCs) can make both drugs bio-accessible. NLCs were synthesised using the high shear homogenisation method and characterised for their physicochemical properties, followed by in vitro cellular evaluation in FaDu oral cancer cells. NLCs showed negatively charged particles smaller than 180 nm with a polydispersity index (PDI) of <0.3. Both drugs were found to encapsulate sufficiently, with >85% entrapment efficiency and an improved drug release profile compared to their pristine counterparts. Differential scanning calorimetry (DSC) thermograms showed conversion into an amorphous matrix in lyophilized NLCs, which was supported by X-ray diffraction (XRD) analysis. The cytotoxicity assay showed the IC 50 concentration for dual drug-loaded NLCs, which was more effective than the pure drug solution. NLCs were found to be internalised in cells in a short time with an almost 95% co-localization rate. Dual drug-loaded NLCs showed maximum depolarisation of the mitochondrial membrane along with more apoptotic changes. Improved apoptosis was confirmed in NLCs using flow cytometry. The in vivo biodistribution of Coumarin-6 labelled NLCs in rats confirmed their efficient distribution in various parts of the oral cavity through oral administration. Optimised dual drug-loaded NLCs provide a better option for delivering both drugs through a single lipid matrix against oral cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a progressive renal complication which significantly affects the patient's life with huge economic burden. Untreated acute kidney injury eventually progresses to a chronic form and end-stage renal disease. Although significant breakthroughs have been made in recent years, there are still no effective pharmacological therapies for the treatment of acute kidney injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response plays a pivotal role in the pathogenesis of acute kidney injury. The expression of TLR4 has been seen in resident renal cells, including podocytes, mesangial cells, tubular epithelial cells and endothelial cells. Activation of TLR4 signaling regulates the transcription of numerous pro-inflammatory cytokines and chemokines, resulting in renal inflammation. Therefore, targeting TLR4 and its downstream effectors could serve as an effective therapeutic intervention to prevent renal inflammation and subsequent kidney damage. For the first time, this review summarizes the literature on acute kidney injury from the perspective of TLR4 from year 2010 to 2020. In the current review, the role of TLR4 signaling pathway in AKI with preclinical evidence is discussed. Furthermore, we have highlighted several compounds of natural and synthetic origin, which have the potential to avert the renal TLR4 signaling in preclinical AKI models and have shown protection against AKI. This scientific review provides new ideas for targeting TLR4 in the treatment of AKI and provides strategies for the drug development against AKI. Unlabelled Image [ABSTRACT FROM AUTHOR]

Diabetes mellitus is an increasingly prevalent disease around the globe. The epidemic of diabetes mellitus and its complications pretenses the foremost health threat globally. Diabetic nephropathy is the notable complication in diabetes, leading to end-stage renal disease (ESRD) and premature death. Abundant experimental evidence indicates that oxidative stress and inflammation are the important mediators in diabetic kidney diseases and interlinked with various signal transduction molecular mechanisms. Inflammasomes are the critical components of innate immunity and are recognized as a critical mediator of inflammation and autoimmune disorders. NOD-like receptor protein 3 (NLRP3) inflammasome is the well-characterized protein and it exhibits the sterile inflammation through the regulation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 production in tissues. In recent years, the role of NLRP3 inflammasome in the pathophysiology of diabetic kidney diseases in both clinical and experimental studies has generated great interest. In the current review, we focused on and discussed the role of NLRP3 inflammasome in diabetic nephropathy. A literature review was performed using online databases namely, PubMed, Scopus, Google Scholar and Web of science to explore the possible pharmacological interventions that blunt the NLRP3 inflammasome-caspase-1-IL-1β/IL-18 axis and shown to have a beneficial effect in diabetic kidney diseases. This review describes the inhibition of NLRP3 inflammasome activation as a promising therapeutic target for drug discovery in future. [ABSTRACT FROM AUTHOR]