Conformational Switch of a Peptide Provides a Novel Strategy to Design Peptide Loaded Porous Organic Polymer for Pyroptosis Pathway Mediated Cancer Therapy.

While peptide-based drug development is extensively explored, this strategy has limitations due to rapid excretion from the body (or shorter half-life in the body) and vulnerability to protease-mediated degradation. To overcome these limitations, a novel strategy for the development of a peptide-based anticancer agent is introduced, utilizing the conformation switch property of a chameleon sequence stretch (PEP1) derived from a mycobacterium secretory protein, MPT63. The selected peptide is then loaded into a new porous organic polymer (PG-DFC-POP) synthesized using phloroglucinol and a cresol derivative via a condensation reaction to deliver the peptide selectively to cancer cells. Utilizing ensemble and single-molecule approaches, this peptide undergoes a transition from a disordered to an alpha-helical conformation, triggered by the acidic environment within cancer cells that is demonstrated. This adopted alpha-helical conformation resulted in the formation of proteolysis-resistant oligomers, which showed efficient membrane pore-forming activity selectively for negatively charged phospholipids accumulated in cancer cell membranes. The experimental results demonstrated that the peptide-loaded PG-DFC-POP-PEP1 exhibited significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway, which is established by monitoring numerous associated events starting from lysosome membrane damage to GSDMD-induced cell membrane demolition. This novel conformational switch-based drug design strategy is believed to have great potential in endogenous environment-responsive cancer therapy and the development of future drug candidates to mitigate cancers.

Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.

Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK's) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.

Facile and Green Synthesis of Novel Fluorescent Carbon Quantum Dots and Their Silver Heterostructure: An In Vitro Anticancer Activity and Imaging on Colorectal Carcinoma.

Carbon dots (CQDs) have been widely investigated as prime candidates for developing a tumor theranostic platform due to their tunable fluorescence emission and excitation, high water solubility, good photostability, and biocompatibility. Among the CQDs, natural CQDs are an emerging class of nanomaterials in the carbon family. Herein, highly fluorescent carbon quantum dots (CQDs) were synthesized from orange juice using a one-step hydrothermal method and characterized by different techniques. After that, CQD/Ag heterostructures were synthesized by the reduction of silver salt, in particular silver nitrate (AgNO3) solution using sodium borohydride (NaBH4) in different ratios. The photostability and characterization of CQD/Ag heterostructures were investigated. At last, a comparative cellular toxicity measurement was done to select the superior CQD/Ag heterostructure in the human colorectal carcinoma (HCT 116) cell line along with the imaging property. The detailed cell death signaling was also observed in the HCT 116 cell line via the ROS-dependent mitochondrial-mediated pathway, where Akt (RAC-α serine/threonine-protein kinase) played a important role.

Protective role of Decylubiquinone against secondary melanoma at lung in B16F10 induced mice by reducing E-cadherin expression and ameliorating ROCKII-Limk1/2-Cofiliin mediated metastasis.

Melanoma is one of the most consequential skin cancer with a rising death incidences. Silent but belligerent nature of metastatic sprouting is the leading cause of melanoma related mortality. Invasion of metastatic cells and re-expression of E-Cadherin play the crucial role in the establishment of secondary tumor at distal sites. Thus, manipulation of tumor cell invasion in parallel to regulation of E-Cadherin expression can be considered as potential anti-metastatic strategy. Evidences suggested key role of reactive oxygen species associated ROCK activities in the modulation of metastatic invasion via F-actin stabilization. Here, we first-time report Decylubiquinone, a dietary Coenzyme Q10 analog, as an effective attenuator of pulmonary metastatic melanoma in C57BL/6 mice. Current study depicted detailed molecular interplay associated with Decylubiquinone mediated phosphorylation of ROCKII at Tyr722 along with reduced phosphorylation of ROCKII Ser1366 leading to suppression of Limk1/2-Cofilin-F-actin stabilization axis that finally restricted B16F10 melanoma cell invasion at metastatic site. Analysis further deciphered the role of HNF4α as its nuclear translocation modulated E-Cadherin expression, the effect of reactive oxygen species dependent ROCKII activity in secondarily colonized B16F10 melanoma cells at lungs. Thus unbosoming of related signal orchestra represented Decylubiquinone as a potential remedial agent against secondary lung melanoma.

Activity of ROCKII not ROCKI promotes pulmonary metastasis of melanoma cells via modulating Smad2/3-MMP9 and FAK-Src-VEGF signalling.

Rho-associated coiled-coil kinase (ROCK) inhibition decreases tumourogenic growth, proliferation and angiogenesis. Multifaceted evidences are there about the role of ROCK in cancer progression, but isoform specific analysis in secondary pulmonary melanoma is still unaddressed. This study explored the operating function of ROCK in the metastasis of B16F10 mice melanoma cell line. Inhibition by KD-025 indicated dual wielding role of ROCKII as it is associated with the regulation of MMP9 activity responsible for extra-cellular matrix (ECM) degradation as well as angiogenic invasion as an effect of Src-FAK-STAT3 interaction dependent VEGF switching. We found the assisting role of ROCKII, not ROCKI in nuclear localization of Smads that effectively increased MMP9 expression and activity (p < 0.01). This cleaved the protein components of ECM thereby played a crucial role in tissue remodeling at secondary site during establishment of metastatic tumour. ROCKII phosphorylation at Ser1366 as an activation of the same was imprinted essential for oncogenic molecular bagatelle leading to histo-architectural change of pulmonary tissue with extracellular matrix degradation as a consequence of invasion. Direct correlation of pROCKIISer1366 with MMP9 as well as VEGF expression in vivo studies cue to demonstrate the importance of pROCKIISer1366 inhibition in the context of angiogenesis, and metastasis suggesting ROCKII signaling as a possible target for the treatment of secondary lung cancer specially in metastatic melanoma.

Various theranostics and immunization strategies based on nanotechnology against Covid-19 pandemic: An interdisciplinary view.

COVID-19 pandemic is still a major risk to human civilization. Besides the global immunization policy, more than five lac new cases are documented everyday. Some countries newly implement partial/complete nationwid lockdown to mitigate recurrent community spreading. To avoid the new modified stain of SARS-CoV-2 spreading, some countries imposed any restriction on the movement of the citizens within or outside the country. Effective economical point of care diagnostic and therapeutic strategy is vigorously required to mitigate viral spread. Besides struggling with repurposed medicines, new engineered materials with multiple unique efficacies and specific antiviral potency against SARS-CoV-2 infection may be fruitful to save more lives. Nanotechnology-based engineering strategy sophisticated medicine with specific, effective and nonhazardous delivery mechanism for available repurposed antivirals as well as remedial for associated diseases due to malfeasance in immuno-system e.g. hypercytokinaemia, acute respiratory distress syndrome. This review will talk about gloomy but critical areas for nanoscientists to intervene and will showcase about the different laboratory diagnostic, prognostic strategies and their mode of actions. In addition, we speak about SARS-CoV-2 pathophysiology, pathogenicity and host specific interation with special emphasis on altered immuno-system and also perceptualized, copious ways to design prophylactic nanomedicines and next-generation vaccines based on recent findings.

Association of p38MAPK-p53-Fas aggregation in S-allyl cysteine mediated regulation of hepatocarcinoma.

Bioactive components of dietary phytochemicals have been reported to possess antitumor activities. Evidences suggested key role of stress responsive p38MAPK in the induction of nutraceuticals mediated apoptosis in hepatocellular carcinoma (HCC). Current study demonstrated detailed molecular bagatelle associated with p38 MAPK mediated effective suppression of cell growth both in HepG2 and chemically induced liver carcinoma after S-allyl cysteine (SAC) treatment. SAC promoted p38MAPK activity responsible for p53 phosphorylation, its stabilization followed by nuclear translocation leading to induction in expression and oligomerization of Fas protein. Distinctive p38MAPK-p53 axis dependent Fas-FasL-FADD mediated caspase activities along with perturbed cell cycling became normalized with continuation of SAC treatment for another month to diethylnitrosamine induced liver carcinoma. Co-treatment with SB203580, the p38MAPK inhibitor, prevented pro-apoptotic effect of SAC by altering p53 phosphorylation and death inducing signaling complex conformation in HepG2 and induced HCC. Collectively study suggested significant contribution of p38MAPK-p53-DISC-Caspase pathway in the regulation of anti-neoplastic activity of SAC against HCC.

Cathepsin B mediated scramblase activation triggers cytotoxicity and cell cycle arrest by andrographolide to overcome cellular resistance in cisplatin resistant human hepatocellular carcinoma HepG2 cells.

Andrographolide regimen in single or in combination with anticancer drugs is a promising new strategy to reverse chemoresistance in heaptocellular carcinoma. Apoptosis inducing factor (AIF) may regulate a complementary, cooperative or redundant pathway, along with caspase cascades. Despite these findings, mechanisms underlying caspase-dependent and-independent signaling pathways in andrographolide -induced apoptosis in cisplatin-resistant human hepatocellular carcinoma cell line (HepG2CR) remain unclear. Andrographolide treatment effectively reduced NF-κß nuclear localization by modulating protein kinase A- protein phosphatase 2 A- Iκß kinase (PKA/PP2 A/IKK) axis that in turn maintains initiator caspase8 activity. Lysosomal distribution of tBid stimulates cytosolic cathepsin B resulting accumulation of truncated-AIF with induction in scramblase mediated phosphatidylserine exposure in HepG2CR cells. Andrographolide treatment thereby switch on subG1 phase arrest by modulating cellular check points (cyclin A, B, cyclin dependent kinase-1) cueing to the apoptosis event. Collectively, this study suggested antineoplastic potential of andrographolide through PKA/PP2 A/IKK pathway in HepG2CR cells.

Modulation of adenylate cyclase signaling in association with MKK3/6 stabilization under combination of SAC and berberine to reduce HepG2 cell survivability.

Cancer cells often have faulty apoptotic pathways resulting in sustenance of survivability, tumour metastasis and resistance to anticancer drugs. Alternate strategies are sought to improve therapeutic efficacy and therefore HepG2 cells were treated with S-allyl-cysteine (SAC) and berberine (BER) to analyze their mechanistic impact upon necroptosis along with its interacting relationship to apoptosis. In the present study we observed that SAC and BER exposure reduced NFκß nuclear translocation through adenylate cyclase-cAMP-protein kinaseA axis and eventually evaded c-FLIP inhibition. Effective RIP1 k63-polyubiquitination and persistent MKK3/MKK6 expression during drug treatment potentiated caspase8 activity via p53-DISC conformation. Resultant tBid associated lysosomal protease mediated AIF truncation induced DNA fragmentation and persuaded effector caspase mediated scramblase activation resulting induction of necroptosis in parallel to apoptotic events. SAC+BER effectively reduced Rb-phosphorylation resulting insignificant nuclear E2F presence led to ending of cell proliferation. Therefore necroptosis augmented the drug response and may be targeted alongside cell proliferation inhibition in formation of efficient therapeutics against liver cancer.

Spectroscopic studies of 2-(2-bromo-ethyl)-6-nitro-benzo[de]isoquinolene-1,3-dione in water/alkanol mixed solvents and nonionic micelle of Igepal CO series.

Spectroscopic studies of newly synthesized bioactive compound 2-(2-bromo-ethyl)-6-nitro-benzo[de]isoquinolene-1,3-dione (BNBIO) have been carried out in polar aprotic solvent, viz. acetonitrile, tetrahydrofuran, 1,4-dioxan, ethylene glycol, dimethyl formamide, and polar protic solvent, viz. methanol, ethanol, propanol, water. Variation in absorbance of BNBIO in water-methanol, water-ethanol and water-propanol mixtures at their different compositions have been observed. Absorption behaviour of the dye has been studied in poly(oxyethylene) nonylphenol surfactants Igepal CO 630, Igepal CO 720 and Igepal CO 890 containing same hydrophobic tail and different numbers of poly(oxyethylene) groups. Experimental results of the BNBIO nonionic micelles have been explained in terms of 1:1 electron donor-acceptor (EDA) complexation and the complexation equilibrium becomes suppressed with increasing number of poly(oxyethylene) residue on the Igepal surfactant. Variation in binding constant of dye-micelle complexation has been rationalized considering a competitive equilibrium process between the BNBIO-water interactions.

Spectroscopic studies of interaction of Safranine T with nonionic micelles and mixed micelles.

The visible spectra of Safranine T (ST) in micellar solution of Brij 58, Tween 20 and Tween 40 and mixed micellar solution of Brij 58/Tween 20 and Brij 58/Tween 40 indicate formation of 1:1 charge transfer (CT) complex between acceptor ST and donor nonionic micelles and mixed micelles. The experimental CT transition energies are well correlated (through Mulliken's equation) with the vertical ionization potential of the donors. The solvent parameters, i.e. the intramolecular charge transfer energy ET(30) have been determined from the Stokes spectral shift. Variations of ionization potential and micropolarity in the mixed micellar region have been investigated as a function of surfactant composition and the obtained results in mixed micellar medium has been compared to the normal micelles. The critical micelle concentration (CMC) values determined at various surfactant compositions are lower than the ideal values indicating a synergistic interaction. The interaction parameter (beta) and micellar stability has been calculated using regular solution theory.

Interface of AOT/Brij mixed reverse micellar systems: conductometric and spectrophotometric investigations.

Solubilization and conductivity studies are carried out with AOT/Brijs (Brij-30, Brij-35, Brij-52, Brij-56, Brij-58, Brij-72, Brij-76, Brij-78)/isooctane/water mixed reverse micellar systems. Replacement of AOT molecules with large head group Brij molecules (Brij-30, Brij-35, Brij-56, Brij-58, Brij-76, Brij-78) decreases the solubilization capacity, whereas those with smaller polar head groups (Brij-52 and Brij-72) increases it. The former blends assist the conductance percolation whereas the latter retard it. An attempt has been taken to obtain more insight on the interfacial composition of the mixed interface with the help of spectrophotometric studies using 7-hydroxycoumarin as the fluorophore. The results obtained from the solubilization and conductometric studies have been correlated with those obtained from the spectroscopic studies.