Polymer Nanoparticles for Preferential Delivery of Drugs Only by Exploiting the Slightly Elevated Temperature of Cancer Cells and Real-Time Monitoring of Drug Release.

Rapid proliferation and a faster rate of glycolysis in cancer cells often result in an elevated local temperature (40-43 °C) at the tumor site. Nanoparticles prepared from polymers with two lower critical solution temperatures (LCSTs) can be utilized to take advantage of this subtle temperature elevation to deliver anticancer drugs preferably to the cancer cells, thereby enhancing the overall therapeutic efficacy and reducing side effects. In this direction, we synthesized N-vinyl-2-pyrrolidone (NVP) and substituted NVP (sub-NVP: C2-NVP, C4-NVP)-based polymers with precisely controlled LCSTs by varying the ratio of NVP and sub-NVP. The first LCST (LCST1) was kept below 37 °C to promote self-assembly, drug loading, and structural stability in physiological conditions and the second LCST (LCST2) was in the range of 40-43 °C to ensure mild hyperthermia-induced drug release. Additionally, covalent attachment of tetraphenylethylene (TPE, AIEgen) resulted in aggregation-induced emission in thermoresponsive micellar nanoparticles in which TPE acted as a Förster Resonance Energy Transfer (FRET) pair with the loaded anticancer drug doxorubicin (DOX). Tracking of FRET-induced fluorescence recovery of TPE molecules was utilized to confirm the real-time thermoresponsive release of DOX from nanoparticles and eventual localization of TPE in the cytoplasm and DOX in the nucleus. In vitro cellular studies such as cytotoxicity, cellular uptake, and thermoresponsive drug release showed that the DOX-loaded polymeric nanoparticles were nontoxic to normal cells (HEK-293) but significantly more effective in cancer cells (MCF-7) at 40 °C. To our knowledge, this is the first report of preferential delivery of anticancer drugs only by exploiting the slightly elevated temperature of cancer cells.

A Virtual Drug Discovery Screening Illuminates Campesterol as a Potent Estrogen Receptor Alpha Inhibitor in Breast Cancer.

Breast cancer remains a global health challenge, and innovative strategies are required to target estrogen receptor α (ERα), a key player in its development. This study investigates the potential of campesterol, a natural phytosterol, as an ERα inhibitor for breast cancer. Our approach integrates in silico, in vitro, and ex vivo experiments to assess the therapeutic potential of campesterol. In silico analyses highlight campesterol as a promising ERα ligand with favorable binding affinities and dynamic properties. Structural analysis reveals conformational changes in ERα upon campesterol binding. In vitro studies confirm the selective growth inhibition of campesterol against ERα-positive breast cancer cells. This study extends to ER+ breast cancer patient-derived organoids (PDOs), showing the effectiveness of campesterol in ERα-positive breast cancer PDOs. Importantly, it emphasizes the receptor-specific nature of campesterol, providing insights into its context-dependent action. In conclusion, campesterol displays potential as an ERα inhibitor, offering new avenues for ER+ breast cancer treatment.

Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy.

The present study explores the complex roles of High Mobility Group Box 1 (HMGB1) in the context of cancer development, emphasizing glioblastoma (GBM) and other central nervous system (CNS) cancers. HMGB1, primarily known for its involvement in inflammation and angiogenesis, emerges as a multifaceted player in the tumorigenesis of GBM. The overexpression of HMGB1 correlates with glioma malignancy, influencing key pathways like RAGE/MEK/ERK and RAGE/Rac1. Additionally, HMGB1 secretion is linked to the maintenance of glioma stem cells (GSCs) and contributes to the tumor microenvironment's (TME) vascular leakiness. Henceforth, our review discusses the bidirectional impact of HMGB1, acting as both a promoter of tumor progression and a mediator of anti-tumor immune responses. Notably, HMGB1 exhibits tumor-suppressive roles by inducing apoptosis, limiting cellular proliferation, and enhancing the sensitivity of GBM to therapeutic interventions. This dualistic nature of HMGB1 calls for a nuanced understanding of its implications in GBM pathogenesis, offering potential avenues for more effective and personalized treatment strategies. The findings underscore the need to explore HMGB1 as a prognostic marker, therapeutic target, and a promising tool for stimulating anti-tumor immunity in GBM.

Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.

Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future.

Two-Photon-Responsive "TICT + AIE" Active Naphthyridine-BF2 Photoremovable Protecting Group: Application for Specific Staining and Killing of Cancer Cells.

The combined effects of twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) phenomena have demonstrated a significant influence on excited-state chemistry. These combined TICT and AIE features have been extensively utilized to enhance photodynamic and photothermal therapy. Herein, we demonstrated the synergistic capabilities of TICT and AIE phenomena in the design of the photoremovable protecting group (PRPG), namely, NMe2-Napy-BF2. This innovative PRPG incorporates TICT and AIE characteristics, resulting in four remarkable properties: (i) red-shifted absorption wavelength, (ii) strong near-infrared (NIR) emission, (iii) viscosity-sensitive emission property, and (iv) accelerated photorelease rate. Inspired by these intriguing attributes, we developed a nanodrug delivery system (nano-DDS) using our PRPG for cancer treatment. In vitro studies showed that our nano-DDS manifested effective cellular internalization, specific staining of cancer cells, high-resolution confocal imaging of cancerous cells in the NIR region, and controlled release of the anticancer drug chlorambucil upon exposure to light, leading to cancer cell eradication. Most notably, our nano-DDS exhibited a substantially increased two-photon (TP) absorption cross section (435 GM), exhibiting its potential for in vivo applications. This development holds promise for significant advancements in cancer treatment strategies.

Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence.

Understanding protein sequence and structure is essential for understanding protein-protein interactions (PPIs), which are essential for many biological processes and diseases. Targeting protein binding hot spots, which regulate signaling and growth, with rational drug design is promising. Rational drug design uses structural data and computational tools to study protein binding sites and protein interfaces to design inhibitors that can change these interactions, thereby potentially leading to therapeutic approaches. Artificial intelligence (AI), such as machine learning (ML) and deep learning (DL), has advanced drug discovery and design by providing computational resources and methods. Quantum chemistry is essential for drug reactivity, toxicology, drug screening, and quantitative structure-activity relationship (QSAR) properties. This review discusses the methodologies and challenges of identifying and characterizing hot spots and binding sites. It also explores the strategies and applications of artificial-intelligence-based rational drug design technologies that target proteins and protein-protein interaction (PPI) binding hot spots. It provides valuable insights for drug design with therapeutic implications. We have also demonstrated the pathological conditions of heat shock protein 27 (HSP27) and matrix metallopoproteinases (MMP2 and MMP9) and designed inhibitors of these proteins using the drug discovery paradigm in a case study on the discovery of drug molecules for cancer treatment. Additionally, the implications of benzothiazole derivatives for anticancer drug design and discovery are deliberated.

4'-C-Acetamidomethyl-2'-O-methoxyethyl Nucleic Acid Modifications Improve Thermal Stability, Nuclease Resistance, Potency, and hAgo2 Binding of Small Interfering RNAs.

In this study, we designed the 4'-C-acetamidomethyl-2'-O-methoxyethyl (4'-C-ACM-2'-O-MOE) uridine and thymidine modifications, aiming to test them into small interfering RNAs. Thermal melting studies revealed that incorporating a single 4'-C-ACM-2'-O-MOE modification in the DNA duplex reduced thermal stability. In contrast, an increase in thermal stability was observed when the modification was introduced in DNA:RNA hybrid and in siRNAs. Thermal destabilization in DNA duplex was attributed to unfavorable entropy, which was mainly compensated by the enthalpy factor to some extent. A single 4'-C-ACM-2'-O-MOE thymidine modification at the penultimate position of the 3'-end of dT20 oligonucleotides in the presence of 3'-specific exonucleases, snake venom phosphodiesterase (SVPD), demonstrated significant stability as compared to monomer modifications including 2'-O-Me, 2'-O-MOE, and 2'-F. In gene silencing studies, we found that the 4'-C-ACM-2'-O-MOE uridine or thymidine modifications at the 3'-overhang in the passenger strand in combination with two 2'-F modifications exhibited superior RNAi activity. The results suggest that the dual modification is well tolerated at the 3'-end of the passenger strand, which reflects better siRNA stability and silencing activity. Interestingly, 4'-C-ACM-2'-O-MOE-modified siRNAs showed considerable gene silencing even after 96 h posttransfection; it showed that our modification could induce prolonged gene silencing due to improved metabolic stability. Molecular modeling studies revealed that the introduction of the 4'-C-ACM-2'-O-MOE modification at the 3'-end of the siRNA guide strand helps to anchor the strand within the PAZ domain of the hAgo2 protein. The overall results indicate that the 4'-C-ACM-2'-O-MOE uridine and thymidine modifications are promising modifications to improve the stability, potency, and hAgo2 binding of siRNAs.

Carbon Dots for Multiuse Platform: Intracellular pH Sensing and Complementary Intensified T1-T2 Dual Imaging Contrast Nanoprobes.

Measurement of pH in living cells is a great and decisive factor for providing an early and accurate diagnosis factor. Along with this, the multimodal transverse and longitudinal relaxivity enhancement potentiality over single modality within a single platform in the magnetic resonance imaging (MRI) field is a very challenging issue for diagnostic purposes in the biomedical field of application. Therefore, this work aims to design a versatile platform by fabricating a novel nanoprobe through holmium- and manganese-ion doping in carbon quantum dots (Ho-Mn-CQDs), which can show nearly neutral intracellular pH sensing and MRI imaging at the same time. These manufactured Ho-Mn-CQDs acted as excellent pH sensors in the near-neutral range (4.01-8.01) with the linearity between 6.01 and 8.01, which could be useful for the intracellular pH-sensing capability. An innumerable number of carboxyl and amino groups are present on the surface of the prepared nanoprobe, making it an excellent candidate for pH sensing through fluorescence intensity quenching phenomena. Cellular uptake and cell viability experiments were also executed to affirm the intracellular accepting ability of Ho-Mn-CQDs. Furthermore, with this pH-sensing quality, these Ho-Mn-CQDs are also capable of acting as T1-T2 dual modal imaging contrast agents in comparison with pristine Ho-doped and Mn-doped CQDs. The Ho-Mn-CQDs showed an increment of r1 and r2 relaxivity values simultaneously compared with only the negative contrast agent, holmium in holmium-doped CQDs, and the positive contrast agent, manganese in manganese-doped CQDs. The above-mentioned observations elucidate that its tiny size, excitation dependence of fluorescence behavior, low cytotoxicity, and dual modal contrast imaging capability make it an ideal candidate for pH monitoring in the near-neutral range and also as a dual modal MRI imaging contrast enhancement nanoprobe at the same time.

In-silico identification of novel DDI2 inhibitor in glioblastoma via repurposing FDA approved drugs using molecular docking and MD simulation study.

Glioblastoma, the most severe form of brain tumor and a leading cause of death within a year of diagnosis, is characterized by excessive protein synthesis and folding in the lumen of the endoplasmic reticulum (ER), leading to increased ER stress in the cells of GBM tissues. To mitigate this stress the cancer cells have intelligently adopted a plethora of response mechanisms and Unfolded Protein Response (UPR) is one of those. To bear with this exhaustive situation cells upregulate a strong protein degradation system in form of 26S proteasome and blocking of proteasomal gene synthesis may be a potential therapeutic action against GBM. Proteasomal gene synthesis is exclusively dependent on the transcription factor Nuclear respiratory factor 1 (NRF1) and its activating enzyme DNA damage inducible 1 homolog 2 (DDI2). Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

A computational analysis to evaluate deleterious SNPs of GSK3ß, a multifunctional and regulatory protein, for metabolism, wound healing, and migratory processes.

This study focused on GSK-3ß, a critical serine/threonine kinase with diverse cellular functions. However, there is limited understanding of the impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on its structure and function. Through an exhaustive in-silico investigation 12 harmful nsSNPs were predicted from a pool of 172 acquired from the NCBI dbSNP database using 12 established tools that detects deleterious SNPs. Consistently, these nsSNPs were discovered in locations with high levels of conservation. Notably, the three harmful nsSNPs F67C, A83T, and T138I were situated in the active/binding site of GSK-3ß, which may affect the protein's capacity to bind to substrates and other proteins. Molecular dynamics simulations revealed that the F67C and T138I mutants had stable structures, indicating rigidness, whereas the A83T mutant was unstable. Analysis of secondary structures revealed different modifications in all mutant forms, which may affect the stability, functioning, and interactions of the protein. These mutations appear to alter the structural dynamics of GSK-3ß, which may have functional ramifications, such as the formation of novel secondary structures and variations in coil-to-helix transitions. In conclusion, this study illuminates the possible structural and functional ramifications of these GSK-3 nsSNPs, revealing how protein compactness, stiffness, and interactions may affect biological activities.

Selective ADA2 inhibition for enhancing anti-tumor immune response in glioma: Insights from computational screening of flavonoid compounds.

Brain tumors, particularly gliomas, remain difficult to treat due to their complex and dynamic microenvironment and high mortality rate. The presence of tumor-associated macrophages (TAMs) is considered one of the primary factors contributing to a poor prognosis in Glioma. Previous reports have linked elevated levels of Adenosine deaminase 2 (ADA2) with immunosuppression, tumor progression, and angiogenesis via MAPK, PDGFß signaling pathway in the glioma microenvironment. In contrast, Adenosine deaminase 1 (ADA1), another type of adenosine deaminase, plays a pivotal role in purine metabolism, which is essential for lymphocyte survival. Hence, selectively targeting ADA2 while preserving ADA1 activity could offer a viable approach for regulating macrophage polarization and enhancing the anti-tumor immune response. In pursuit of this objective, our study employed a computational approach, unveiling the remarkable attributes of Daidzin, characterized by its exceptional specificity, and binding affinity towards ADA2 while displaying minimal affinity towards ADA1. Furthermore, Define Secondary Structure of Proteins (DSSP) analysis revealed that Daidzin elicits conspicuous conformational alterations within the dimerization domain of the ADA2 receptor, which could have a crucial impact on its activity. However, the ADA1 structure remained unaltered. Our study offers the potential use of Daidzin as a specific therapeutic agent for modulating the tumor microenvironment and revolutionizing glioma management.

Capra cartilage-derived peptide delivery via carbon nano-dots for cartilage regeneration.

Targeted delivery of site-specific therapeutic agents is an effective strategy for osteoarthritis treatment. The lack of blood vessels in cartilage makes it difficult to deliver therapeutic agents like peptides to the defect area. Therefore, nucleus-targeting zwitterionic carbon nano-dots (CDs) have immense potential as a delivery vehicle for effective peptide delivery to the cytoplasm as well as nucleus. In the present study, nucleus-targeting zwitterionic CDs have been synthesized as delivery vehicle for peptides while also working as nano-agents towards optical monitoring of cartilage healing. The functional groups of zwitterion CDs were introduced by a single-step microwave assisted oxidation procedure followed by COL II peptide conjugation derived from Capra auricular cartilage through NHS/EDC coupling. The peptide-conjugated CDs (PCDs) allows cytoplasmic uptake within a short period of time (∼30 m) followed by translocation to nucleus after ∼24 h. Moreover, multicolor fluorescence of PCDs improves (blue, green, and read channel) its sensitivity as an optical code providing a compelling solution towards enhanced non-invasive tracking system with multifunctional properties. The PCDs-based delivery system developed in this study has exhibited superior ability to induce ex-vivo chondrogenic differentiation of ADMSCs as compared to bare CDs. For assessment of cartilage regeneration potential, pluronic F-127 based PCDs hydrogel was injected to rabbit auricular cartilage defects and potential healing was observed after 60 days. Therefore, the results confirm that PCDs could be an ideal alternate for multimodal therapeutic agents.

Temporal Release of Cell Cycle Regulator α-Lipoic Acid: An NIR-Light (Two-Photon) Activatable Quinoxaline-Based Nano-Prodrug Delivery System.

The regulation of the cell cycle has recently opened up a new research perspective for cancer treatment. So far, no effort has been made for temporal control of cell cycles using a photocleavable linker. Presented herein is the first report of regulation of disrupted cell cycles through the temporal release of a well-known cell cycle regulator α-lipoic acid (ALA), enabled by a newly designed NIR-active quinoxaline-based photoremovable protecting group (PRPG). The suitable quinoxaline-based photocage of ALA (tetraphenylethelene conjugated) has been formulated as fluorescent organic nanoparticles (FONs) and used effectively as a nano-DDS (drug delivery system) for better solubility and cellular internalization. Fascinatingly, the enhanced TP (two-photon) absorption cross section of the nano-DDS (503 GM) signifies its utility for biological applications. Using green light, we have successfully controlled the time span of cell cycles and cell growth of skin melanoma cell lines (B16F10) by the temporal release of ALA. Further, in silico studies and PDH activity assay supported the observed regulatory behavior of our nano-DDS with respect to photoirradiation. Overall, this approach expands the research path toward a futuristic photocontrolled toolbox for cell cycle regulation.

Beyond traditional therapy: Mucoadhesive polymers as a new frontier in oral cancer management.

In recent times mucoadhesive drug delivery systems are gaining popularity in oral cancer. It is a malignancy with high global prevalence. Despite significant advances in cancer therapeutics, improving the prognosis of late-stage oral cancer remains challenging. Targeted therapy using mucoadhesive polymers can improve oral cancer patients' overall outcome by offering enhanced oral mucosa bioavailability, better drug distribution and tissue targeting, and minimizing systemic side effects. Mucoadhesive polymers can also be delivered via different formulations such as tablets, films, patches, gels, and nanoparticles. These polymers can deliver an array of medicines, making them an adaptable drug delivery approach. Drug delivery techniques based on these mucoadhesive polymers are gaining traction and have immense potential as a prospective treatment for late-stage oral cancer. This review examines leading research in mucoadhesive polymers and discusses their potential applications in treating oral cancer.

Magnolol and Temozolomide exhibit a synergistic anti-glioma activity through MGMT inhibition.

Temozolomide (TMZ) is the leading chemotherapeutic agent used for glioma therapy due to its good oral absorption and blood-brain barrier permeability. However, its anti-glioma efficacy may be limited due to its adverse effects and resistance development. O6-Methylguanine-DNA-methyltransferase (MGMT), an enzyme associated with TMZ resistance, is activated via the NF-κB pathway, which is found to be upregulated in glioma. TMZ also upregulates NF-κB signaling like many other alkylating agents. Magnolol (MGN), a natural anti-cancer agent, has been reported to inhibit NF-κB signaling in multiple myeloma, cholangiocarcinoma, and hepatocellular carcinoma. MGN has already shown promising results in anti-glioma therapy. However, the synergistic action of TMZ and MGN has not been explored. Therefore, we investigated the effect of TMZ and MGN treatment in glioma and observed their synergistic pro-apoptotic action in both in vitro and in vivo glioma models. To explore the mechanism of this synergistic action, we found that MGN inhibits MGMT enzyme both in vitro and in vivo glioma. Next, we established the link between NF-κB signaling and MGN-induced MGMT inhibition in glioma. MGN inhibits the phosphorylation of p65, a subunit of NF-κB, and its nuclear translocation to block NF-κB pathway activation in glioma. MGN-induced NF-κB inhibition results in the transcriptional inhibition of MGMT in glioma. TMZ and MGN combinatorial treatment also impedes p65 nuclear translocation to inhibit MGMT in glioma. We observed a similar effect of TMZ and MGN treatment in the rodent glioma model. Thus, we concluded that MGN potentiates TMZ-induced apoptosis in glioma by inhibiting NF-κB pathway-mediated MGMT activation.

A self-healable metallohydrogel for drug encapsulations and drug release.

A self-healable metallohydrogel (MOG) of Mn(ii) has been prepared using a low molecular weight gelator, Na2HL {H3L = l-(3,5-di-tert-butyl-2-hydroxy-benzyl)amino aspartic acid}. The MOG has been characterized by MALDI TOF mass spectrometry, rheological studies, IR spectroscopy, and microscopic techniques. Non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) and anti-cancer drug gemcitabine (GEM) were encapsulated into the metallohydrogel. The GEM-loaded metallogel (MOG_GEM) shows better delivery and more adverse cytotoxicity than the drug against breast cancer cell lines MDA-MB-468 and 4T1. The anti-cancer property was evaluated with in vitro MTT cytotoxic assay, live-dead assay and cell migration assay. In vitro cytotoxicity assay against RAW 264.7 cell line with the treatment of MOG_IND shows the improved anti-inflammatory response in the case of MOG_IND compared to the drug alone.

A novel computational predictive biological approach distinguishes Integrin ß1 as a salient biomarker for breast cancer chemoresistance.

Chemoresistance is a primary cause of breast cancer treatment failure, and protein-protein interactions significantly contribute to chemoresistance during different stages of breast cancer progression. In pursuit of novel biomarkers and relevant protein-protein interactions occurring during the emergence of breast cancer chemoresistance, we used a computational predictive biological (CPB) approach. CPB identified associations of adhesion molecules with proteins connected with different breast cancer proteins associated with chemoresistance. This approach identified an association of Integrin ß1 (ITGB1) with chemoresistance and breast cancer stem cell markers. ITGB1 activated the Focal Adhesion Kinase (FAK) pathway promoting invasion, migration, and chemoresistance in breast cancer by upregulating Erk phosphorylation. FAK also activated Wnt/Sox2 signaling, which enhanced self-renewal in breast cancer. Activation of the FAK pathway by ITGB1 represents a novel mechanism linked to breast cancer chemoresistance, which may lead to novel therapies capable of blocking breast cancer progression by intervening in ITGB1-regulated signaling pathways.

Surfactin-like lipopeptides from Bacillus clausii efficiently bind to spike glycoprotein of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) rapidly spread across the globe, infecting millions and causing hundreds of deaths. It has been now around three years but still, it remained a serious threat worldwide, even after the availability of some vaccines. Bio-surfactants are known to have antiviral activities and might be a potential alternative for the treatment of SARS-CoV-2 infection. In the present study, we have isolated and purified, a surfactin-like lipopeptide produced by a probiotic bacterial strain Bacillus clausii TS. Upon purification and characterization with MALDI analysis, the molecular weight of the lipopeptide is confirmed as 1037 Da (similar to surfactin C) which is known to have antiviral activities against various enveloped viruses. Purified surfactin-like lipopeptide showed efficient binding and inhibition of SARS-CoV-2 spike (S1) protein, revealed by competitive ELISA assay. Further, we have explored the complete thermodynamics of the inhibitory binding of surfactin-like lipopeptide with S1 protein using isothermal titration calorimetric (ITC) assay. ITC results are in agreement with ELISA with a binding constant of 1.78 × 10-4 M-1. For further validation of the inhibitory binding of surfactin-like lipopeptide with S1 protein and its receptor binding domain (RBD), we performed molecular docking, dynamics, and simulation experiments. Our results suggested that surfactin could be a promising drug agent for the spike protein targeting drug development strategy against SARS-CoV-2 and other emerging variants.Communicated by Ramaswamy H. Sarma.

Magnolol induces cytotoxic autophagy in glioma by inhibiting PI3K/AKT/mTOR signaling.

Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management.

A two-photon responsive hydroxyphenylquinazolinone (HPQ)-based fluorescent organic nanoprodrug for H2S release against oxidative stress.

Light-activated H2S donors have attracted considerable interest in understanding the physiological role and clinical potential of H2S, as their release is highly localized and controlled. Herein, we have evolved a new HPQ chromophore-based fluorescent organic nanosystem localized in a target area that tolerates oxidative stress and precisely releases H2S under one- and two-photon irradiation with real-time monitoring capability. The two-photon absorption cross-section of this new phototrigger was calculated to be 283 GM at 720 nm. H2S photorelease was also demonstrated in vitro on the MDA-MB-468 cell line in the presence of excess ROS. Our developed H2S nanoprodrug can be applied to living systems to release the H2S-gasotransmitter under laser irradiation in a phototherapeutic window.