siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression.

BACKGROUND: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets. METHODS: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells. Clinical relevance of the key genes was determined using Kaplan-Meier survival analyses on The Cancer Genome Atlas dataset of breast cancer patients. Gene overexpression/knockdown, spheroid formation, flow cytometric analysis, chromatin immunoprecipitation, immunocytochemistry, wound healing/transwell migration assays, and cancer stem cell transcription factor activation profiling array were used to elucidate the regulatory mechanism of integrin α11 expression. Tumour-bearing xenograft models were used to demonstrate integrin α11 is a potential therapeutic target. RESULTS: Integrin α11 was consistently upregulated in drug-resistant breast cancer cells, and its silencing inhibited cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) while restoring sensitivity to anticancer drugs. HIF1α, GLI-1, and EZH2 contributed the most to the regulation of integrin α11 and EZH2 expression, with EZH2 being more necessary for EZH2 autoinduction than HIF1α and GLI-1. Additionally, unlike HIF1α or EZH2, GLI-1 was the sole transcription factor activated by integrin-linked focal adhesion kinase, indicating GLI-1 as a key driver of the EZH2-integrin α11 axis operating for cancer stem cell survival and EMT. Kaplan-Meier survival analysis using The Cancer Genome Atlas (TCGA) dataset also revealed both EZH2 and integrin α11 could be strong prognostic factors of relapse-free and overall survival in breast cancer patients. However, the superior efficacy of integrin α11 siRNA therapy over EZH2 siRNA treatment was demonstrated by enhanced inhibition of tumour growth and prolonged survival in murine models bearing tumours. CONCLUSION: Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.

Surface termination and strain-induced modulation of the structure and electronic properties in 2D perovskites (Cs2BCl4 & CsB2Cl5, B = Pb, Sn): a first-principles study.

Two-dimensional (2D) halide perovskites have demonstrated impressive long-term stability and superior device performance as compared to their three-dimensional (3D) counterparts. The potential of 2D halide perovskites for advanced photovoltaic applications can be enhanced by an understanding of how external factors like strain could be used to tune their optoelectronic properties. This study explores the effects of biaxial strain on the structure and electronic transport properties of 2D halide perovskites, focusing on the lowest energy (001) surfaces of (Cs2BCl4 and CsB2Cl5, B = Pb or Sn) with CsCl and BCl2 terminations. Using first-principles calculations, we find that the lower energy CsCl terminated surface, resulting in Cs2BCl4, couples strongly with biaxial strain. This termination shows bandgap modulations from approximately 1.5 eV to 1.8 eV for Cs2PbCl4 and 1.2 eV to 1.5 eV for Cs2SnCl4 with biaxial strain. Within the acoustic deformation potential theory, we compute hole mobilities, and find substantial enhancements of approximately 80% for Pb-based and 50% for Sn-based systems, thereby emphasizing the potential of strain engineering to further optimize charge transport properties in 2D halide perovskites.

Recent patent-based review on the role of three-dimensional printing technology in pharmaceutical and biomedical applications.

Three-dimensional printing (3DP) is emerging as an innovative manufacturing technology for biomedical and pharmaceutical applications, since the US FDA approval of Spritam as a 3D-printed drug. In the present review, we have highlighted the potential benefits of 3DP technology in healthcare, such as the ability to create patient-specific medical devices and implants, as well as the possibility of on-demand production of drugs and personalized dosage forms. We have further discussed future research to optimize 3DP processes and materials for pharmaceutical and biomedical applications. Cohesively, we have put forward the current state of active patents and applications related to 3DP technology in the healthcare and pharmaceutical industries including hearing aids, prostheses, medical devices and drug-delivery systems.

Patent landscape highlighting therapeutic implications of peptides targeting myristoylated alanine-rich protein kinase-C substrate (MARCKS).

INTRODUCTION: MARCKS protein, a protein kinase C (PKC) substrate, is known to be at the intersection of several intracellular signaling pathways and plays a pivotal role in cellular physiology. Unlike PKC inhibitors, MARCKS-targeting drug (BIO-11006) has shown early success in clinical trials involving lung diseases. Recent research investigations have identified two MARCKS-targeting peptides which possess multifaceted implications against asthma, cancer, inflammation, and lung diseases. AREAS COVERED: This review article provides the patent landscape and recent developments on peptides targeting MARCKS for therapeutic purposes. Online free open-access databases were used to fetch out the patent information, and research articles were fetched using PubMed. EXPERT OPINION: Research studies highlighting the intriguing role of MARCKS in human disease and physiology have dramatically increased in recent years. A similar increasing trend in the number of patents has also been observed related to the MARCKS-targeting peptides. Thus, there is a need to amalgamate and translate such a trend into therapeutic intervention. Our review article provides an overview of such recent advances, and we believe that our compilation will fetch the interest of researchers around the globe to develop MARCKS-targeting peptides in future for human diseases.

Nanotheranostics: The Fabrication of Theranostics with Nanoparticles and their Application to Treat the Neurological Disorders.

BACKGROUND: Theranostics is a method that focuses on providing patient-centred care and is evolving as a targeted, safe, and effective pharmacotherapy. Nanotheranostics combines diagnosis and therapeutic modalities that bridge traditional treatment and personalised medicine. Theranostics provides novel ideas for nanotechnology. This review describes the current state of nanotechnology-based therapies used to treat neurological illnesses. Some patents on theranostics are also discussed in this review. OBJECTIVE: This study aims to provide a more comprehensive review of the diagnosis and therapeutic properties of nanotheranostics, the present state of nanotechnology-based treatment of neurological disorders, and the future potential of theranostics. METHOD: The phrase "theranostics" refers to a treatment strategy that integrates therapeutics and diagnostics to monitor treatment response and enhance drug efficacy and safety. Theranostics is a crucial component of personalised medicine and calls for significant advancements in predictive medicine. The term "theranostics" refers to a diagnosis that screens patients for potential adverse drug reactions and targets drug delivery depending on the test results. Theranostics treats neurological disorders (like brain tumours (glioma), Parkinson's disease, Alzheimer's disease, and neurovascular diseases). Many review articles on Google Scholar, PubMed, Google Patents, and Scopus were used to gather information for this review. Data acquired from many sources was compiled in this review to provide more information on theranostics. RESULT: The role of various nanocarrier systems as theranostic agents for neurological illnesses and the fabrication of nanomaterials for theranostics are discussed in this article after evaluating a substantial number of review articles. CONCLUSION: The distinctive intrinsic features of nanoparticles make them useful for functionalization and imaging. Theranostics in nuclear medicine include diagnostic imaging and therapy using the same molecule that is radiolabeled differently or the same medication at various doses. It is possible to determine if a patient will benefit from a given treatment by visualising potential targets. Targeted nuclear therapy has been shown to be beneficial in patients if chosen carefully and has a good safety profile.

Aluminene as a Low-Cost Anode Material for Li- and Na-Ion Batteries.

Two-dimensional (2D) materials are promising candidates for next-generation battery technologies owing to their high surface area, excellent electrical conductivity, and lower diffusion energy barriers. In this work, we use first-principles density functional theory to explore the potential for using a 2D honeycomb lattice of aluminum, referred to as aluminene, as an anode material for metal-ion batteries. The metallic monolayer shows strong adsorption for a range of metal atoms, i.e., Li, Na, K, and Ca. We observe surface diffusion barriers as low as 0.03 eV, which correlate with the size of the adatom. The relatively low average open-circuit voltages of 0.27 V for Li and 0.42 V for Na are beneficial to the overall voltage of the cell. The estimated theoretical specific capacity has been found to be 994 mA h/g for Li and 870 mA h/g for Na. Our research highlights the promise of aluminene sheets in the development of low-cost, high-capacity, and lightweight advanced rechargeable ion batteries.

Hydrogen adsorption and diffusion through a two dimensional sheet of lithium: a first principles study.

Two-dimensional (2D) materials have shown promise as highly selective, ultrathin membranes to transport ions, and atomic and subatomic particles. They have also been regarded as potential hydrogen storage candidates due to their chemical stability and high specific surface area. However, most of these studies have been carried out with semiconducting 2D materials. With recent explorations towards the existence and stability of 2D metals, we explore the hydrogen adsorption and diffusion through a 2D metallic sheet of lithium. We report that in the lowest energy metallic configuration, the sheet is predicted to crystallize in a highly buckled honeycomb structure. We calculate the adsorption energy for the diffusion of hydrogen on various high symmetry sites in the lattice, and find that adsorption is energetically favoured. We study the minimum energy pathways for diffusion through the sheet and find that the lowest energy barriers exist for tunneling through the honeycomb ring. Our results would be of direct technological relevance to the applications of 2D metallic nanostructures as membranes for selective transport or towards storage.

Postnatal ontogeny of Neuromedin S and its receptors NMUR1 and NMUR2 expression in mouse testis.

Neuromedin S (NMS) is a well-known anorexigenic neuropeptide. Despite some reports of the presence of its transcript and precursor protein in testis, the expression and localization of NMS and its receptors during the postnatal development of mammalian testis remains elusive. We investigated the expression patterns and testicular localization of NMS and its receptors NMUR1 and NMUR2, during 5, 10, 20, 30, and 90 days of postnatal development, using real time PCR, immunoblot analysis and immunohistochemistry in mice. NMS and its receptors are present at all age groups at transcript level in mouse testis. At the protein level, NMS and NMUR2 are present in all age groups, whereas NMUR1 is present primarily in 30- and 90-day testis. Immunolocalization study showed that NMS and NMUR2 are expressed in spermatogonia, spermatocytes, Sertoli cells, and Leydig cells, in contrast to NMUR1 which is expressed exclusively in the Leydig cells of 30- and 90-day testis. The results also confirm the intranuclear localization of NMS in spermatogonia and spermatocytes. Although NMS-NMUR2 is expressed in Sertoli cells at all stages of the spermatogenic cycle, they showed a stage-specific expression pattern in spermatogonia and primary spermatocytes. In conclusion, NMS and its receptors NMUR1 and NMUR2 are expressed in the testis and may regulate spermatogenesis, possibly by modulating steroidogenesis and Sertoli cell function in the testis.

Theoretical exploration on structures, bonding aspects and molecular docking of α-aminophosphonate ligated copper complexes against SARS-CoV-2 proteases.

Recent years have witnessed a growing interest in the biological activity of metal complexes of α-aminophosphonates. Here for the first time, a detailed DFT study on five α-aminophosphonate ligated mononuclear/dinuclear CuII complexes is reported using the dispersion corrected density functional (B3LYP-D2) method. The electronic structures spin densities, FMO analysis, energetic description of spin states, and theoretical reactivity behaviour using molecular electrostatic potential (MEP) maps of all five species are reported. All possible spin states of the dinuclear species were computed and their ground state S values were determined along with the computation of their magnetic coupling constants. NBO analysis was also performed to provide details on stabilization energies. A molecular docking study was performed for the five complexes against two SARS-CoV-2 coronavirus protein targets (PDB ID: 6LU7 and 7T9K). The docking results indicated that the mononuclear species had a higher binding affinity for the targets compared to the dinuclear species. Among the species investigated, species I showed the highest binding affinity with the SARS-CoV-2 Omicron protease. NPA charge analysis showed that the heteroatoms of model species III had a more nucleophilic nature. A comparative study was performed to observe any variations and/or correlations in properties among all species.

Sub-chronic restraint stress exposure in adult rats: An insight into possible inhibitory mechanism on testicular function in relation to germ cell dynamics.

Psychological stress is now widely recognized as one of the major risk factors for male fertility. Its impact on the dynamics of testicular germ cells, however, has yet to be fully investigated. Therefore, we used the rat restraint stress (RS) model as a psychological stressor to assess the impact of psychological stress on testicular germ cell dynamics. Adult male SD rats were exposed to sub-chronic RS for 1.5 and 3 h per day for 30 days. The quality of cauda epididymis spermatozoa was adversely affected by RS exposure, and the frequency of spermatozoa with tail abnormalities was higher than that of spermatozoa with head abnormalities. RS exposure adversely affected testicular daily sperm production by disturbing the meiotic and post meiotic germ cell kinetics in the testis. The histomorphology of the testis was altered by loosening and vacuolization in the seminiferous epithelium, germ cell exfoliation and the presence of giant cells. Seminiferous tubules of stage I-VI and VII-VIII were severely affected in rats exposed to RS for 3 h. By interfering with steroidogenic enzymes, RS exposure disrupts testosterone biosynthesis. The testicular oxidative balance was also disturbed by RS exposure, which disrupted the levels/activities of lipid peroxidation, Nrf-2, superoxide dismutase and catalase. There was also an increase in caspase-3 activity and a decrease in the Bax-Bcl2 ratio. In conclusion, our findings suggest that psychological stressors like RS impair testicular functions in rats by disrupting germ cell dynamics, downregulating testicular androgenesis and increasing oxidative stress and apoptosis.

Intermittent feedback induces attractor selection.

We present a method for attractor selection in multistable dynamical systems. It involves a feedback term that is active only when the dynamics of the system is in a particular fraction of state space of the attractor. We implement this method first on a simplest symmetric chaotic flow and then on a bistable neuronal system. We find that adding this space-dependent feedback term to the dynamical equations of these systems will drive the dynamics to the desired attractor by annihilating the other. We further demonstrate that the attractor selection due to this feedback term can be used in construction of logic gates, which is one of the practical applications of the proposed method.

Serum ßhCG and Lipid Profile in Early Second Trimester as Predictors of Pregnancy-Induced Hypertension.

OBJECTIVES: A variety of biological, biochemical, and biophysical markers implicated in the pathophysiology of pre-eclampsia during the last two decades have instigated the growing interest in this study to include both ßhCG and lipid profile studies in the early second trimester as early predictors of pregnancy-induced hypertension. Early identification of at-risk women may help in taking timely preventive and curative management to prevent or delay complications associated with pregnancy-induced hypertension. METHOD: A prospective study was performed on 120 patients attending the outpatient department of the Obstetrics and Gynaecology of the Maharaja Agrasen Hospital. All the patients were screened for serum ßhCG and serum lipid profile in their early second trimester (14-20 weeks) and followed up till their delivery. Comparative studies of serum ßhCG and serum lipid profile were performed between those who remain normotensive (group I) and those who developed pregnancy-induced hypertension (group II). RESULTS: TG, total cholesterol, VLDL, and LDL values for those women who developed PIH (group II) were significantly higher than those who remain normotensive (group I), with p value of <0.05 which is statistically significant. HDL and ßhCG values for group II were not higher than those in group I with p value >0.05 which is statistically insignificant. CONCLUSION: Maternal lipid profile in second trimester is very good noninvasive test which can be used for prediction of pregnancy-induced hypertension before its clinical onset. However, there is no correlation between maternal serum ßhCG and pregnancy-induced hypertension.

Evaluation of hydrophilic, hydrophobic and waxy matrix excipients for sustained release tablets of venlafaxine hydrochloride.

OBJECTIVE: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets. MATERIALS AND METHODS: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism. RESULTS: Dissolution data showed that commercial formulations Venlor XR(®) and Venfax PR(®) released the entire drug withIn 8 h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14-15 h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively. CONCLUSION: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.

Comparative evaluation of isosorbide mononitrate and alendronate in management of postmenopausal osteoporosis.

BACKGROUND: Osteoporosis, a skeletal disorder that adversely affects bone strength , is common among postmenopausal women primarily due to reduced ovarian estrogens. PURPOSE: The present study was taken up to evaluate the role of isosorbide mononitrate (IMN) in the management of postmenopausal osteoporosis and to compare its efficacy with that of alendronate. METHODS: This prospective systematic randomized study was conducted on 90 postmenopausal women with lumbar spine BMD >2.5 SD below the young adult reference range. The participants received either Tab Alendronate 70 mg orally, once weekly (Group I) or Tab IMN 40 mg orally once daily (Group II) for 9 months, in addition to 500 mg of oral calcium daily. The BMD of the lumbar spine was measured using DEXA scan at enrolment and after 9 months. The data was analyzed by Student's t test and Chi-square test. RESULTS: The mean baseline BMD was 0.67 + 0.097 and 0.68 + 0.067 g/cm(2) in Group I and II, respectively. An increase of 11.94% in the mean BMD was noted after 9 months of treatment with alendronate as against 8.82% with IMN. Headache, flushing and palpitations in Group II and nausea, epigastric pain and heart burn in Group I were the most common adverse effects. CONCLUSION: IMN has a beneficial effect on bone turnover in cases of postmenopausal osteoporosis and that the effect is comparable to that of alendronate. IMN is a promising and safe alternative to alendronate for the management of postmenopausal osteoporosis.