Inhalable chitosan-coated nano-assemblies potentiate niclosamide for targeted abrogation of non-small-cell lung cancer through dual modulation of autophagy and apoptosis.

Lung carcinoma, particularly non-small-cell lung cancer (NSCLC), accounts for a significant portion of cancer-related deaths, with a fatality rate of approximately 19 %. Niclosamide (NIC), originally an anthelmintic drug, has attracted attention for its potential in disrupting cancer cells through various intracellular signaling pathways. However, its effectiveness is hampered by limited solubility, reducing its bioavailability. This study investigates the efficacy of NIC against lung cancer using inhalable hybrid nano-assemblies with chitosan-functionalized Poly (ε-caprolactone) (PCL) as a carrier for pulmonary delivery. The evaluation encompasses various aspects such as aerodynamic and physicochemical properties, drug release kinetics, cellular uptake, biocompatibility, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Increasing NIC dosage correlates with enhanced inhibition of cell proliferation, showing a dose-dependent profile (approximately 75 % inhibition efficiency at 20 µg/ml of NIC). Optimization of inhaled dosage and efficacy is conducted in a murine model of NNK-induced tumor-bearing lung cancer. Following inhalation, NIC-CS-PCL-NA demonstrates significant lung deposition, retention, and metabolic stability. Inhalable nano-assemblies promote autophagy flux and induce apoptotic cell death. Preclinical trials reveal substantial tumor regression with minimal adverse effects, underscoring the potential of inhalable NIC-based nano-formulation as a potent therapeutic approach for NSCLC, offering effective tumor targeting and killing capabilities.

Targeted delivery of the metastasis-specific tumour homing TMTP1 peptide to non-small-cell lung cancer (NSCLC) using inhalable hybrid nano-assemblies.

Lung cancer is one of the most fatal malignancies, with the highest death rate (∼19%), and the NSCLC type accounts for ∼85% of lung cancers. In the search for new treatments, antimicrobial peptides have received much attention due to their propensity for selective destruction of cancer cells. In the current study, we evaluated the efficacy of the metastasis-specific tumour-homing-TMTP1 peptide against lung cancer using inhalable hybrid nano-assemblies of the PEG-PLGA copolymer as a carrier for pulmonary delivery which was assessed for aerodynamic and physicochemical properties, along with the peptide-release profile, physical stability, cellular uptake and biocompatibility, generation of reactive oxygen species, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Optimization of inhaled dose, lung retention, and efficacy studies was conducted to evaluate the formulation in an NNK (nicotine-derived nitrosamine ketone) induced tumour-bearing lung cancer murine model. After inhalation, the formulation with nano-scale physiognomies showed good lung deposition, retention, and metabolic stability. The inhalable nano-assemblies have shown enhanced generation of reactive oxygen species with increased autophagy flux and apoptotic cell death. Pre-clinical animal trials show substantial tumour regression by inhalable TMTP1-based nano-formulation with limited side effects. Our results on metastasis targeting and tumour-homing peptide TMTP1 demonstrate its effective tumour targeting and tumour-killing efficacy and provide a reference for the development of new therapeutics for NSCLC.

Strategic Developments in Polymer-Functionalized Liposomes for Targeted Colon Cancer Therapy: An Updated Review of Clinical Trial Data and Future Horizons.

Liposomes, made up of phospholipid bilayers, are efficient nanocarriers for drug delivery because they can encapsulate both hydrophilic and lipophilic drugs. Conventional cancer treatments sometimes involve considerable toxicities and adverse drug reactions (ADRs), which limits their clinical value. Despite liposomes' promise in addressing these concerns, clinical trials have revealed significant limitations, including stability, targeted distribution, and scaling challenges. Recent clinical trials have focused on enhancing liposome formulations to increase therapeutic efficacy while minimizing negative effects. Notably, the approval of liposomal medications like Doxil demonstrates their potential in cancer treatment. However, the intricacy of liposome preparation and the requirement for comprehensive regulatory approval remain substantial impediments. Current clinical trial updates show continued efforts to improve liposome stability, targeting mechanisms, and payload capacity in order to address these issues. The future of liposomal drug delivery in cancer therapy depends on addressing these challenges in order to provide patients with more effective and safer treatment alternatives.

Quality by Design in Pulmonary Drug Delivery: A Review on Dry Powder Inhaler Development, Nanotherapy Approaches, and Regulatory Considerations.

Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Susceptibility of clinical isolates of novel pathogen Stenotrophomonas sepilia to novel benzoquinolizine fluoroquinolone levonadifloxacin.

Background: Stenotrophomonas sepilia, identified in 2021, is part of the Stenotrophomonas maltophilia complex (Smc) and shares high genomic identity with S. maltophilia. Resistance to levofloxacin, the recommended fluoroquinolone for S. maltophilia, is being increasingly reported. Recent studies indicate that levonadifloxacin, a novel benzoquinolizine, may be more effective. This study evaluates the antimicrobial efficacy of levofloxacin and levonadifloxacin against clinical isolates of S. sepilia. Objectives: To assess the antibacterial effectiveness of levofloxacin and levonadifloxacin against novel pathogen S. sepilia. Methods: A total of 116 S. maltophilia isolates, identified by MALDI-TOF MS, were collected from five centres across India. S. sepilia was confirmed by PCR using primers targeting a unique genomic sequence (NCBI accession number LXXZ00000000.1). Minimum inhibitory concentrations (MICs) of levonadifloxacin and levofloxacin were determined by using the microbroth-dilution method and Etest as per CLSI guidelines. The levofloxacin breakpoint was used to interpret MICs of levonadifloxacin. Results: Among a total of 116 circulating S. maltophilia isolates collected, 46 were identified as S. sepilia, representing a prevalence rate of (∼40%), thus highlighting its significance as an important pathogen within the Smc. Both levofloxacin and levonadifloxacin demonstrated a 98% inhibition rate against the 46 S. sepilia tested. Only one S. sepilia isolate resistant to levofloxacin showed intermediate susceptibility to levonadifloxacin, which consistently had lower MICs. Conclusions: Levofloxacin and levonadifloxacin show similar susceptibility rates against S. sepilia, with levonadifloxacin exhibiting lower MICs. Further studies are required to establish clinical utility of levonadifloxacin in managing these infections.

Effective cerebral tuberculosis treatment via nose-to-brain transport of anti-TB drugs using mucoadhesive nano-aggregates.

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Anomalies in the Dirac bands in the proximity of correlated electrons.

Dirac fermions, particles with zero rest mass, are observed in topological materials and are believed to play a key role in the exotic phenomena in fundamental science and the advancement of quantum technology. Most of the topological systems studied so far are weakly correlated systems and the study of their properties in the presence of electron correlation is an interesting emerging area of research, where the electron correlation is expected to enhance the effective mass of the particles. Here, we studied the properties of Dirac bands in a non-symmorphic layered Kondo lattice system, CeAgSb2, employing high-resolution angle-resolved photoemission spectroscopy and first-principles calculations. In addition to the Dirac cones due to non-symmorphic symmetry, this material hosts Dirac fermions in the squarenet layer in the proximity of a strongly correlated Ce layer exhibiting Kondo behavior. Experimental results reveal crossings of the highly dispersive linear bands at the Brillouin zone boundary due to non-symmorphic symmetry. In addition, there are anisotropic Dirac cones constituted by the squarenet Sb 5p states forming a diamond-shaped nodal line. These Dirac bands are linear in a wide energy range with an unusually high slope. Interestingly, near the local Ce 4f bands, these bands exhibit a change in the slope akin to the formation of a 'kink' observed in other materials due to electron-phonon coupling. The emergence of such exotic properties in proximity to strongly correlated electronic states has significant implications in the study of complex quantum materials including unconventional superconductors.

Healthcare Utilization and Costs in Children Receiving Home Mechanical Ventilation in Ontario: A 14-Year Cohort Study.

RATIONALE: Home mechanical ventilation (HMV) is an advanced medical therapy offered to children with medical complexity. Despite the growing pediatric HMV population in North America, there are limited studies describing healthcare utilization and predictors of highest costs using robust health administrative data. OBJECTIVES: To describe patterns of healthcare utilization and costs in children receiving HMV over a 14-year period in Ontario, Canada. METHODS: We conducted a retrospective population-based cohort study (April 1, 2003 to March 31, 2017) of children aged 0-18 years receiving HMV via invasive mechanical ventilation (IMV) or non-invasive ventilation (NIV). Paired t-tests compared healthcare system utilization and costs two years before and two years after HMV approval. We developed linear models to analyze variables associated with children in the top quartile of health service utilization and costs. RESULTS: We identified 835 children receiving HMV. In the two years after HMV approval compared to the 2 years prior, children had decreased hospitalization days (median 9 (IQR 3-30) versus 29 (6-99), p<0.0001) and ICU admission days (6.6 (1.9-18.0) versus 17.1 (3.3-70.9), p<0.0001) but had increased homecare service approvals (195 (24-522) versus 40 (12-225), p<0.0001) and outpatient Pulmonology visits (3 (1-4) versus 2 (1-3), p<0.0001). Total healthcare costs were higher in the two years after HMV approval (mean $164,892 (SD $214,187) versus $128,941 ($194,199), p<0.0001). However, all-cause hospital admission costs were reduced ($66,546 ($142,401) versus $81,578 ($164,672), p<0.0001). Highest total 2-year costs were associated with IMV (OR 3.45, 95% CI 2.24-5.31; reference NIV), number of medical devices at home (OR 1.63, 95% CI 1.35-1.96; reference no technology), and increased healthcare costs in the year prior to HMV initiation (OR 2.23, 95% CI 1.84-2.69). CONCLUSIONS: Children progressing to the need for HMV represent a worsening in their respiratory status that will undoubtedly increase healthcare utilization and costs. We found that the initiation of HMV in these children can reduce inpatient healthcare utilization and costs but can still increase overall healthcare expenditures, especially in the outpatient setting.

Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease.

Changes in the transition metal homeostasis in the brain are closely linked with Alzheimer's disease (AD), including intraneuronal iron accumulation and extracellular copper and zinc pooling in the amyloid plague. The brain copper, zinc, and iron surplus are commonly acknowledged characteristics of AD, despite disagreements among some. This has led to the theory that oxidative stress resulting from abnormal homeostasis of these transition metals may be a causative explanation behind AD. In the nervous system, the interaction of metals with proteins appears to be an essential variable in the development or suppression of neurodegeneration. Chelation treatment may be an option for treating neurodegeneration induced by transition metal ion dyshomeostasis. Some clinicians even recommend using chelating agents as an adjunct therapy for AD. The current review also looks at the therapeutic strategies that have been attempted, primarily with metal-chelating drugs. Metal buildup in the nervous system, as reported in the AD, could be the result of compensatory mechanisms designed to improve metal availability for physiological functions.

A polylactic acid-carbon nanofiber-based electro-conductive sensing material and paper-based colorimetric sensor for detection of nitrates.

Plastics are ubiquitous in today's lifestyle, and their indiscriminate use has led to the accumulation of plastic waste in landfills and oceans. The waste accumulates and breaks into micro-particles that enter the food chain, causing severe threats to human health, wildlife, and the ecosystem. Environment-friendly and bio-based degradable materials offer a sustainable alternative to the vastly used synthetic materials. Here, a polylactic acid and carbon nanofiber-based membrane and a paper-based colorimetric sensor have been developed. The membrane had a surface area of 3.02 m2 g-1 and a pore size of 18.77 nm. The pores were evenly distributed with a pore volume of 0.0137 cm3 g-1. The membrane was evaluated in accordance with OECD guidelines and was found to be safe for tested aquatic and terrestrial models. The activated PLA-CNF membrane was further used as a bio-based electrode for the electrochemical detection of nitrates (NO3-) in water samples with a detection limit of 0.046 ppm and sensitivity of 1.69 × 10-4 A ppm-1 mm-2, whereas the developed paper-based colorimetric sensor had a detection limit of 156 ppm for NO3-. This study presents an environment-friendly, low-carbon footprint disposable material for sensing applications as a sustainable alternative to plastics.

Biogenic synthesis of CuO/ZnO nanocomposite from Bauhinia variegate flower extract for highly sensitive electrochemical detection of vitamin B2.

In this study, we report the preparation of bio-inspired binary CuO/ZnO nanocomposite (bb-CuO/ZnO nanocomposite) via the biological route using Bauhinia variegata flower extract following hydrothermal treatment. The prepared bb-CuO/ZnO nanocomposite was electrophoretically deposited (EPD) on indium tin oxide (ITO) substrate to develop bb-CuO/ZnO/ITO biosensing electrode which is employed for the determination of vitamin B2 (Riboflavin) through electrochemical techniques. Physicochemical assets of the prepared bb-CuO/ZnO nanocomposite have been extensively evaluated and make use of different characterization techniques including powder XRD, FT-IR, AFM, SEM, TEM, EDX, XPS, Raman, and TGA. Electrochemical characteristics of the bb-CuO/ZnO/ITO biosensing electrode have been studied towards vitamin B2 determination. Furthermore, different biosensing parameters such as response time, reusability, stability, interference, and real sample analysis were also estimated. From the linear plot of scan rate, charge transfer rate constant (Ks), surface concentration of electrode (γ), and diffusion coefficient (D) have been calculated, and these are found to be 6.56 × 10-1 s-1, 1.21 × 10-7 mol cm-2, and 6.99 × 10-3 cm2 s-1, respectively. This biosensor exhibits the linear range of vitamin B2 detection from 1 to 40 µM, including sensitivity and limit of detection (LOD) of 1.37 × 10-3 mA/µM cm2 and 0.254 µM, respectively. For higher concentration range detection linearity is 50-100 µM, with sensitivity and the LOD of 1.26 × 10-3 mA/µM cm2 and 0.145 µM, respectively. The results indicate that the bio-inspired nanomaterials are promising sustainable biosensing platforms for various food and health-based biosensing devices.

Self-actuating inflammation responsive hydrogel microsphere formulation for controlled drug release in rheumatoid arthritis (RA): Animal trials and study in human fibroblast like synoviocytes (hFLS) of RA patients.

Patients with rheumatoid arthritis (RA) often have one or more painfuljoints despite adequate medicine. Local drug delivery to the synovial cavity bids for high drug concentration with minimal systemic adverse effects. However, anti-RA drugs show short half-lives in inflamed joints after intra-articular delivery. To improve the therapeutic efficacy, it is essential to ensure that a drug is only released from the formulation when it is needed. In this work, we developed an intelligent "Self-actuating" drug delivery system where Disease-modifying anti-rheumatic Drug (DMARD) methotrexate is incorporated within a matrix intended to be injected directly into joints. This formulation has the property to sense the need and release medication only when joints are inflamed in response to inflammatory enzyme Matrix metalloproteinases (MMP). These enzymes are important proteases in RA pathology, and several MMP are present in augmented levels in synovial fluid and tissues. A high level of MMP present in synovial tissues of RA patients would facilitate the release of drugs in response and ascertain controlled drug release. The formulation is designed to be stable within the joint environment, but to dis-assemble in response to inflammation. The synthesized enzyme-responsive methotrexate (Mtx) encapsulated micron-sized polymer-lipid hybrid hydrogel microspheres (Mtx-PLHM) was physiochemically characterized and tested in synovial fluid, Human Fibroblast like synoviocytes (h-FLS) (derived from RA patients) and a rat arthritic animal model. Mtx-PLHM can self-actuate and augment the release of Mtx drug upon contact with either exogenously added MMP or endogenous MMP present in the synovial fluid of patients with RA. The drug release from the prepared formulation is significantly amplified to several folds in the presence of MMP-2 and MMP-9 enzymes. In the rat arthritic model, Mtx-PLHM showed promising therapeutic results with the significant alleviation of RA symptoms through decrease in joint inflammation, swelling, bone erosion, and joint damage examined by X-ray analysis, histopathology and immune-histology. This drug delivery system would be nontoxic as it releases more drug only during the period of exacerbation of inflammation. This will simultaneously protect patients from unwanted side effects when the disease is inactive and lower the need for repeated joint injections.

Combined effects of polyethylene microplastics and carbendazim on Eisenia fetida: A comprehensive ecotoxicological study.

Microplastic (MP) pollution is becoming an emerging environmental concern across aquatic and terrestrial ecosystems. Plastic mulching and the use of pesticides in agriculture can lead to microplastics and agrochemicals in soil, which can result in unintended exposure to non-target organisms. The combined toxicity of multiple stressors represents a significant paradigm shift within the field of ecotoxicology, and its exploration within terrestrial ecosystems involving microplastics is still relatively limited. The present study investigated the combined effects of polyethylene MP (PE-MP) and the agrochemical carbendazim (CBZ) on the earthworm Eisenia fetida at different biological levels of organization. While E. fetida survival and reproduction did not exhibit significant effects following PE-MP treatment, there was a reduction in cocoon and hatchling numbers. Notably, prolonged exposure revealed delayed toxicity, leading to substantial growth impairment. Exposure to CBZ led to significant alterations in the endpoints mentioned above. While there was a decrease in cocoon and hatchling numbers, the combined treatment did not yield significant effects on earthworm reproduction except at higher concentrations. However, lower concentrations of PE-MP alongside CBZ induced a noteworthy decline in biomass content, signifying a form of potentiation interaction. In addition, concurrent exposure led to synergistic effects, from oxidative stress to modifications in vital organs such as the body wall, intestines, and reproductive structures (spermathecae, seminal vesicles, and ovarian follicles). The comparison of multiple endpoints revealed that seminal vesicles and ovarian follicles were the primary targets during the combined exposure. The research findings suggest that there are variable and complex responses to microplastic toxicity in terrestrial ecosystems, especially when combined with other chemical stressors like agrochemicals. Despite these difficulties, the study implies that microplastics can alter earthworms' responses to agrochemical exposure, posing potential ecotoxicological risks to soil fauna.

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.

Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1-depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2 and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2 and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1-depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.

Microglial Neuroinflammation-Independent Reversal of Demyelination of Corpus Callosum by Arsenic in a Cuprizone-Induced Demyelinating Mouse Model.

Demyelination is the loss of myelin in CNS, resulting in damaged myelin sheath. Oxidative stress and neuroinflammation play a key role in inducing demyelinating diseases like MS; hence, controlling oxidative stress and neuroinflammation is important. Cuprizone (CPZ), a copper chelator, generates oxidative stress and neuroinflammation, thereby inducing demyelination. Therefore, the CPZ-induced demyelinating mouse model (CPZ model) is widely used in research. The present study was intended to unravel a mechanism of inhibition of demyelination by arsenic in a CPZ model, which is otherwise known for its toxicity. We investigated an alternative mechanism of inhibition of demyelination by arsenic through the reversal of SOD1 activity employing in silico analysis, analytical chemistry techniques, and in vitro and in vivo experiments. In vivo experiments showed protection of body weight, survivability, and myelination of the corpus callosum in CPZ and arsenic-co-exposed animals, where neuroinflammation was apparently not involved. In vitro experiments revealed that arsenic-mediated reversal of impaired SOD1 activity leads to reduced cellular ROS levels and better viability of primary oligodendrocytes. Reversal of SOD1 activity was also observed in the corpus callosum tissue isolated from experimental animals. In silico and analytical chemistry studies revealed that similar to copper, arsenic can potentially bind to CPZ and thereby make the copper freely available for SOD1 activity. Suitable neurobehavior tests further validated the protective effect of arsenic. Taken together, the present study revealed that arsenic protects oligodendrocytes and demyelination of corpus callosum by reversing CPZ-induced impaired SOD1 activity.

Recent Developments in Tyrosine Kinase Inhibitor-based Nanotherapeutics for EGFR-resistant Non-small Cell Lung Cancer.

The advent of drug resistance in response to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitor (TKI) targeted therapy represents a serious challenge in the management of non-small cell lung cancer (NSCLC). These acquired resistance mutations, attributed to several advanced EGFR mutations and, necessitated the development of new-generation TKIs. Nanomedicine approaches provide a plausible way to address these problems by providing targeted delivery and sustained release, which have demonstrated success in preclinical trials. This review article provides a summary of nano-formulations designed for EGFR-TKI-resistant NSCLC, highlighting their efficacy in both in vitro and in vivo models. These findings reveal insights into the design of nanoparticles and multifunctional nanosystems, offering a potential avenue for efficacious treatment of EGFR-TKIresistant NSCLC.

Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism.

Insulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature and reversible self-assembly property indicating the peptide's ability to recognize its own amino acid sequence. M10 inhibited LPS-induced nuclear translocation of NF-κB in L6 myotubes and also reduced LPS-induced IL-6 and TNF-α production in peritoneal macrophages of BALB/c mice. Remarkably, M10 inhibited IL-6 and TNF-α secretion in diabetic, db/db mice. Notably, M10 abrogated IR in insulin-resistant L6 myotubes, which was associated with an increase in glucose uptake and a decrease in Ser307-phosphorylation of IRS1, TNF-α-induced JNK activation and nuclear translocation of NF-κB in these cells. Alternate day dosing with M10 (10 and 20 mg/kg) for 30 days in db/db mice significantly lowered blood glucose and improved glucose intolerance after loading, 3.0 g/kg glucose orally. Furthermore, M10 increased insulin and adiponectin secretion in db/db mice. M10-induced glucose uptake in L6 myotubes involved the activation of PI3K/AKT/GLUT4 pathways. A scrambled M10-analog was mostly inactive. Overall, the results show the identification of a 10-mer peptide from the DD of MyD88 with anti-inflammatory and anti-diabetic properties, suggesting that targeting of TLR4-inflammatory pathway, could lead to the discovery of molecules against IR and diabetes.

A descriptive study of hepatitis C in people who inject drugs.

BACKGROUND OBJECTIVES: The seroprevalence of the hepatitis C virus (HCV) in general population is higher than that of human immunodeficiency virus (HIV) in India. People who inject drugs (PWIDs) constitute a high-risk group for all blood-borne infections. Multiple behavioural surveillance surveys have provided a rich typology of HIV-infected PWIDs, but this information is missing for HCV infection. We describe awareness, transmission risk factors and the treatment continuum for HCV infection among PWID. We also report spatial clustering of HCV infection in PWIDs residing in Bengaluru. METHODS: Information from clinical records was collected and telephonic interviews of retrospectively identified PWIDs who received treatment at a tertiary-level addiction treatment facility between 2016 and 2021 were conducted. RESULTS: We identified 391 PWIDs; 220 (56.26%) received an anti-HCV antibody test (4 th Generation HCV-Tridot). Individuals reporting unsafe injection practices were more often tested than those who did not ( χ2 =44.9, df=1, P <0.01). Almost half of the tested and more than a quarter of the whole sample (109/220, 49.9%; 109/391, 27.9%) were seropositive for HCV infection. The projected seropositivity in this group was between 27.9 per cent (best case scenario, all untested assumed negative) and 71.6 per cent (worst case scenario, all untested assumed positive). Only a minority of participants interviewed were aware of HCV (27/183, 14.7%). HCV infection and its associated risk behaviour (PWID) were clustered in certain localities (Diggle and Chetwynd Test; P =0.001) in Bengaluru in the southern district of Karnataka. INTERPRETATION CONCLUSIONS: Undetected HCV infection is common in PWIDs; awareness and treatment uptake is poor in this group. Spatial clustering of infections in a district shows transmission in close networks and provides opportunities for targeted interventions.