Enhanced Skin Penetration and Efficacy: First and Second Generation Lipoidal Nanocarriers in Skin Cancer Therapy.

Skin carcinoma remains one of the most widespread forms of cancer, and its global impact continues to increase. Basal cell carcinoma, melanoma, and squamous cell carcinoma are three kinds of cutaneous carcinomas depending upon occurrence and severity. The invasive nature of skin cancer, the limited effectiveness of current therapy techniques, and constraints to efficient systems for drug delivery are difficulties linked with the treatment of skin carcinoma. In the present era, the delivery of drugs has found a new and exciting horizon in the realm of nanotechnology, which presents inventive solutions to the problems posed by traditional therapeutic procedures for skin cancer management. Lipid-based nanocarriers like solid lipid nanoparticles and nanostructured lipid carriers have attracted a substantial focus in recent years owing to their capability to improve the drug's site-specific delivery, enhancing systemic availability, and thus its effectiveness. Due to their distinct structural and functional characteristics, these nanocarriers can deliver a range of medications, such as peptides, nucleic acids, and chemotherapeutics, via different biological barriers, such as the skin. In this review, an effort was made to present the mechanism of lipid nanocarrier permeation via cancerous skin. In addition, recent research advances in lipid nanocarriers have also been discussed with the help of in vitro cell lines and preclinical studies. Being a nano size, their limitations and toxicity aspects in living systems have also been elaborated.

Novel mycophenolic acid precursor-based fluorescent probe for intracellular H2O2 detection in living cells and Daphnia magna and Zebrafish model systems.

Innovative for the scientific community and attracting attention in the extensive biomedical field are novel compact organic chemosensing systems built upon unique core molecular frameworks. These systems may demonstrate customized responses and may be adaptable to analytes, showing promise for potential in vivo applications. Our recent investigation focuses on a precursor of Mycophenolic acid, resulting in the development of LBM (LOD = 13 nM) - a specialized probe selective for H2O2. This paper details the synthesis, characterization, and thorough biological assessments of LBM. Notably, we conducted experiments involving living cells, daphnia, and zebrafish models, utilizing microscopy techniques to determine probe nontoxicity and discern distinct patterns of probe localization. Localization involved the distribution of the probe in the Zebrafish model within the gut, esophagus, and muscles of the antennae.

Evaluation of Fluorescence-Based Screening Assays for the Detection and Quantification of Silyl Hydrolase Activity.

This study reports the development of fluorometric assays for the detection and quantification of silyl hydrolase activity using silicatein as a model enzyme. These assays employed a series of organosilane substrates containing either mycophenolate or umbelliferone moieties, which become fluorescent upon hydrolysis of a scissile Si-O bond. Among these substrates, the mycophenolate-derived molecule MycoF, emerged as the most promising candidate due to its relative stability in aqueous media, which resulted in good differentiation between the enzyme-catalyzed and uncatalyzed background hydrolysis. The utility of MycoF was also demonstrated in the detection of enzyme activity in cell lysates and was found to be capable of qualitative identification of positive "hit" candidates in a high-throughput format. These fluorogenic substrates were also suitable for use in quantitative kinetic assays, as demonstrated by the acquisition of their Michaelis-Menten parameters.

Antifungal activity of synthetic xanthenone against fluconazole-resistant Candida auris and its mechanism of action.

Candida auris, an emerging multidrug-resistant fungal pathogen discovered in Japan in 2009, poses a significant global health threat, with infections reported in about 25 countries. The escalation of drug-resistant strains underscores the urgent need for new treatment options. This study aimed to investigate the antifungal potential of 2,3,4,4a-tetrahydro-1H-xanthen-1-one (XA1) against C. auris, as well as its mechanism of action and toxic profile. The antifungal activity of XA1 was first evaluated by determining the minimum inhibitory concentration (MIC), time-kill kinetics and biofilm inhibition. In addition, structural changes, membrane permeability, reactive oxygen species (ROS) production, and in vitro and in vivo toxicity of C. auris after exposure to XA1 were investigated. The results indicated that XA1 exhibited an MIC of 50 µg/mL against C. auris, with time-kill kinetics highlighting its efficacy. Field emission scanning electron microscopy (FE-SEM) showed structural damage in XA1-treated cells, supported by increased membrane permeability leading to cell death. Furthermore, XA1 induced ROS production and significantly inhibited biofilm formation. Importantly, XA1 exhibited low cytotoxicity in human epidermal keratinocytes (HaCaT), with a cell viability of over 90% at 6.25 µg/mL. In addition, an LD50 of 17.68 µg/mL was determined in zebrafish embryos 24 hours post fertilization (hpf), with developmental delay observed at prolonged exposure at 6.25 µg/mL (48-96 hpf). These findings position XA1 as a promising candidate for further research and development of an effective antifungal agent.

Clinical spectrum, phenotypic and molecular characterization, and antifungal susceptibility of an emerging human pathogen, Acrophialophora, from India.

Acrophialophora is implicated in superficial and invasive infections, especially in immunosuppressed individuals. The present study was undertaken to provide clinical, microbiological, phylogenetic, and antifungal susceptibility testing (AFST) profile of Acrophialophora isolated from India. All the isolates identified as Acrophialophora species at the National Culture Collection for Pathogenic Fungi, Chandigarh, India were revived. Phenotypic and molecular characterization was performed, followed by temperature studies, scanning electron microscopy (SEM), and AFST. We also performed systematic review of all the cases of Acrophialophora species reported till date. A total of nine isolates identified as Acrophialophora species were identified by molecular method as A. fusispora (n = 8) and A. levis (n = 1), from brain abscess (n = 4), respiratory tract (n = 3), and corneal scraping (n = 2). All patients but two had predisposing factors/co-morbidities. Acrophialophora was identified as mere colonizer in one. Temperature studies and SEM divulged variation between both species. Sequencing of the internal transcribed spacer ribosomal DNA and beta-tubulin loci could distinguish species, while the LSU ribosomal DNA locus could not. AFST showed the lowest minimum inhibitory concentrations (MICs) for triazoles and the highest for echinocandins. Systematic literature review revealed 16 cases (11 studies), with ocular infections, pulmonary and central nervous system infections, and A. fusispora was common species. All the patients except three responded well. High MICs were noted for fluconazole, micafungin, and caspofungin. This is the first study delineating clinical, phenotypic, and genotypic characteristics of Acrophialophora species from India. The study highlights microscopic differences between both species and emphasizes the role of molecular methods in precise identification. Triazoles appear to be the most effective antifungals for managing patients.

We describe clinical, phenotypic, and genotypic characteristics of Acrophialophora species. This species causes mild infection to fatal infection in immunosuppressed individuals. Triazoles are effective in treating such infections.

Lyso-H2S: A Mycophenolic Acid-Derived Probe for Ultra-Low Toxicity, Intracellular H2S Detection, and Zebrafish Model Validation.

In several biological processes, H2S is known to function as an endogenous gaseous agent. It is very necessary to monitor H2S and relevant physiological processes in vivo. Herein, a new type of fluorophore with a reliable leaving group allows for excited-state intramolecular transfer characteristics (ESIPT), inspired by mycophenolic acid. A morpholine ring was connected at the maleimide position to target the lysosome. Subsequently, the dinitrophenyl group known for a photoinduced electron transfer (PET) effect, was connected to allow for an effective "turn-on" probe Lyso-H2S. Lyso-H2S demonstrated strong selectivity towards H2S, large Stokes shift (111 nm), and an incredibly low detection limit (41.8 nM). The imaging of endogenous and exogenous H2S in living cells (A549 cell line) was successfully achieved because of the specificity and ultra-low toxicity (100 % cell viability at 50 µM concentration of Lyso-H2S.) Additionally, Lyso-H2S was also employed to visualize the activity of H2S in the gallbladder and intestine in a living zebrafish model. This is the first report of a fluorescent probe to track H2S sensing in specific organ systems to our knowledge.

A mouse model of TB-associated lung fibrosis reveals persistent inflammatory macrophage populations during treatment.

Post-TB lung disease (PTLD) causes a significant burden of global disease. Fibrosis is a central component of many clinical features of PTLD. To date, we have a limited understanding of the mechanisms of TB-associated fibrosis and how these mechanisms are similar to or dissimilar from other fibrotic lung pathologies. We have adapted a mouse model of TB infection to facilitate the mechanistic study of TB-associated lung fibrosis. We find that the morphologies of fibrosis that develop in the mouse model are similar to the morphologies of fibrosis observed in human tissue samples. Using Second Harmonic Generation (SHG) microscopy, we are able to quantify a major component of fibrosis, fibrillar collagen, over time and with treatment. Inflammatory macrophage subpopulations persist during treatment; matrix remodeling enzymes and inflammatory gene signatures remain elevated. Our mouse model suggests that there is a therapeutic window during which adjunctive therapies could change matrix remodeling or inflammatory drivers of tissue pathology to improve functional outcomes after treatment for TB infection.

In-depth Mechanism, Challenges, and Opportunities of Delivering Therapeutics in Brain Using Intranasal Route.

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.

Nano-nutraceuticals to Combat Oxidative Stress: Unlocking Newer Paradigms in Adjuvant Therapy.

Nutraceuticals are products that provide both nutritional and therapeutic benefits. These compounds can slow the aging process and provide physiological effects shielding individuals from acute and chronic diseases. People's interests have shifted from allopathic to Ayurvedic to nutraceuticals in recent years. These are often common dietary supplements that have drawn customers worldwide because of their high nutritional safety and lack of adverse effects when used for a long time. Although conventional dosage forms, including pills, tablets, and semi-solids, are still available, they nevertheless have poorer bioavailability, less stability, and less effectiveness for targeted delivery of bioactives. The use of effective nanocomplex systems as nano-antioxidants using nanotechnology has become a promising field. Among its many uses, nanotechnology is mostly used to create foods and nutraceuticals that are more bioavailable, less toxic, and more sustainable. Additionally, it has been emphasized how precisely nano-pharmaceuticals for oxidative stress produce the desired effects. These improvements show improved antioxidant delivery to the target region, reduced leakage, and increased targeting precision. The outcomes demonstrated that oxidative stress-related illnesses can be effectively treated by lowering ROS levels with the use of nanonutraceuticals. The major ideas and uses of nano-nutraceuticals for health are outlined in this review, with an emphasis on reducing oxidative stress.

Biosorption of arsenic (III) from aqueous solution using calcium alginate immobilized dead biomass of Acinetobacter sp. strain Sp2b.

This study presents a novel biosorbent developed by immobilizing dead Sp2b bacterial biomass into calcium alginate (CASp2b) to efficiently remove arsenic (AsIII) from contaminated water. The bacterium Sp2b was isolated from arsenic-contaminated industrial soil of Punjab, a state in India. The strain was designated Acinetobacter sp. strain Sp2b as per the 16S rDNA sequencing, GenBank accession number -OP010048.The CASp2b was used for the biosorption studies after an initial screening for the biosorption capacity of Sp2b biomass with immobilized biomass in both live and dead states. The optimum biosorption conditions were examined in batch experimentations with contact time, pH, biomass, temperature, and AsIII concentration variables. The maximum biosorption capacity (qmax = 20.1 ± 0.76 mg/g of CA Sp2b) was obtained at pH9, 35 ̊ C, 20 min contact time, and 120 rpm agitation speed. The isotherm, kinetic and thermodynamic modeling of the experimental data favored Freundlich isotherm (R2 = 0.941) and pseudo-2nd-order kinetics (R2 = 0.968) with endothermic nature (ΔH° = 27.42) and high randomness (ΔS° = 58.1).The scanning electron microscopy with energy dispersive X-ray (SEM-EDX) analysis indicated the As surface binding. The reusability study revealed the reasonable usage of beads up to 5 cycles. In conclusion, CASp2b is a promising, efficient, eco-friendly biosorbent for AsIII removal from contaminated water.

Midperipheral mini-capsulorhexis as an additional step for safe phacoemulsification in white intumescent cataracts.

ABSTRACT: The present article describes a novel surgical technique of a primary mini-capsulorhexis in midperiphery to minimize surgical complications in white intumescent cataracts. Patients with white mature cataracts with a convex anterior capsule or swollen lens fibers were selected. An initial puncture was made 3-4 mm away from the center, in the midperipheral anterior capsule, with a conventional cystitome. A mini-capsulorhexis (2-2.5 mm) was created. Loose cortical matter and fluidic contents were aspirated to reduce the intralenticular pressure. Two cuts were made at the margin of the mini-capsulorhexis, and an adequately sized secondary rhexis was completed, after which phacoemulsification was done. A circular curvilinear capsulorhexis was successfully achieved in all cases, including those with a small pupil. Rhexis could be completed in a patient where an initial extension occurred due to head movement. This refined technique aims to enhance the safety and precision of capsulorhexis in intumescent cataracts, thereby reducing the risk of complications such as the Argentinian flag sign. Further exploration and validation of this approach through clinical trials are warranted to establish its efficacy and safety profile.

The molecular interplay between human and bacterial amyloids: Implications in neurodegenerative diseases.

Neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD) are linked with the assembly and accumulation of proteins into structured scaffold called amyloids. These diseases pose significant challenges due to their complex and multifaceted nature. While the primary focus has been on endogenous amyloids, recent evidence suggests that bacterial amyloids may contribute to the development and exacerbation of such disorders. The gut-brain axis is emerging as a communication pathway between bacterial and human amyloids. This review delves into the novel role and potential mechanism of bacterial amyloids in modulating human amyloid formation and the progression of AD and PD.

Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

Solitary Ganglioneuromatous Hamartoma Tongue in a Newborn - A Rare Entity.

Ganglioneuromatous hamartoma is a benign tumour of autonomic ganglia with very few cases reported in head and neck region. In this report, we are presenting a case of ganglioneuromatous hamartoma in a 20 day old female child who presented with a tongue mass. She underwent a surgical excision and the definitive diagnosis was made by histopathology. This case reports discusses presentation and management of a case of ganglioneuromatous hamartoma.

Characterization of G-quadruplex structures in genes involved in survival and pathogenesis of Acinetobacter baumannii as a potential drug target.

Acinetobacter baumannii is a notorious pathogen that commonly thrives in hospital environments and is responsible for numerous nosocomial infections in humans. The burgeoning multi-drug resistance leaves relatively minimal options for treating the bacterial infection, posing a significant problem and prompting the identification of new approaches for tackling the same. This motivated us to focus on non-canonical nucleic acid structures, mainly G-quadruplexes, as drug targets. G-quadruplexes have recently been gaining attention due to their involvement in multiple bacterial and viral pathogenesis. Herein, we sought to explore conserved putative G-quadruplex motifs in A. baumannii. In silico analysis revealed the presence of eight conserved motifs in genes involved in bacterial survival and pathogenesis. The biophysical and biomolecular analysis confirmed stable G-quadruplex formation by the motifs and showed a high binding affinity with the well-reported G-quadruplex binding ligand, BRACO-19. BRACO-19 exposure also decreased the growth of bacteria and downregulated the expression of G-quadruplex-harboring genes. The biofilm-forming ability of the bacteria was also affected by BRACO-19 addition. Taking all these observations into account, we have shown here for the first time the potential of G-quadruplex structures as a promising drug target in Acinetobacter baumannii, for addressing the challenges posed by this infamous pathogen.

The menace within: bacterial amyloids as a trigger for autoimmune and neurodegenerative diseases.

Bacteria are known to produce amyloids, proteins characterized by a conserved cross-beta sheet structure, which exhibit structural and functional similarities to human amyloids. The deposition of human amyloids into fibrillar plaques within organs is closely linked to several debilitating human diseases, including Alzheimer's and Parkinson's disease. Recently, bacterial amyloids have garnered significant attention as potential initiators of human amyloid-associated diseases as well as autoimmune diseases. This review aims to explore how bacterial amyloid, particularly curli found in gut biofilms, can act as a trigger for neurodegenerative and autoimmune diseases. We will elucidate three primary mechanisms through which bacterial amyloids exert their influence: By delving into these three distinct modes of action, this review will provide valuable insights into the intricate relationship between bacterial amyloids and the onset or progression of neurodegenerative and autoimmune diseases. A comprehensive understanding of these mechanisms may open new avenues for therapeutic interventions and preventive strategies targeting amyloid-associated diseases.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

PURPOSE: Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. METHODS: Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. RESULTS: The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. CONCLUSION: To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Outcomes of Simple Limbal Epithelial Transplantation Without Amniotic Membrane Grafting in Unilateral Limbal Stem Cell Deficiency: A Case Series of 6 Patients.

PURPOSE: This study describes the technique of simple limbal epithelial transplantation (SLET) without amniotic membrane grafting (AMG) in limbal stem cell deficiency (LSCD). METHODS: Retrospective, interventional case series of 6 patients who underwent SLET without AMG were included. The procedure followed the standard technique, involving limbal biopsy from the healthy eye, resection of symblephera, and pannus dissection in the affected eye. Following host bed preparation, limbal explants were placed on the bare cornea and secured with fibrin glue. A large-diameter bandage contact lens was applied post surgery. No amniotic membrane was used. Preoperative data, including age, gender, cause of LSCD, best-corrected visual acuity, and previous ocular surgeries, were recorded. Postoperative clinical information, such as the duration of follow-up and recurrence of LSCD, best-corrected visual acuity, and other ocular examination findings, was recorded in an excel sheet. RESULTS: Preoperatively, 2 patients had total LSCD (secondary to a firecracker injury and excision biopsy for ocular surface squamous neoplasia). 4 patients had partial LSCD (3 chemical injuries, 1 firecracker injury). The mean age of participants was 30.67 ± 15.91 years, with a mean follow-up duration of 9.33 ± 8.04 months. Intraoperatively, all patients exhibited a smooth corneal surface after pannus removal. Postoperatively, all limbal explants remained securely attached, with complete corneal epithelialization achieved within 2 to 3 weeks. The ocular surface remained stable throughout, and no recurrence of LSCD was observed in any patient. No loss of explants was seen. CONCLUSIONS: The present series suggests that AMG may not be a necessary step for performing SLET.

Intelligent Drug Delivery: Pioneering Stimuli-Responsive Systems to Revolutionize Disease Management- An In-depth Exploration.

In recent years, there has been an escalating interest in stimuli-responsive drug delivery systems (SRDDS) due to their ability to revolutionize the delivery of therapeutics. SRDDSs offer a multitude of benefits in comparison to conventional drug delivery systems (DDS), including spatiotemporal control of drug release, targeted delivery, and improved therapeutic efficacy. The development of various classes of stimuli-responsive DDS, such as pH-responsive, temperature-responsive, photo-responsive, redox responsive systems, has been propelled by advances in materials science, nanotechnology, and biotechnology. These systems exploit specific environmental or physiological cues to trigger drug release in a precisely controlled manner, making them highly promising for the treatment of various diseases. In this review article, an in-depth exploration of the principles, mechanisms, and applications of SRDDS in the context of diverse pathologies such as cancer, arthritis, Alzheimer's disease, atherosclerosis and tissue engineering has been provided. Furthermore, this article delves into the discussion of recent patents, market overview and the progress of research in clinical trials. Overall, this article underscores the transformative potential of SRDDS in enabling personalized, precise, and effective drug delivery for the treatment of the above-mentioned diseases.