Organogels: "GelVolution" in Topical Drug Delivery - Present and Beyond.

Topical drug delivery holds immense significance in dermatological treatments due to its non-invasive nature and direct application to the target site. Organogels, a promising class of topical drug delivery systems, have acquired substantial attention for enhancing drug delivery efficiency. This review article aims to explore the advantages of organogels, including enhanced drug solubility, controlled release, improved skin penetration, non-greasy formulations, and ease of application. The mechanism of organogel permeation into the skin is discussed, along with formulation strategies, which encompass the selection of gelling agents, cogelling agents, and additives while considering the influence of temperature and pH on gel formation. Various types of organogelators and organogels and their properties, such as viscoelasticity, non-birefringence, thermal stability, and optical clarity, are presented. Moreover, the biomedical applications of organogels in targeting skin cancer, anti-inflammatory drug delivery, and antifungal drug delivery are discussed. Characterization parameters, biocompatibility, safety considerations, and future directions in optimizing skin permeation, ensuring long-term stability, addressing regulatory challenges, and exploring potential combination therapies are thoroughly examined. Overall, this review highlights the immense potential of organogels in redefining topical drug delivery and their significant impact on the field of dermatological treatments, thus paving the way for exciting prospects in the domain.

Nano-Innovations in Cancer Therapy: The Unparalleled Potential of MXene Conjugates.

MXenes are two-dimensional transition metal carbides, nitrides, and carbonitrides that have become important materials in nanotechnology because of their remarkable mechanical, electrical, and thermal characteristics. This review emphasizes how crucial MXene conjugates are for several biomedical applications, especially in the field of cancer. These two-dimensional (2D) nanoconjugates with photothermal, chemotherapeutic, and photodynamic activities have demonstrated promise for highly effective and noninvasive anticancer therapy. MXene conjugates, with their distinctive optical capabilities, have been employed for bioimaging and biosensing, and their excellent light-to-heat conversion efficiency makes them perfect biocompatible and notably proficient nanoscale agents for photothermal applications. The synthesis and characterization of MXenes provide a framework for an in-depth understanding of various fabrication techniques and their importance in the customized formation of MXene conjugates. The following sections explore MXene-based conjugates for nanotheranostics and demonstrate their enormous potential for biomedical applications. Nanoconjugates, such as polymers, metals, graphene, hydrogels, biomimetics, quantum dots, and radio conjugates, exhibit unique properties that can be used for various therapeutic and diagnostic applications in the field of cancer nanotheranostics. An additional layer of understanding into the safety concerns of MXene nanoconjugates is provided by detailing their toxicity viewpoints. Furthermore, the review concludes by addressing the opportunities and challenges in the clinical translation of MXene-based nanoconjugates, emphasizing their potential in real-world medical practices.

Ameliorative anticancer effect of dendrimeric peptide modified liposomes of letrozole: In vitro and in vivo performance evaluations.

Letrozole (LTZ) loaded dendrimeric nano-liposomes were prepared for targeted delivery to breast cancer cells. Surface modification with cationic peptide dendrimers (PDs) and a cancer specific ligand, transferrin (Tf), was attempted. Arginine-terminated PD (D-1) and Arginine-terminated, lipidated PD (D-2) were synthesized using Solid Phase Peptide Synthesis, purified by preparative HPLC and characterized using 1HNMR, MS and DSC analyses. Surface modification of drug loaded liposomes with Tf and/or PD was carried out. Formulations were characterized using FTIR, DSC, 1HNMR, XRD and TEM. Tf-conjugated LTZ liposomes (LTf) and Tf/D-2-conjugated LTZ liposomes (LTfD-2) showed greater cytotoxic potential (IC50 = 95.03 µg/mL and 23.75 µg/mL respectively) with enhanced cellular uptake in MCF7 cells compared to plain LTZ. Blocking studies of Tf (Tf-receptor mediated internalization) revealed decreased uptake of LTf and LTfD-2 confirming the role of Tf in uptake of Tf-conjugated liposomes. Intravenous treatment with LTfD-2 caused highest reduction in tumor volumes of female BALB/c-nude mice (145 mm3) compared to plain LTZ (605 mm3) and unconjugated LTZ liposomes (LP) (300 mm3). In vivo biodistribution studies revealed higher fluorescence in tumor tissue and liver of LTfD-2 treated mice than LTf or LP treatment. Immunohistochemical studies revealed greater apoptotic potential of LTfD-2 as indicated by TUNEL assay and ROS detection assay. The study reveals the superior therapeutic efficacy of the developed LTZ liposomal nanocarriers using PDs to enhance the transfection efficiency in addition to modifying the surface characteristics by attaching a targeting ligand for active drug targeting to breast cancer cells.

Isolation and characterization of pseudo degradation products of acalabrutinib using ESI-HRMS/MS and NMR: Formation of possible geometrical isomers.

A forced degradation study of acalabrutinib (ACB), used to treat relapsed mantle cell lymphoma, was performed to identify and characterize all possible major degradation products formed under different stress conditions. The degradation products (DP) were separated using reverse phase UHPLC system on Kinetex EVO C18 column. Major DPs formed were isolated using semi-preparative HPLC and characterized by LC-ESI-HRMS/MS and NMR. ACB degraded to form seven major degradants (DP-I to DP-VII). DP-I and DP-V were formed under alkaline stress condition, whereas DP-II, DP-III, DP-VI and DP-VII were formed under both acidic and basic conditions. Further, DP-IV was formed when ACB drug was exposed to hydrogen peroxide stress condition. ACB was found to be stable when subjected to aqueous (neutral pH), thermal and UV radiation of 254 nm, as it has not shown any significant degradation under these conditions. Interestingly, two pairs of pseudo geometrical isomeric DPs (DP-II and DP-III, DP-VI and DP-VII) were observed. The plausible degradation pathway of ACB and fragmentation patterns of both ACB and major DPs were discussed.

Role of autophagy in tumor response to radiation: Implications for improving radiotherapy.

Autophagy is an evolutionary conserved, lysosome-involved cellular process that facilitates the recycling of damaged macromolecules, cellular structures, and organelles, thereby generating precursors for macromolecular biosynthesis through the salvage pathway. It plays an important role in mediating biological responses toward various stress, including those caused by ionizing radiation at the cellular, tissue, and systemic levels thereby implying an instrumental role in shaping the tumor responses to radiotherapy. While a successful execution of autophagy appears to facilitate cell survival, abortive or interruptions in the completion of autophagy drive cell death in a context-dependent manner. Pre-clinical studies establishing its ubiquitous role in cells and tissues, and the systemic response to focal irradiation of tumors have prompted the initiation of clinical trials using pharmacologic modifiers of autophagy for enhancing the efficacy of radiotherapy. However, the outcome from the Phase I/II trials in many human malignancies has so far been equivocal. Such observations have not only precluded the advancement of these autophagy modifiers in the Phase III trial but have also raised concerns regarding their introduction as an adjuvant to radiotherapy. This warrants a thorough understanding of the biology of the cancer cells, including its spatio-temporal context, as well as its microenvironment all of which might be the crucial factors that determine the success of an autophagy modifier as an anticancer agent. This review captures the current understanding of the interplay between radiation induced autophagy and the biological responses to radiation damage as well as provides insight into the potentials and limitations of targeting autophagy for improving the radiotherapy of tumors.

Membrane Depolarization Sensitizes Pseudomonas aeruginosa Against Tannic Acid.

The use of dietary polyphenols as antimicrobial agents has gained immense popularity in recent years, although few of them-like tannic acid has limited use in this field of research; one of the main reasons is its restricted access through the bacterial membrane. Dissipating the bacterial membrane potential with a sub-lethal dosage of the protonophore, carbonyl cyanide m-chlorophenyl hydrazone, enhanced the tannic acid-cytotoxicity with subsequent inhibition of aerobic respiration in Pseudomonas aeruginosa strains which otherwise exhibited a minimum response to tannic acid. However, ascorbic acid, an antioxidant and bacterial membrane-stabilizing compound, had rescued the cells from both tannic acid- and CCCP-mediated lethality. The results suggested that dispersing the membrane potential with a protonophore can enhance the antibacterial properties of tannic acid.

Subcellular compartmentalization of glutathione peroxidase 1 allelic isoforms differentially impact parameters of energy metabolism.

Specific genetic variations in the gene for the selenium-containing antioxidant protein glutathione peroxidase 1 (GPX1) are associated with the risk of a variety of common diseases, including cancer, diabetes, and cardiovascular disorders. Two common variations have been focused upon, one resulting in leucine or proline at codon 198 and another resulting in 5, 6, or 7 alanine repeats were previously shown to affect the distribution of GPX1 between the cytoplasm and mitochondria. Human MCF7 cells engineered to exclusively express GPX1 with five alanine repeats at amino terminus and proline at codon 198 (A5P) and seven alanine repeats at amino terminus and leucine at codon 198 (A7L), as well as derivatives targeted to the mitochondria by the addition of a mitochondrial localization sequence (mA5P and mA7L) were used to assess the consequences of the expression of these proteins on the cellular redox state and bioenergetics. Ectopic expression of A5P and A7L reduced the levels of reactive oxygen species, and the mitochondrially targeted derivatives exhibited better activity in these assays. Bioenergetics and mitochondrial integrity were assessed by measuring mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP) levels, and the levels of lactate dehydrogenase. The results of these assays indicated distinctively, and sometimes opposing, patterns with regard to differences between the consequences of the expression of A5P, A7L, mA5P, and mA7L. These data provide new information on the consequences of differences in the primary structure and cellular location of GPX1 proteins and contribute to the understanding of how these effects might contribute to human disease.

Gallic Acid and Gallates in Human Health and Disease: Do Mitochondria Hold the Key to Success?

Gallic acid and gallate esters are widely used as dietary supplements or additives with clinical significances. Over the last few decades, a large number of publications have been reported stating the antioxidative, antiapoptotic, cardioprotective, neuroprotective, and anticancer properties of gallic acid and gallates, and mostly demonstrated their antioxidative or prooxidative properties influencing the reactive oxygen species (ROS) signaling networks. However, very little focus has been paid to clinical trials, and this restricted their use as a prescribed preventative supplement. Since mitochondria are the principal organelles responsible for ROS generation, we reviewed the existing literature of mitochondria-specific effects of gallates including ROS production, respiration, mitochondrial biogenesis, apoptosis, and the physico-chemical parameters affecting the outcome of gallate supplementation to various health scenarios such as cardiovascular diseases, neurodegeneration, hepatic ailments, or cancers. The major signaling pathways and the molecules targeted by gallic acid and its derivatives have also been discussed with emphasis on mitochondria as the target site. This review provides a better understanding of the effect of gallic acid and gallate esters on mitochondrial functions and in designing effective preventative measures against the onset of various diseases.

Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants.

The recent Zika viral (ZIKV) epidemic has been associated with severe neurological pathologies such as neonatal microcephaly and Guillain-Barre syndrome but unfortunately no vaccine or medication is effectively available yet. Zika NS2B-NS3pro is essential for the proteolysis of the viral polyprotein and thereby viral replication. Thus NS2B-NS3pro represents an attractive target for anti-Zika drug discovery/design. Here, we have characterized the solution conformations and catalytic parameters of both linked and unlinked Zika NS2B-NS3pro complexes and found that the unlinked complex manifested well-dispersed NMR spectra. Subsequently with selective isotope-labeling using NMR spectroscopy, we demonstrated that C-terminal residues (R73-K100) of NS2B is highly disordered without any stable tertiary and secondary structures in the Zika NS2B-NS3pro complex in the free state. Upon binding to the well-characterized serine protease inhibitor, bovine pancreatic trypsin inhibitor (BPTI), only the extreme C-terminal residues (L86-K100) remain disordered. Additionally, we have identified five flavonoids and one natural phenol rich in edible plants including fruits and vegetables, which inhibit Zika NS2B-NS3pro in a non-competitive mode, with Ki ranging from 770 nM for Myricetin to 34.02 µM for Apigenin. Molecular docking showed that they all bind to a pocket on the back of the active site and their structure-activity relationship was elucidated. Our study provides valuable insights into the solution conformation of Zika NS2B-NS3pro and further deciphers its susceptibility towards allosteric inhibition by natural products. As these natural product inhibitors fundamentally differ from the currently-known active site inhibitors in terms of both inhibitory mode and chemical scaffold, our finding might open a new avenue for development of better allosteric inhibitors to fight ZIKV infection.

Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy.

The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis, and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME-the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for the development of novel treatment strategies for cancer.

Naringenin Alleviates Cadmium-Induced Toxicity through the Abrogation of Oxidative Stress in Swiss Albino Mice.

The present study evaluates the protective potential of the flavonoid naringenin (NRG) against experimentally induced cadmium (Cd) toxicity in Swiss albino mice. NRG (4 and 8 mg/kg) was orally administered to mice 30 min before oral administration of CdCl2 (12 mg/kg) for 11 consecutive days. On the 12th day, we evaluated body and organ weights, hematological profiles, serum biochemical profiles, and hepatic and renal tissue antioxidative parameters including lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. Cotreatment with NRG markedly and significantly normalized body and organ weights, hematological profiles, and serum biochemical profiles and significantly modulated all of the hepatic and renal tissue biochemical parameters in Cd-intoxicated mice. The present findings show that NRG possesses a remarkable alleviative effect against Cd-induced toxicity in albino mice, mediated by abrogation of Cd-induced oxidative stress by multiple mechanisms.

CAF cellular glycolysis: linking cancer cells with the microenvironment.

Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.

Assessing biochemical changes during standardization of fermentation time and temperature for manufacturing quality black tea.

In black tea manufacturing, one of the most important steps is fermentation which influences the quality of tea. The macerated tea leaves were fermented at various temperatures (20, 25, 30, 35 °C) for different duration. Changes in polyphenoloxidase and peroxidase activities, depletion patterns of individual catechins, differences in individual theaflavin levels and formation of thearubigins were measured in leaves during fermentation. Higher stability of polyphenoloxidase and peroxidase enzymes was observed at lower temperature (20 °C), and increase in temperature, led to enzyme instability. The rate of degradation of all the catechins was found to be fastest at 35 °C and slowest at 20 °C. The formation and depletion of individual theaflavins varied with temperature and fermentation duration. The time required for the formation of maximum total theaflavins (TF) was highest at lower temperature and this time duration also varied for different theaflavins formation. Maximum amount of thearubigins (TR) content and liquor colour development was observed at 35 °C, and decrease in temperature reduced thearubigins accumulation. However, maximum brightness as well as TF/TR ratio was obtained at 20 °C, which suggests that fermentation at lower temperature is suitable for manufacturing quality black tea.

ß-Carotene ameliorates arsenic-induced toxicity in albino mice.

The present study evaluated the ameliorative potential of ß-carotene (BCT) against experimentally induced arsenic toxicity in Swiss albino mice. BCT (5 and 10 mg/kg) was administered orally to mice 30 min before oral administration of arsenic trioxide (3 mg/kg) for 14 consecutive days. On 15th day, the body weights, organ weights, hematological profiles, serum biochemical profile; hepatic and renal antioxidative parameters viz. lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase; and DNA fragmentation were evaluated. Co-treatment with BCT markedly and significantly normalized body weights, organ weights, hematological profiles, serum biochemical profile and significantly modulated all the hepatic and renal biochemical parameters and DNA fragmentation in arsenic-intoxicated mice. The present findings conclude that ß-carotene possessed remarkable ameliorative effect against arsenic-induced toxicity in albino mice mediated by its antioxidant and antigenotoxic properties.

Naringenin, a citrus flavonoid, ameliorates arsenic-induced toxicity in Swiss albino mice.

In the present study, we evaluated the ameliorative potential of a citrus flavonoid, naringenin (NRG), against experimentally induced arsenic toxicity in Swiss albino mice. NRG (5 and 10 mg kg-l) was administered orally to mice 30 minutes before oral administration of arsenic trioxide (3 mg kg-l) for 14 consecutive days. On day 15, the following parameters were evaluated: body weight; organ weight; hematological profile; serum biochemical profile; hepatic and renal tissue antioxidative parameters including lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase levels; and DNA fragmentation. Co-treatment with NRG markedly and significantly normalized body weights, organ weights, hematological profiles, and serum biochemical profiles and significantly modulated all of the hepatic and renal tissue biochemical parameters and DNA fragmentation in arsenic-intoxicated mice. The present findings indicate that naringenin remarkably ameliorated the effects of arsenic-induced toxicity in albino mice due to its strong antioxidant property.

Internal jugular vein phlebectasia presenting with hoarseness of voice.

Internal jugular phlebectasia presents as a soft cystic mass in the neck that appears on straining. We present a case of a 7-year-old girl who presented with a painless soft cystic mass in the neck associated with hoarseness of voice. Based on clinical examination and CT image, diagnosis of right internal jugular phlebectasia was made.

Identification of Michael acceptor-centric pharmacophores with substituents that yield strong thioredoxin reductase inhibitory character correlated to antiproliferative activity.

AIMS: The role of thioredoxin reductase (TrxR) in tumorigenesis has made it an attractive anticancer target. A systematic approach for development of novel compounds as TrxR inhibitors is currently lacking. Structurally diversified TrxR inhibitors share in common electrophilic propensities for the sulfhydryl groups, among which include the Michael reaction acceptors containing an α,ß-unsaturated carbonyl moiety. We aimed to identify features among structurally diversified Michael acceptor-based compounds that would yield a strong TrxR inhibitory character. RESULTS: Structurally dissimilar Michael acceptor-based natural compounds such as isobutylamides, zerumbone, and shogaols (SGs) were found to possess a poor TrxR inhibitory activity, indicating that a sole Michael acceptor moiety was insufficient to produce TrxR inhibition. The 1,7-diphenyl-hept-3-en-5-one pharmacophore in 3-phenyl-3-SG, a novel SG analog that possessed comparable TrxR inhibitory and antiproliferative potencies as 6-SG, was modified to yield 1,5-diphenyl-pent-1-en-3-one (DPPen) and 1,3-diphenyl-pro-1-en-3-one (DPPro, also known as chalcone) pharmacophores. These Michael acceptor-centric pharmacophores, when substituted with the hydroxyl and fluorine groups, gave rise to analogs displaying a TrxR inhibitory character positively correlated to their antiproliferative potencies. Lead analogs 2,2'-diOH-5,5'-diF-DPPen and 2-OH-5-F-DPPro yielded a half-maximal TrxR inhibitory concentration of 9.1 and 10.5 µM, respectively, after 1-h incubation with recombinant rat TrxR, with the C-terminal selenocysteine residue found to be targeted. INNOVATION: Identification of Michael acceptor-centric pharmacophores among diversified compounds demonstrates that a systematic approach to discover and develop Michael acceptor-based TrxR inhibitors is feasible. CONCLUSION: A strong TrxR inhibitory character correlated to the antiproliferative potency is attributed to structural features that include an α,ß-unsaturated carbonyl moiety centered in a DPPen or DPPro pharmacophore bearing hydroxyl and fluorine substitutions.

Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1).

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described.

Indoor air pollution from biomass burning activates Akt in airway cells and peripheral blood lymphocytes: a study among premenopausal women in rural India.

Biomass burning is a major source of indoor air pollution in rural India. The authors investigated in this study whether cumulative exposures to biomass smoke cause activation of the serine/threonine kinase Akt in airway cells and peripheral blood lymphocytes (PBL). For this, the authors enrolled 87 premenopausal (median age 34 years), nonsmoking women who used to cook with biomass (wood, dung, crop wastes) and 85 age-matched control women who cooked with cleaner fuel liquefied petroleum gas. Immunocytochemical and immunoblotting assays revealed significantly higher levels of phosphorylated forms of Akt protein (p-Akt(ser473) and p-Akt(thr308)) in PBL, airway epithelial cells, alveolar macrophages, and neutrophils in sputum of biomass-using women than control. Akt activation in biomass users was associated with marked rise in generation of reactive oxygen species and concomitant depletion of superoxide dismutase. Measurement of particulate matter having a diameter of less than 10 and 2.5 µm in indoor air by real-time aerosol monitor showed 2 to 4 times more particulate pollution in biomass-using households, and Akt activation was positively associated with particulate pollution after controlling potential confounders. The findings suggest that chronic exposure to biomass smoke activates Akt, possibly via generation of oxidative stress.

Structural and functional characterization of a novel homodimeric three-finger neurotoxin from the venom of Ophiophagus hannah (king cobra).

Snake venoms are a mixture of pharmacologically active proteins and polypeptides that have led to the development of molecular probes and therapeutic agents. Here, we describe the structural and functional characterization of a novel neurotoxin, haditoxin, from the venom of Ophiophagus hannah (King cobra). Haditoxin exhibited novel pharmacology with antagonism toward muscle (alphabetagammadelta) and neuronal (alpha(7), alpha(3)beta(2), and alpha(4)beta(2)) nicotinic acetylcholine receptors (nAChRs) with highest affinity for alpha(7)-nAChRs. The high resolution (1.5 A) crystal structure revealed haditoxin to be a homodimer, like kappa-neurotoxins, which target neuronal alpha(3)beta(2)- and alpha(4)beta(2)-nAChRs. Interestingly however, the monomeric subunits of haditoxin were composed of a three-finger protein fold typical of curaremimetic short-chain alpha-neurotoxins. Biochemical studies confirmed that it existed as a non-covalent dimer species in solution. Its structural similarity to short-chain alpha-neurotoxins and kappa-neurotoxins notwithstanding, haditoxin exhibited unique blockade of alpha(7)-nAChRs (IC(50) 180 nm), which is recognized by neither short-chain alpha-neurotoxins nor kappa-neurotoxins. This is the first report of a dimeric short-chain alpha-neurotoxin interacting with neuronal alpha(7)-nAChRs as well as the first homodimeric three-finger toxin to interact with muscle nAChRs.