Over-the-Counter Medicine-Seeking Behavior in Patients With Dermatophyte Infections Across Various Socioeconomic Strata: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVE: In dermatology outpatient departments in India, dermatophytosis is the most commonly encountered dermatosis. The objective was to collect data regarding the prevalence of over-the-counter (OTC) medication, knowledge of the illness, and hygiene habits among people with dermatophyte infections across various socioeconomic classes. METHODS: At a tertiary care facility in central India, a cross-sectional study was carried out over six months. Data about socioeconomic class, hygiene routines, prior history of any type of treatment, understanding of the condition, and family history of similar illnesses were noted. A total of 551 patients were included in the study. The correlation was evaluated using Spearman's correlation coefficient (rho). RESULTS: Socioeconomic class had little impact on seeking dermatologist advice. Steroids were prescribed to approximately 81.8% of all patients. There was a positive correlation (rho = 0.237) between the use of steroids and the severity of the condition. Around 34% of patients took prescription medications, as recommended by a pharmacist. The use of steroids positively correlated (rho = 0.426, p<0.001) with prescriptions by pharmacists. Over-the-counter drug availability and individuals believing pharmacists were qualified to identify and treat illnesses were significant contributing causes. CONCLUSIONS: People from all socioeconomic strata need to be made more aware of the risks associated with the inappropriate use of medications and skin problems in general. Strict regulations to control prescription drug sales and deter practitioners of alternative medicine from prescribing allopathic medications may be beneficial.

Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma.

BACKGROUND: The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. METHODS: We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 µM) and Sorafenib (1-10 µM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. RESULTS: The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. CONCLUSIONS: In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.

Effects of Sodium Salts of Fatty Acids and Their Derivatives on Skin Permeation of Cromolyn Sodium.

Atopic dermatitis is a chronic inflammatory disorder with rising prevalence. The safety concerns over usually used steroids are driving the need for developing an effective atopic dermatitis treatment. The use of therapeutic agents such as cromolyn sodium (CS) is suggested. However, due to its physicochemical properties, CS permeation across the skin is a challenge. The aim of this study was to investigate the effect of sodium salts of fatty acids or their derivatives with varied carbon chain lengths as potential enhancers on the skin permeation of CS. These included sodium caprylate, salcaprozate sodium, sodium decanoate, sodium palmitate, and sodium oleate dissolved in propylene glycol along with CS (4% w/w). In vitro permeation of the formulations across the dermatomed porcine ear skin was investigated over 24 h using Franz Diffusion cells. The amount of CS permeation from propylene glycol was 5.54 ± 1.06 µg/cm2 after 24 h. Initial screening of enhancers (enhancer: drug::1:1) showed enhancement in permeation of CS using sodium oleate and sodium caprylate, which were then investigated in higher ratio of drug: enhancer (1:2). Among all the formulations tested, sodium oleate (enhancer: drug::1:2) was observed to significantly (p < 0.05) enhance the permeation of CS with the highest total delivery of 359.79 ± 78.92 µg/cm2 across skin in 24 h and higher drug retention in the skin layers (153.0 ± 24.93 µg/cm2) as well. Overall, sodium oleate was found to be the most effective enhancer followed by sodium caprylate for improving the topical delivery of CS.

Plant growth promoting potential of urea doped calcium phosphate nanoparticles in finger millet (Eleusine coracana (L.) Gaertn.) under drought stress.

Drought is a leading threat that impinges on plant growth and productivity. Nanotechnology is considered an adequate tool for resolving various environmental issues by offering avant-garde and pragmatic solutions. Using nutrients in the nano-scale including CaP-U NPs is a novel fertilization strategy for crops. The present study was conducted to develop and utilize environment-friendly urea nanoparticles (NPs) based nano-fertilizers as a crop nutrient. The high solubility of urea molecules was controlled by integrating them with a matrix of calcium phosphate nanoparticles (CaP NPs). CaP NPs contain high phosphorous and outstanding biocompatibility. Scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and X-ray diffraction analysis (XRD) were used to characterize the fabricated NPs. FE-SEM determined no areas of phase separation in urea and calcium phosphate, indicating the successful formation of an encapsulated nanocomposite between the two nano matrices. TEM examination confirmed a fiber-like structure of CaP-U NPs with 15 to 50 nm diameter and 100 to 200 nm length. The synthesized CaP-U NPs and bulk urea (0.0, 0.1% and 0.5%) were applied by foliar sprays at an interval of 15 days on pre-sowed VL-379 variety of finger millet (Eleusine coracana (L.) Gaertn.), under irrigated and drought conditions. The application of the CaP-U NPs significantly enhanced different plant growth attributes such as shoot length (29.4 & 41%), root length (46.4 & 51%), shoot fresh (33.6 & 55.8%) and dry weight (63 & 59.1%), and root fresh (57 & 61%) and dry weight (78 & 80.7%), improved pigment system (chlorophyll) and activated plant defense enzymes such as proline (35.4%), superoxide dismutase (47.7%), guaiacol peroxidase (30.2%), ascorbate peroxidase (70%) under both irrigated and drought conditions. Superimposition of five treatment combinations on drought suggested that CaP-U NPs at 0.5 followed by 0.1% provided the highest growth indices and defense-related enzymes, which were significantly different. Overall, our findings suggested that synthesized CaP-U NPs treatment of finger millet seeds improved plant growth and enzymatic regulation, particularly more in drought conditions providing insight into the strategy for not only finger millet but probably for other commercial cereals crops which suffer from fluctuating environmental conditions.

Synergistic impact of nanomaterials and plant probiotics in agriculture: A tale of two-way strategy for long-term sustainability.

Modern agriculture is primarily focused on the massive production of cereals and other food-based crops in a sustainable manner in order to fulfill the food demands of an ever-increasing global population. However, intensive agricultural practices, rampant use of agrochemicals, and other environmental factors result in soil fertility degradation, environmental pollution, disruption of soil biodiversity, pest resistance, and a decline in crop yields. Thus, experts are shifting their focus to other eco-friendly and safer methods of fertilization in order to ensure agricultural sustainability. Indeed, the importance of plant growth-promoting microorganisms, also determined as "plant probiotics (PPs)," has gained widespread recognition, and their usage as biofertilizers is being actively promoted as a means of mitigating the harmful effects of agrochemicals. As bio-elicitors, PPs promote plant growth and colonize soil or plant tissues when administered in soil, seeds, or plant surface and are used as an alternative means to avoid heavy use of agrochemicals. In the past few years, the use of nanotechnology has also brought a revolution in agriculture due to the application of various nanomaterials (NMs) or nano-based fertilizers to increase crop productivity. Given the beneficial properties of PPs and NMs, these two can be used in tandem to maximize benefits. However, the use of combinations of NMs and PPs, or their synergistic use, is in its infancy but has exhibited better crop-modulating effects in terms of improvement in crop productivity, mitigation of environmental stress (drought, salinity, etc.), restoration of soil fertility, and strengthening of the bioeconomy. In addition, a proper assessment of nanomaterials is necessary before their application, and a safer dose of NMs should be applicable without showing any toxic impact on the environment and soil microbial communities. The combo of NMs and PPs can also be encapsulated within a suitable carrier, and this method aids in the controlled and targeted delivery of entrapped components and also increases the shelf life of PPs. However, this review highlights the functional annotation of the combined impact of NMs and PPs on sustainable agricultural production in an eco-friendly manner.

The distinctive mechanical and structural signatures of residual force enhancement in myofibers.

In muscle, titin proteins connect myofilaments together and are thought to be critical for contraction, especially during residual force enhancement (RFE) when force is elevated after an active stretch. We investigated titin's function during contraction using small-angle X-ray diffraction to track structural changes before and after 50% titin cleavage and in the RFE-deficient, mdm titin mutant. We report that the RFE state is structurally distinct from pure isometric contractions, with increased thick filament strain and decreased lattice spacing, most likely caused by elevated titin-based forces. Furthermore, no RFE structural state was detected in mdm muscle. We posit that decreased lattice spacing, increased thick filament stiffness, and increased non-crossbridge forces are the major contributors to RFE. We conclude that titin directly contributes to RFE.

Contributions of Titin and Collagen to Passive Stress in Muscles from mdm Mice with a Small Deletion in Titin's Molecular Spring.

Muscular dystrophy with myositis (mdm) is a naturally occurring mutation in the mouse Ttn gene that results in higher passive stress in muscle fibers and intact muscles compared to wild-type (WT). The goal of this study was to test whether alternative splicing of titin exons occurs in mdm muscles, which contain a small deletion in the N2A-PEVK regions of titin, and to test whether splicing changes are associated with an increase in titin-based passive tension. Although higher levels of collagen have been reported previously in mdm muscles, here we demonstrate alternative splicing of titin in mdm skeletal muscle fibers. We identified Z-band, PEVK, and C-terminus Mex5 exons as splicing hotspots in mdm titin using RNA sequencing data and further reported upregulation in ECM-associated genes. We also treated skinned mdm soleus fiber bundles with trypsin, trypsin + KCl, and trypsin + KCL + KI to degrade titin. The results showed that passive stress dropped significantly more after trypsin treatment in mdm fibers (11 ± 1.6 mN/mm2) than in WT fibers (4.8 ± 1 mN/mm2; p = 0.0004). The finding that treatment with trypsin reduces titin-based passive tension more in mdm than in WT fibers supports the hypothesis that exon splicing leads to the expression of a stiffer and shorter titin isoform in mdm fibers. After titin extraction by trypsin + KCl + KI, mdm fibers (6.7 ± 1.27 mN/mm2) had significantly higher collagen-based passive stress remaining than WT fibers (2.6 ± 1.3 mN/mm2; p = 0.0014). We conclude that both titin and collagen contribute to higher passive tension of mdm muscles.

Residual force enhancement is reduced in permeabilized fiber bundles from mdm muscles.

Residual force enhancement (RFE) is the increase in steady-state force after active stretch relative to the force during isometric contraction at the same final length. The muscular dystrophy with myositis (mdm) mutation in mice, characterized by a small deletion in N2A titin, has been proposed to prevent N2A titin-actin interactions so that active mdm muscles are more compliant than wild type (WT). This decrease in active muscle stiffness is associated with reduced RFE. We investigated RFE in permeabilized soleus (SOL) and extensor digitorum longus (EDL) fiber bundles from WT and mdm mice. On each fiber bundle, we performed active and passive stretches from an average sarcomere length of 2.6-3.0 µm at a slow rate of 0.04 µm s-1, as well as isometric contractions at the initial and final lengths. One-way ANOVA showed that SOL and EDL fiber bundles from mdm mice exhibited significantly lower RFE than WT mice (P<0.0001). This result is consistent with previous observations in single myofibrils and intact muscles. However, it contradicts the results from a previous study that appeared to show that compensatory mechanisms could restore titin force enhancement in single fibers from mdm psoas. We suggest that RFE measured previously in mdm single fibers was an artifact of the high variability in passive tension found in degenerating fibers, which begins after ∼24 days of age. The results are consistent with the hypothesis that RFE is reduced in mdm skeletal muscles owing to impaired Ca2+-dependent titin-actin interactions resulting from the small deletion in N2A titin.

Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid overdose.

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p < 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.

Delivering therapeutic cannabinoids via skin: Current state and future perspectives.

Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date.

N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle.

Since its belated discovery, our understanding of the giant protein titin has grown exponentially from its humble beginning as a sarcomeric scaffold to recent recognition of its critical mechanical and signaling functions in active muscle. One uniquely useful model to unravel titin's functions, muscular dystrophy with myositis (mdm), arose spontaneously in mice as a transposon-like LINE repeat insertion that results in a small deletion in the N2A region of titin. This small deletion profoundly affects hypertrophic signaling and muscle mechanics, thereby providing insights into the function of this specific region and the consequences of its dysfunction. The impact of this mutation is profound, affecting diverse aspects of the phenotype including muscle mechanics, developmental hypertrophy, and thermoregulation. In this review, we explore accumulating evidence that points to the N2A region of titin as a dynamic "switch" that is critical for both mechanical and signaling functions in skeletal muscle. Calcium-dependent binding of N2A titin to actin filaments triggers a cascade of changes in titin that affect mechanical properties such as elastic energy storage and return, as well as hypertrophic signaling. The mdm phenotype also points to the existence of as yet unidentified signaling pathways for muscle hypertrophy and thermoregulation, likely involving titin's PEVK region as well as the N2A signalosome.