Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions.

Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in-depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions.

Clinicopathological Study of Lesions of Upper Gastrointestinal Tract.

Conditions affecting the upper digestive system are often seen in clinical practice and are associated with a high rate of death and disability. Histopathological confirmation is one of the foundations for good treatment planning and the definite diagnosis of illnesses of the upper gastrointestinal tract. The numerous methods employed in the diagnosis of gastrointestinal lesions have come a long way in the previous 25 years. The identification and diagnosis of gastrointestinal lesions have been substantially aided by the development of endoscopy, endoscopic biopsy, and other surgical techniques. This research aimed to examine the variety of gastrointestinal tract (GI) lesions and to draw connections between the clinical and pathological manifestations of these conditions. Materials and Methods: A two-year cross-sectional study was conducted in the Department of Pathology, from June 2018 to May 2020, which included surgical specimens of 140 cases from the upper gastrointestinal tract, of which 111 cases were biopsy, and 29 cases were resected surgical specimens. The data were analyzed using SPSS software. Furthermore, P values, sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results: This study was a two-year cross-sectional study conducted in the Department of Pathology during the period of June 2018-May 2020.

Emerging role of osmoprotectant glycine betaine to mitigate heavy metals toxicity in plants: a systematic review.

Heavy metals (HMs) toxicity has become one of the major global issues and poses a serious threat to the environment in recent years. HM pollution in agricultural soil is caused by metal mining, smelting, volcanic activity, industrial discharges, and excessive use of phosphate fertilizers. HMs above a threshold level adversely affect the cellular metabolism of plants by producing reactive oxygen species (ROS), which attack cellular proteins. There are different mechanisms (physiological and morphological) adopted by plants to survive in the era of abiotic stress. Various osmoprotectants or compatible solutes, including amino acids, sugar, and betaines, enable the plants to counteract the HM stress. Glycine betaine (GB) is an effective osmolyte against HM stress among compatible solutes. GB has been shown to improve plant growth, photosynthesis, uptake of nutrients, and minimize oxidative stress in plants under HM stress. Additionally, GB increases the activity of antioxidant enzymes such as CAT (catalase), SOD (superoxide dismutase), and POD (peroxidase), which are effective in scavenging unwarranted ROS. Since not all species of plants can naturally produce or accumulate GB in response to stress, various approaches have been explored for introducing them. Plant hormones like salicylic acid, ABA (abscisic acid), and JA (jasmonic acid) co-ordinately stimulate the accumulation of GB inside the cell under HM stress. Apart from the exogenous application, the introduction of GB pathway genes in GB deficient species via genetic engineering also seems to be efficient in mediating HM stress. This review complied the beneficial effects of GB in mitigating HM stress and its role as a plant growth regulator. Additionally, the review explores the potential for engineering GB biosynthesis in plants as a strategy to bolster their resilience to HMs.

Exploring the Therapeutic Potential of Anticancer Heterocyclic Compounds: Role in Nanoscale Pharmacotherapy.

There are a large number of pharmaceutical products in the market containing heterocyclic compounds. Heterocyclic compounds are explored in the field of therapeutics due to their unique physicochemical and pharmacological properties. A large number of heterocyclic compounds existing in the pharmaceutical market have marked anticancer activity and many of them are under research investigations to treat different types of cancers. Anticancer heterocyclic compounds show many shortcomings such as other anticancer agents in bioavailability and site-specific drug delivery resulting in toxicity and decreased patient compliance. These shortcomings can be eliminated by applying the principles of nanotechnology. The present review discloses the biochemical mechanism of action, different biological targets, intrinsic shortcomings, and structure-activity relationships of anticancer heterocyclic compounds. Furthermore, the role of different nanocarrier systems in selective biological targeting and alteration of pharmacokinetic and pharmacodynamic characteristics of anticancer heterocyclic compounds will be discussed in detail.

Overview of Inorganic Nanoparticles: An Expanding Horizon in Tumor Therapeutics.

BACKGROUND: Cancer is characterized by uncontrolled cell division in the human body damaging normal tissues. There are almost a hundred types of cancers studied to date that are conventionally treated with chemotherapy, radiation therapy, and surgery. Conventional methods have drawbacks like non-specific distribution of drugs, low concentration of drugs in tumors, and adverse effects like cardiotoxicity. Therefore, inorganic nanoparticles are explored nowadays to achieve better results in cancer treatment. OBJECTIVE: The objective of this review paper was to summarize the role of inorganic nanoparticles in cancer treatment by revealing their preclinical status and patents. METHODS: Literature survey for the present work was conducted by exploring various search engines like PubMed, Google Scholar, and Google patents. RESULTS: Inorganic nanoparticles come under the advanced category of nanomedicine explored in cancer therapeutics. The structural properties of inorganic nanoparticles make them excellent candidates for targeting, imaging, and eradication of cancer cells. Besides this, they also show high biocompatibility and minimum systemic toxicity. CONCLUSION: This review paper concludes that inorganic nanoparticles may be better alternatives to conventional approaches for the treatment of cancer. However, their presence in global pharmaceutical markets will be governed by the development of novel scale-up techniques and clinical evaluation.

Exploration of high dimensional free energy landscapes by a combination of temperature-accelerated sliced sampling and parallel biasing.

Temperature-accelerated sliced sampling (TASS) is an enhanced sampling method for achieving accelerated and controlled exploration of high-dimensional free energy landscapes in molecular dynamics simulations. With the aid of umbrella bias potentials, the TASS method realizes a controlled exploration and divide-and-conquer strategy for computing high-dimensional free energy surfaces. In TASS, diffusion of the system in the collective variable (CV) space is enhanced with the help of metadynamics bias and elevated-temperature of the auxiliary degrees of freedom (DOF) that are coupled to the CVs. Usually, a low-dimensional metadynamics bias is applied in TASS. In order to further improve the performance of TASS, we propose here to use a highdimensional metadynamics bias, in the same form as in a parallel bias metadynamics scheme. Here, a modified reweighting scheme, in combination with artificial neural network is used for computing unbiased probability distribution of CVs and projections of high-dimensional free energy surfaces. We first validate the accuracy and efficiency of our method in computing the four-dimensional free energy landscape for alanine tripeptide in vacuo. Subsequently, we employ the approach to calculate the eight-dimensional free energy landscape of alanine pentapeptide in vacuo. Finally, the method is applied to a more realistic problem wherein we compute the broad four-dimensional free energy surface corresponding to the deacylation of a drug molecule which is covalently complexed with a ß-lactamase enzyme. We demonstrate that using parallel bias in TASS improves the efficiency of exploration of high-dimensional free energy landscapes.

Synthesis, molecular docking and extensive structure activity relationship of substituted DHP derivatives: a new class of herbicides.

In the present study, twenty-two derivatives of dihydropyridine (DHP) have been synthesized using the Boric acid catalyst in solventless conditions. The synthesis was confirmed by FTIR analysis, 1HNMR, and 13CNMR analysis. The quantitative structure-activity relationship for all the synthesized derivatives was performed using an artificial neural network with correlation coefficient (R2) 0.8611, mean standard error 0.19, and Comparative molecular field analysis (CoMFA) with correlation coefficient (R2) 0.713, mean standard error 0.27. The molecular docking activity of synthesized compounds was tested using "AUTODOCK VINA" against "Acetohydroxyacid synthase protein receptors (PDB code 1YHZ)" acquired from the "RCSB Protein Data Bank". Docking experiments demonstrated favorable interaction among synthesized DHP derivatives and protein receptors with significant binding energy values. These synthesized derivatives have been screened for their pre-emergence herbicidal bioassay against weed species Echinochola crus galli, and the IC50 value were calculated and activity was compared with Butachlor, significant activity was exhibited by all the derivatives. All the synthesized compounds were also screened for their post emergence herbicidal activity against Echinochola crus galli, and the activity of DHPs were compared with penoxulum. All the synthesized compounds show good to moderate activity. Thus, it is concluded that substituted DHP derivatives may be developed as potential herbicides.

Left ventricular function and N-terminal pro b-type natriuretic peptide levels in women with hypertensive disorders of pregnancy: A prospective observational study.

To evaluate left ventricular function and measure N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in women with hypertensive disorders of pregnancy (HDP) in comparison to normotensive women and correlate these with maternal and neonatal outcomes. This was a prospective observational case-control study from 2018 to 2020 in an Indian tertiary care hospital and included antenatal women beyond 20 weeks of pregnancy with 160 women with HDP as cases and 160 normotensive women as controls. Echocardiography was performed to assess left ventricular structure and function. Quantitative analysis of NT-proBNP levels was performed based on fluorescence immunochromatography. Women with HDP were observed to have a significant difference in the value of left ventricular structure and function (P < 0.001). Mild systolic dysfunction was found in 13 (8.1%) women in the HDP group 8 (20%) women with severe pre-eclampsia and 5 (33.3%) women with eclampsia). Significantly lower values of left ventricular ejection fraction and higher values of NT-proBNP were recorded in women with HDP who developed maternal complications and had adverse neonatal outcomes (P < 0.001). Echocardiography and NT-proBNP levels have been shown to have a significant role in women with severe forms of HDP to detect early signs of cardiac dysfunction.

Corrigendum to: Oleic Acid Vesicles as a New Approach for Transdermal Delivery of Econazole Nitrate: Development, Characterization, and In-vivo Evaluation in Wistar Rats.

The authors wish to add words "Research Scholar" and "Research Supervisor" to their affiliations [1]. The original article can be found online at https://doi.org/10.2174/1574891X15999201110212725 The corrected affiliation is: 1Department of Pharmaceutics, Rayat-Bahra College of Pharmacy, Hoshiarpur, Punjab 146001, India; 2Faculty of Pharma-ceutical Sciences, Department of Pharmaceutics, PCTE Group of Institutes, Ludhiana, Punjab 142021, India; 3Research Scholar, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India; 4Research Supervisor, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India.

Corrigendum to: Transethosomes of Econazole Nitrate for Transdermal Delivery: Development, In-vitro Characterization, and Ex-vivo Assessment.

The authors wish to add words "Research Scholar" and "Research Supervisor" to their affiliations [1]. The original article can be found online at https://doi.org/10.2174/2211738506666180813122102.

Mean force based temperature accelerated sliced sampling: Efficient reconstruction of high dimensional free energy landscapes.

Temperature accelerated sliced sampling (TASS) is an efficient method to compute high dimensional free energy landscapes. The original TASS method employs the weighted histogram analysis method (WHAM) which is an iterative post-processing to reweight and stitch high dimensional probability distributions in sliced windows that are obtained in the presence of restraining biases. The WHAM necessitates that TASS windows lie close to each other for proper overlap of distributions and span the collective variable space of interest. On the other hand, increase in number of TASS windows implies more number of simulations, and thus it affects the efficiency of the method. To overcome this problem, we propose herein a new mean-force (MF) based reweighting scheme called TASS-MF, which enables accurate computation with a fewer number of windows devoid of the WHAM post-processing. Application of the technique is demonstrated for alanine di- and tripeptides in vacuo to compute their two- and four-dimensional free energy landscapes, the latter of which is formidable in conventional umbrella sampling and metadynamics. The landscapes are computed within a kcal mol-1 accuracy, ensuring a safe usage for broad applications in computational chemistry.

Robust immunity induced by multi-epitope DnaK peptides, potential vaccine candidates against Salmonella: An in vitro study.

Enteric fever is a common yet serious issue, most troublesome in underdeveloped and developing nations affecting all age group primarily children. Pitfalls of existing vaccines along with rapidly rising Multi-Drug-Resistant Salmonella strains necessitate the need for the development of new vaccine candidates having potential to provide complete protection. Several vaccine strategies are being pursued to stimulate protective immunity against typhoid, including conjugate vaccines for the elicitation of cellular and humoral responses as both arms of immunity are essential for complete protection. Bacterial HSPs are highly immunogenic to produce humoral and cellular immune responses. In this study, we are reporting in vitro immunostimulatory activity of immunodominant multi-epitope protective antigenic DnaK peptides identified earlier by immunoinformatics approach. Remarkable increase in antibody titer, lymphocyte proliferation, cytokines and NO level with individual /mixture of DnaK peptides as compared to control demonstrate immunogenic potential of these peptides that effectively augments both humoral and cellular immune responses. None of the peptides cause any hemolysis in human RBCs. Overall; our findings strongly elucidate the immune-stimulatory potential of DnaK peptides to be explored as potent vaccine candidates against multiple pathogens.

Multi-epitope DnaK peptide vaccine accords protection against lethal S. typhimurium challenge: Elicits both cell mediated immunity and long-lasting serum-neutralizing antibody titers.

Typhoid vaccine development has been impeded by inability of currently available vaccines to induce cellular immunity along with neutralizing antibodies against all serovars of S. Typhi and S. Paratyphi. Unfortunately, antibiotic treatment has shown to be an ineffective therapy due to development of resistance against multiple antibiotics. In the present study, we have explored the immunogenicity and protective efficacy of in-silico designed multi-epitope DnaK peptides as candidate vaccine molecules against Salmonella. Immunization studies in mouse typhoid model revealed three of these peptides (DP1, DP5 and DP7) are highly efficacious, stimulating both humoral and cell mediated immunity along with long lasting antibody memory response. There was significant increase in antibody titers (IgG, IgG1, IgG2a, IgA and IgM), lymphocyte proliferative responses and cytokine levels. Immunized groups showed marked reduction in organ bacterial load, fecal shedding and pronounced protection (upto 80%) as compared to unimmunized controls after challenge with S. typhimurium. Our results demonstrate the huge potential of DnaK peptide vaccine candidates (DP1, DP5 and DP7) to accord protective immunity with significant increase in survivability against Salmonella infection in mice, thus commending these molecules as promising agents to tackle typhoid.

Oleic Acid Vesicles as a new Approach for Transdermal Delivery of Econazole Nitrate: Development, Characterization, and In-vivo Evaluation in Wistar rats.

BACKGROUND: Cutaneous candidiasis is a deep-seated skin fungal infection that is most commonly observed in immunocompromised patients. This fungal infection is conventionally treated with various formulations like gels and creams which are having different side effects and least therapeutic efficacy. Hence, it becomes necessary to develop a novel carrier system for the treatment of this deep-seated skin fungal infection. Econazole nitrate is the most widely used antifungal for the treatment of cutaneous candidiasis, therefore, in present research work we developed and evaluated econazole nitrate loaded oleic acid vesicles for treatment of cutaneous candidiasis through transdermal route. METHODS: Econazole nitrate loaded oleic acid vesicles were prepared by thin-film hydration and characterized for drug entrapment, vesicle size, zeta potential, polydispersity index (PDI), Fourier Transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis. Furthermore, the oleic acid vesicular gel was evaluated for ex-vivo skin permeation/retention and in-vitro and in-vivo antifungal activity in Wistar rats. RESULTS: Econazole nitrate loaded oleic acid vesicles showed high encapsulation of drug (74.76 ± 3.0%), acceptable size (373.4 ± 2.9 nm), and colloidal characteristics (PDI = 0.231 ± 0.078, zeta potential = -13.27 ± 0.80 mV). The oleic acid vesicular gel showed high skin permeation (Transdermal flux = 61.98 ± 2.45 µg/cm2/h), skin retention (35.90 ± 2.06%), in-vitro, and in-vivo antifungal activity compared to marketed cream (EcodermR) of econazole nitrate for a prolonged period of time (4 days). CONCLUSION: Developed econazole nitrate loaded oleic acid vesicles could be used effectively in the treatment of cutaneous candidiasis with minimization of side effects of econazole nitrate with increased therapeutic efficacy.

A Novel Case of Spontaneous Coronary Artery Dissection During Cabergoline Therapy for Prolactinoma.

We present a case of spontaneous coronary artery dissection associated with cabergoline treatment for prolactinoma. A 31-year-old woman with history of hypertension and prolactinoma, treated with cabergoline, presented with chest pain. She had non-ST-segment elevation myocardial infarction with double vessel coronary artery dissection and was treated with coronary artery bypass grafting. (Level of Difficulty: Beginner.).

Percutaneous Closure of the Patent Foramen Ovale on Right Ventricular Mechanical Circulatory Support.

Right ventricular infarction can precipitate severe right-to-left shunting and refractory hypoxia from a previously dormant patent foramen ovale. Right ventricle mechanical circulatory support and patent foramen ovale closure can play a crucial role in the treatment of hypoxia and right ventricular recovery. We report a case of successful percutaneous patent foramen ovale closure on right ventricle mechanical circulatory support in a patient with right ventricular shock. (Level of Difficulty: Intermediate.).

Vesicular nanocarrier based treatment of skin fungal infections: Potential and emerging trends in nanoscale pharmacotherapy.

Occurrence of skin fungal infections is increasing nowadays and their presence is more prominent in patients suffering from immunocompromised diseases like AIDS. Skin fungal infections are a major cause of visits by patients to dermatology clinics. Although, a large number of antifungal agents are available for treatment of skin fungal infections, but, their toxic profile and physicochemical characteristics reduce therapeutic outcome. When these antifungal agents are delivered topically using conventional formulations like creams and gels, they may cause various side effects like redness, burning, and swelling at the site of application. Therefore, various vesicular formulations (phospholipid based or non phospholipid based) have been explored by pharmaceutical scientists to treat skin fungal infections topically. Vesicular formulation explored for the purpose are liposomes, ethosomes, transfersomes, transethosomes, niosomes, spanlastics, oleic acid vesicles, and nanoparticles. These formulations show various advantages like bioavailability enhancement of bioactives, high skin permeation power, no side effects at application site, dosing frequency reduction, and sustained drug release. Therefore, in the present article, we have discussed about the utility of various vesicular nanocarrier systems to treat skin fungal infections.

Nanotechnological Carriers for Treatment of Acne.

BACKGROUND: Acne is a multifactorial skin disease associated with pilosebaceous unit and caused by bacteria Propionibacterium acnes and Acne vulgaris. Near about 95% people throughout the world suffer from acne at some point in their life span. This disease is more prominent in adults compared to neonates and prepubescent children. Conventionally it is treated with either creams or gels having large number of side effects on patients. METHODS: We searched about recent advancements in the use of nanotechnological carriers for effective treatment of acne. We focused on the use of liposomes, niosomes, microemulsions, microsponge, microspheres, and nanoparticles to improve anti-acne therapy. Patents regarding use of nanocarrier systems to eliminate acne were also discussed in this review. RESULTS: The encapsulation of anti-acne drugs in various nanotechnological carriers improve their efficacy and reduce side effects. These carriers show controlled drug release and improved drug penetration even upto pilosebaceous unit of skin. Local tolerability of anti-acne molecules can be improved by adjusting the concentration in nanotechnological carriers. CONCLUSIONS: Nanotechnological carriers have opened a new window to design novel, effective and low dose systems for effective eradication acne disease. However, very few nanocarrier based formulations are available in market for topical use and much progress is required in this field to improve anti-acne therapy.

Transethosomes of Econazole Nitrate for Transdermal Delivery: Development, In-vitro Characterization, and Ex-vivo Assessment.

BACKGROUND: Transdermal drug delivery is an attractive approach for both local and systemic therapeutics of various diseases. Transdermal drug delivery systems show various advantages like reduction of local irritation, prevention of first-pass hepatic metabolism, and bioavailability enhancement of bioactive molecules over conventional drug delivery systems. OBJECTIVE: The main objective of the present research work was to develop and characterize (in-vitro and ex-vivo) econazole nitrate loaded transethosomes and their comparison with marketed cream of econazole nitrate [Ecoderm, Brown and Burk Pharmaceutical (Pvt.) Ltd., Bengaluru, India] for effective transdermal delivery. METHOD: Transethosomes loaded with econazole nitrate were developed by homogenization method and evaluated for entrapment (%), vesicular size, zeta potential, polydispersity index (PDI), and invitro drug release. Furthermore, optimized econazole nitrate loaded transethosomes were added to Carbopol 934 gel and this gel was evaluated for viscosity, pH, drug content, ex-vivo skin permeation and retention studies followed by in-vitro antifungal activity against C. albicans fungus. RESULTS: The optimized transethosomes loaded with econazole nitrate showed vesicle size of 159.3 ± 4.3 nm, entrapment efficiency about 78.3 ± 2.8%, acceptable colloidal properties like (zeta potential = -27.13 ± 0.33 mV, PDI = 0.244 ± 0.045), approximately 57.56 ± 2.33% drug release up to 24 h. Results of DSC analysis confirmed the encapsulation of econazole nitrate inside transethosomes. Optimized transethosomes showed drug release following zero order through diffusion mechanism. Transethosomal gel showed high drug content (92.35 ± 0.63%) and acceptable values of pH (5.68 ± 0.86) or viscosity (10390 ± 111 cPs). Transethosomal gel showed less ex-vivo skin penetration (17.53 ± 1.20%), high ex-vivo skin retention (38.75 ± 2.88%), and high in-vitro antifungal activity compared to the marketed cream of econazole nitrate. CONCLUSION: Therefore, it can be concluded that econazole nitrate loaded transethosomes are effective to deliver econazole nitrate transdermally in a controlled fashion for effective elimination of cutaneous candidiasis.

Multi-epitope DnaK peptide vaccine against S.Typhi: An in silico approach.

Salmonella is one of the key global causes of food and water borne enteric infections, responsible for significant morbidity and mortality worldwide especially in developing countries. Currently available vaccines against typhoid are moderately effective with several side effects and not efficacious against all Salmonella serovars. Due to limitations of these vaccines and emerging threats of multidrug resistance, developing an effective vaccine against these infections has increasingly become a priority. Heat shock proteins (Hsps), being evolutionarily conserved, represent dominant antigens in the host immune response. In continuation of our earlier studies on the development of S. Typhi DnaK and GroEL vaccine candidates, highly efficacious against Salmonella and multiple pathogens, in the present study, we have designed multi-epitope vaccine candidates common to multiple serovars of Salmonella using bioinformatics approach. Implementing various immunoinformatics tools such as IEDB, EpiJen, BCPRED, ElliPro and VaxiJen, led to the identification of many immunogenic B and T cell epitopes. The 3-D structure model of DnaK was generated to predict conformational B-cell epitopes using ElliPro server. Most promising T cell epitopes (29 CTLs, 18 T-helper cells) were selected based on their binding efficiency with commonly occurring MHC alleles. Finally we narrowed down to 5 protective antigenic peptides (PAPs), comprising highly conserved, antigenic and immunogenic B /T cell epitopes, least homologous with human host. These PAPs were predicted to be non-allergenic by allergenicity prediction tools (SORTALLER and AllerHunter). Hence, these immunogenic epitopes can be used for prophylactic or therapeutic usages specifically to defeat antibiotic-resistant Salmonella. These antigens have been reported for the first time and their conserved nature endow them as potential future vaccine candidates against other multiple pathogens as well.