Current development of therapeutic vaccines for the treatment of chronic infectious diseases.

Chronic infectious diseases refer to diseases that require a long period of time from onset to cure or death, the use of therapeutic vaccines has recently emerged to eradicate diseases. Currently, clinical research is underway to develop therapeutic vaccines for chronic infectious diseases based on various vaccine formulations, and the recent success of the messenger RNA vaccine platform and efforts to apply it to therapeutic vaccines are having a positive impact on conquering chronic infectious diseases. However, since research on the development of therapeutic vaccines is still relatively lacking compared to prophylactic vaccines, there is a need to focus more on the development of therapeutic vaccines to overcome threats to human health caused by chronic infectious diseases. In order to accelerate the development of therapeutic vaccines for chronic infectious diseases in the future, it is necessary to establish a clear concept of therapeutic vaccines suitable for the characteristics of each chronic infectious disease, as well as standardize vaccine effectiveness evaluation methods, secure standards/reference materials, and simplify the vaccine approval procedure.

Ecological monitoring of urban thermal field variance index and determining the surface urban heat island effects in Lahore, Pakistan.

Lahore is the second major metropolitan city in Pakistan in terms of urban population and built-up area, making the city a more ideal place to form the surface urban heat island (SUHI) effects. In the last two decades, the considerable land-use conversion from a natural surface (vegetation) and permeable (waterbody) surface into an impervious (built-up area) surface has lead to an increase in land surface temperature (LST) in Lahore. The human thermal comfort (HTC) of the residents is also impacted by the higher LST. The present study uses multi-temporal Landsat (5&8) satellite imageries to examine the ecological and thermal conditions of Lahore between 2000 and 2020. The ecological and thermal conditions of Lahore are assessed by calculating the urban heat islands and UTFVI (urban thermal field variance index), based on LST data which quantitatively assessed the UHI effect and the quality of human life. The outcomes establish that the urban built-up area has increased by 18%, while urban vegetation, vacant land, and waterbody decreased by 13%, 4%, and 0.04%, respectively. In the last 20 years, the mean LST of the study region has risen by about 3.67 °C. The UHI intensity map shows intensification and a rise in surface temperature variation from 4.5 °C (2000) to 5.9 °C (2020). Furthermore, the finding shows that the ecological and thermal conditions are worse in construction sites, transition zones, and urban areas in comparison to nearby rural areas. The lower UTFVI was observed in dense vegetation cover areas while a hot spot of higher UTFVI was predominantly observed in the areas of transition zones and built-up area expansion. Those areas with higher hot spots are more vulnerable to the urban heat island effect. The main conclusions of this study are essential for educating city officials and urban planners in developing a sustainable urban land development plan to reduce urban heat island effects by investing in open green spaces for urban areas of cities.

Oncolytic Virotherapy.

Oncolytic virotherapy opens up avenues for cancer treatment by selectively targeting the cancer cells and destructs them either through direct lysis or by inducing an immune response in the tumor microenvironment. This platform technology utilizes a diverse range naturally existing or genetically modified oncolytic viruses for their immunotherapeutic potential. Due to the limitations associated with the conventional cancer therapies, immunotherapies using oncolytic viruses (OVs) have generated a great deal of interest in the modern era. Currently, several oncolytic viruses have entered clinical trials and have proven successful for a number of different cancers as monotherapies as well as in combination with the standard treatment methods like chemotherapy, radiotherapy, or immunotherapy. Efficacy of OVs can be further enhanced by utilizing several approaches. Efforts of the scientific community for getting better knowledge of individual patient tumor immune responses will enable medical community to treat cancer patients more precisely. In this regard, OV seems to be a part of multimodality cancer treatment option in the near future. In this chapter, the fundamental characteristics and mechanism of actions of oncolytic viruses are initially described and then overview of the important clinical trials of various oncolytic viruses for a number of cancers is presented.

High-risk spatiotemporal patterns of cutaneous leishmaniasis: a nationwide study in Iran from 2011 to 2020.

BACKGROUND: Cutaneous leishmaniasis (CL) is a wide-reaching infection of major public health concern. Iran is one of the six most endemic countries in the world. This study aims to provide a spatiotemporal visualization of CL cases in Iran at the county level from 2011 to 2020, detecting high-risk zones, while also noting the movement of high-risk clusters. METHODS: On the basis of clinical observations and parasitological tests, data of 154,378 diagnosed patients were obtained from the Iran Ministry of Health and Medical Education. Utilizing spatial scan statistics, we investigated the disease's purely temporal, purely spatial, spatial variation in temporal trends and spatiotemporal patterns. At P = 0.05 level, the null hypothesis was rejected in every instance. RESULTS: In general, the number of new CL cases decreased over the course of the 9-year research period. From 2011 to 2020, a regular seasonal pattern, with peaks in the fall and troughs in the spring, was found. The period of September-February of 2014-2015 was found to hold the highest risk in terms of CL incidence rate in the whole country [relative risk (RR) = 2.24, P < 0.001)]. In terms of location, six significant high-risk CL clusters covering 40.6% of the total area of the country were observed, with the RR ranging from 1.87 to 9.69. In addition, spatial variation in the temporal trend analysis found 11 clusters as potential high-risk areas that highlighted certain regions with an increasing tendency. Finally, five space-time clusters were found. The geographical displacement and spread of the disease followed a moving pattern over the 9-year study period affecting many regions of the country. CONCLUSIONS: Our study has revealed significant regional, temporal, and spatiotemporal patterns of CL distribution in Iran. Over the years, there have been multiple shifts in spatiotemporal clusters, encompassing many different parts of the country from 2011 to 2020. The results reveal the formation of clusters across counties that cover certain parts of provinces, indicating the importance of conducting spatiotemporal analyses at the county level for studies that encompass entire countries. Such analyses, at a finer geographical scale, such as county level, might provide more precise results than analyses at the scale of the province.

The COVID-19 Mortality Rate Is Associated with Illiteracy, Age, and Air Pollution in Urban Neighborhoods: A Spatiotemporal Cross-Sectional Analysis.

There are different area-based factors affecting the COVID-19 mortality rate in urban areas. This research aims to examine COVID-19 mortality rates and their geographical association with various socioeconomic and ecological determinants in 350 of Tehran's neighborhoods as a big city. All deaths related to COVID-19 are included from December 2019 to July 2021. Spatial techniques, such as Kulldorff's SatScan, geographically weighted regression (GWR), and multi-scale GWR (MGWR), were used to investigate the spatially varying correlations between COVID-19 mortality rates and predictors, including air pollutant factors, socioeconomic status, built environment factors, and public transportation infrastructure. The city's downtown and northern areas were found to be significantly clustered in terms of spatial and temporal high-risk areas for COVID-19 mortality. The MGWR regression model outperformed the OLS and GWR regression models with an adjusted R2 of 0.67. Furthermore, the mortality rate was found to be associated with air quality (e.g., NO2, PM10, and O3); as air pollution increased, so did mortality. Additionally, the aging and illiteracy rates of urban neighborhoods were positively associated with COVID-19 mortality rates. Our approach in this study could be implemented to study potential associations of area-based factors with other emerging infectious diseases worldwide.

The role of dietary antioxidants in type 2 diabetes and neurodegenerative disorders: An assessment of the benefit profile.

Healthy diet is vital to cellular health. The human body succumbs to numerous diseases which afflict severe economic and psychological burdens on the patient and family. Oxidative stress is a possible crucial regulator of various pathologies, including type 2 diabetes and neurodegenerative diseases. It generates reactive oxygen species (ROS) that trigger the dysregulation of essential cellular functions, ultimately affecting cellular health and homeostasis. However, lower levels of ROS can be advantageous and are implicated in a variety of signaling pathways. Due to this dichotomy, the terms oxidative "eustress," which refers to a good oxidative event, and "distress," which can be hazardous, have developed. ROS affects multiple signaling pathways, leading to compromised insulin secretion, insulin resistance, and ß-cell dysfunction in diabetes. ROS is also associated with increased mitochondrial dysfunction and neuroinflammation, aggravating neurodegenerative conditions in the body, particularly with age. Treatment includes drugs/therapies often associated with dependence, side effects including non-selectivity, and possible toxicity, particularly in the long run. It is imperative to explore alternative medicines as an adjunct therapy, utilizing natural remedies/resources to avoid all the possible harms. Antioxidants are vital components of our body that fight disease by reducing oxidative stress or nullifying the excess toxic free radicals produced under various pathological conditions. In this review, we focus on the antioxidant effects of components of dietary foods such as tea, coffee, wine, oils, and honey and the role and mechanism of action of these antioxidants in alleviating type 2 diabetes and neurodegenerative disorders. We aim to provide information about possible alternatives to drug treatments used alone or combined to reduce drug intake and encourage the consumption of natural ingredients at doses adequate to promote health and combat pathologies while reducing unwanted risks and side effects.

Molecular Analysis and Conformational Dynamics of Human MC4R Disease-Causing Mutations.

Obesity is a chronic disease with increasing cases among children and adolescents. Melanocortin 4 receptor (MC4R) is a G protein-coupled transporter involved in solute transport, enabling it to maintain cellular homeostasis. MC4R mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. A number of mutations have been reported in MC4R that are responsible for causing obesity and related complications. Delineating these mutations and analyzing their effect on MC4R's structure will help in the clinical intervention of the disease condition as well as designing potential drugs against it. Sequence-based pathogenicity and structure-based protein stability analyses were conducted on naturally occurring variants. We used computational tools to analyze the conservation of these mutations on MC4R's structure to map the structural variations. Detailed structural analyses were carried out for the active site mutations (i.e., D122N, D126Y, and S188L) and their influence on the binding of calcium and the agonist or antagonist. We performed molecular dynamics (MD) simulations of the wild-type and selected mutations to delineate the conformational changes, which provided us with possible reasons for MC4R's instability in these mutations. This study provides insight into the potential direction toward understanding the molecular basis of MC4R dysfunction in disease progression and obesity.

Characterization of rotavirus strains isolated from children with acute gastroenteritis in Rawalpindi, Pakistan.

Diarrhea is the leading cause of childhood morbidity and mortality particularly in developing countries and rotavirus has been identified as the major pathogen associated with diarrheal infections. This study was conducted to detect genotypic distribution of predominant rotavirus strains circulating in children suffering from acute gastroenteritis in Rawalpindi, Pakistan. Stool specimens were collected from children ≤5 years of age, visiting Military Hospital, Rawalpindi, with signs and symptoms of acute gastroenteritis. Two hundred and eighty-four specimens were collected during the period from April 2017 to March 2018. Enzyme immunoassay was performed for detection of rotavirus and reverse transcription-PCR (RT-PCR) was carried out for amplification of VP7 and VP4 gene segments followed by multiplex PCR using genotype-specific primers. Out of 284 children, 71 were found rotavirus positive and among them, 54% were females and 46% males. Our findings showed 92% of infection among children ≤2 years of age, while, the peak age of rotavirus incidence was found to be 6-12 months. Although, rotavirus infection was observed throughout the year but frequency increased in winter. Subtype G1P[8] was more prevalent followed by G2P[4], G3P[8], and G4P[6] subtypes. The results of this study provide insight into the disease burden as well as information on rotavirus diversity which will be useful to develop future strategies to control and prevent diarrheal infections among children.

Plasma Bead Entrapped Liposomes as a Potential Drug Delivery System to Combat Fungal Infections.

Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic efficacy exploiting innovative ideas, including the use of plasma alginate composite matrices, proteolytic inhibitors, cross linkers, and dual entrapment in various liposomal formulations. In vitro efficacy of the different formulations was examined. Pharmacokinetics of the formulations encapsulating Amphotericin B (AmpB), an antifungal compound, were investigated in Swiss albino mice. While administration of the free AmpB led to its rapid elimination (<72 h), PB/liposome-PB systems were significantly effective in sustaining AmpB release in the circulation (>144 h) and its gradual accumulation in the vital organs, also compared to the liposomal formulations alone. Interestingly, the slow release of AmpB from PB was unusual compared to other small molecules in our earlier findings, suggesting strong interaction with plasma proteins. Molecular interaction studies of bovine serum albumin constituting approximately 60% of plasma with AmpB using isothermal titration calorimetry and in silico docking verify these interactions, explaining the slow release of AmpB entrapped in PB alone. The above findings suggest that PB/liposome-PB could be used as safe and effective delivery systems to combat fungal infections in humans.

Melanocortin-4 receptor complexity in energy homeostasis,obesity and drug development strategies.

The melanocortin-4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease-causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain-of-function variants seem to rescue obesity and related complications via specific pathways such as beta-arrestin (ß-arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß-arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha-melanocyte-stimulating hormone is the major endogenous MC4R agonist, but structure-based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity.

The role of amyloids in Alzheimer's and Parkinson's diseases.

With varying clinical symptoms, most neurodegenerative diseases are associated with abnormal loss of neurons. They share the same common pathogenic mechanisms involving misfolding and aggregation, and these visible aggregates of proteins are deposited in the central nervous system. Amyloid formation is thought to arise from partial unfolding of misfolded proteins leading to the exposure of hydrophobic surfaces, which interact with other similar structures and give rise to form dimers, oligomers, protofibrils, and eventually mature fibril aggregates. Accumulating evidence indicates that amyloid oligomers, not amyloid fibrils, are the most toxic species that causes Alzheimer's disease (AD) and Parkinson's disease (PD). AD has recently been recognized as the 'twenty-first century plague', with an incident rate of 1% at 60 years of age, which then doubles every fifth year. Currently, 5.3 million people in the US are afflicted with this disease, and the number of cases is expected to rise to 13.5 million by 2050. PD, a disorder of the brain, is the second most common form of dementia, characterized by difficulty in walking and movement. Keeping the above views in mind, in this review we have focused on the roles of amyloid in neurodegenerative diseases including AD and PD, the involvement of amyloid in mitochondrial dysfunction leading to neurodegeneration, are also considered in the review.

Safety of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease.

BACKGROUND: Patients with pre-existing autoimmune disease (AD) have been largely excluded from clinical trials of immune checkpoint inhibitors (ICI), so data on safety of ICIs among patients with pre-existing AD are relatively limited. There is a need for deeper understanding of the type and management of complications from ICI in patients with pre-existing AD. We sought to investigate the safety of ICIs in patients with pre-existing ADs as well as factors associated with AD flare. METHODS: Consecutive patients with pre-existing AD who received monotherapy as well as combination of ICI therapies at our institution from September 2015 through September 1st, 2018 were identified. Clinical information was abstracted via manual chart review. Clinical factors associated with AD flare were determined using multivariable logistic regression. RESULTS: A total of 42 patients were identified of whom 12 developed AD flare. All flares were treated with oral or topical corticosteroids, while a patient with flare of rheumatoid arthritis was treated with tofacitinib and another patient with Crohn's flare was treated with infliximab. Female sex, smoking status, higher age at the start of ICI therapy, cancer type, such as melanoma and lung cancer as compared to other cancers, were not significantly associated with AD flare, however, patients with underlying rheumatologic AD were noted to have a five times greater likelihood of flare as compared to other non-rheumatologic AD. Nine patients developed new immune related adverse events (IRAEs) unrelated to underlying AD, such as inflammatory poly-arthropathy, neuropathy, hypothyroidism, diarrhea, lichenoid drug eruptions, which were managed with oral and/or topical corticosteroids. ICI was stopped in six patients due to AD flare, in four patients due to IRAE flare (out of which one resumed ICI after resolution of IRAE). CONCLUSIONS: In patients with pre-existing AD treated with ICI, AD flare occurred in 28% of patients and were managed successfully with corticosteroids alone or with additional disease-modifying therapies. ICI could be considered in patients with AD, but with very close monitoring and preemptive multidisciplinary collaboration.

Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies.

Protein misfolding and aggregation can be induced by a wide variety of factors, such as dominant disease-associated mutations, changes in the environmental conditions (pH, temperature, ionic strength, protein concentration, exposure to transition metal ions, exposure to toxins, posttranslational modifications including glycation, phosphorylation, and sulfation). Misfolded intermediates interact with similar intermediates and progressively form dimers, oligomers, protofibrils, and fibrils. In amyloidoses, fibrillar aggregates are deposited in the tissues either as intracellular inclusion or extracellular plaques (amyloid). When such proteinaceous deposit occurs in the neuronal cells, it initiates degeneration of neurons and consequently resulting in the manifestation of various neurodegenerative diseases. Several different types of molecules have been designed and tested both in vitro and in vivo to evaluate their anti-amyloidogenic efficacies. For instance, the native structure of a protein associated with amyloidosis could be stabilized by ligands, antibodies could be used to remove plaques, oligomer-specific antibody A11 could be used to remove oligomers, or prefibrillar aggregates could be removed by affibodies. Keeping the above views in mind, in this review we have discussed protein misfolding and aggregation, mechanisms of protein aggregation, factors responsible for aggregations, and strategies for aggregation inhibition.

Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial cell dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions.

Geospatial Analysis of COVID-19: A Scoping Review.

The outbreak of SARS-CoV-2 in Wuhan, China in late December 2019 became the harbinger of the COVID-19 pandemic. During the pandemic, geospatial techniques, such as modeling and mapping, have helped in disease pattern detection. Here we provide a synthesis of the techniques and associated findings in relation to COVID-19 and its geographic, environmental, and socio-demographic characteristics, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) methodology for scoping reviews. We searched PubMed for relevant articles and discussed the results separately for three categories: disease mapping, exposure mapping, and spatial epidemiological modeling. The majority of studies were ecological in nature and primarily carried out in China, Brazil, and the USA. The most common spatial methods used were clustering, hotspot analysis, space-time scan statistic, and regression modeling. Researchers used a wide range of spatial and statistical software to apply spatial analysis for the purpose of disease mapping, exposure mapping, and epidemiological modeling. Factors limiting the use of these spatial techniques were the unavailability and bias of COVID-19 data-along with scarcity of fine-scaled demographic, environmental, and socio-economic data-which restrained most of the researchers from exploring causal relationships of potential influencing factors of COVID-19. Our review identified geospatial analysis in COVID-19 research and highlighted current trends and research gaps. Since most of the studies found centered on Asia and the Americas, there is a need for more comparable spatial studies using geographically fine-scaled data in other areas of the world.

Ligand decorated biodegradable nanomedicine in the treatment of cancer.

Cancer is one of the major global health problems, responsible for the second-highest number of deaths. The genetic and epigenetic changes in the oncogenes or tumor suppressor genes alter the regulatory pathways leading to its onset and progression. Conventional methods are used in appropriate combinations for the treatment. Surgery effectively treats localized tumors; however, it fails to treat metastatic tumors, leading to a spread in other organs, causing a high recurrence rate and death. Among the different strategies, the nanocarriers-based approach is highly sought for, but its nonspecific delivery can cause a profound side effect on healthy cells. Targeted nanomedicine has the advantage of targeting cancer cells specifically by interacting with the receptors overexpressed on their surface, overcoming its non-specificity to target healthy cells. Nanocarriers prepared from biodegradable and biocompatible materials are decorated with different ligands by encapsulating therapeutic or diagnostic agents or both to target cancer cells overexpressing the receptors. Scientists are now utilizing a theranostic approach to simultaneously evaluate nanocarrier bio-distribution and its effect on the treatment regime. Herein, we have summarized the recent 5-year efforts in the development of the ligands decorated biodegradable nanocarriers, as a targeted nanomedicine approach, which has been highly promising in the treatment of cancer.

Impact of autoimmune rheumatic diseases on birth outcomes: a population-based study.

Objectives: Autoimmune rheumatic diseases (ARDs) affect women of childbearing age and have been associated with adverse birth outcomes. The impact of diseases like ankylosing spondylitis and psoriatic arthritis (PsA) on birth outcomes remains less studied to date. Our objective was to evaluate the impact of ARDs on preterm birth (PTB), congenital anomalies, low birth weight (LBW) and small for gestational age (SGA), in a large cohort of women. Methods: We conducted a propensity score-matched analysis to predict ARD from a retrospective birth cohort of all live, singleton births in California occurring between 2007 and 2012. Data were derived from birth certificate records linked to hospital discharge International Classification of Diseases, ninth revision codes. Results: We matched 10 244 women with a recorded ARD diagnosis (rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome, PsA); ankylosing spondylitis and juvenile idiopathic arthritis (JIA) to those without an ARD diagnosis. The adjusted OR (aOR) of PTB was increased for women with any ARD (aOR 1.93, 95% CI 1.78 to 2.10) and remained significant for those with RA, SLE, PsA and JIA. The odds of LBW and SGA were also significantly increased among women with an ARD diagnosis. ARDs were not associated with increased odds of congenital anomalies. Conclusion: Consistent with prior literature, we found that women with ARDs are more likely to have PTB or deliver an SGA infant. Some reassurance is provided that an increase in congenital anomalies was not found even in this large cohort.

Nanoparticle formulations in the diagnosis and therapy of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common age-related diseases that occurs because of the deposition of amyloid fibrils in a form of extracellular plaques containing ß-amyloid peptide (Aß) and tangles are found as intracellular deposit in the brain made up of twisted strands of aggregated microtubule binding protein. Scores of small molecule inhibitors have been designed for the treatment of AD. However some of these drugs cannot pass through the brain-blood-barrier (BBB). To overcome this problem, various nanoparticles (NPs) or nanomedicines (NMs) have been synthesized. These nanoparticles exploit the existing physiological mechanisms of passing through the BBB, including receptor- and adsorptive-mediated transcytosis that facilitate the transcellular transport of nanoparticle from the blood to the brain. During the last decades, varieties of nanoparticles that differ in the composition have been developed, and they have the potential application in the diagnostics and therapy of AD. The most common NP formulations that have major impact in the diagnosis and therapy of AD include polymeric NPs (PPs), gold NPs, gadolinium NPs, selenium NPs, protein-based NPs, polysaccharide-based NPs, etc. The goal of this review is to provide discussion of the application of different types of NP formulations in the diagnosis and therapy of AD.

Ionic gradient liposomes: Recent advances in the stable entrapment and prolonged released of local anesthetics and anticancer drugs.

Liposomes have established themselves as great pharmaceutical carriers over the past three decades. These phospholipid vesicular systems have undergone great technical advances including remote drug loading, targeted delivery, and combinatorial drug therapy. Ionic gradient liposomes (IGL) necessitates active loading of the drug in preformed vesicles exhibiting a transmembrane pH or ion gradient, with a low intra liposome pH (∼ 4-5), and a high outside pH (∼7-8). It allows high drug encapsulation and prolonged release, particularly for amphipathic weak acids and weak bases. Most local anesthetics (Bupivacaine, Ropivacaine, Tetracaine, and others) have a pka in the range of 7-9, which makes them ideal candidates for their entrapment in IGL. The same is true for most anthracyclines which have great anti-tumor properties (Doxorubicin, Daunorubicin, Idarubicin, and others). Many FDA approved liposomal drugs utilise ion gradient for their encapsulation. Considering their immense utility, we summarize here in this review, the recent contributions made by various research groups utilizing IGL, to accentuate the development of these carriers in drug delivery. This would possibly be helpful in carrying new investigations and further contributions in the optimization and advancements of new drugs for better therapeutics.

Emerging Targets and Latest Proteomics Based Therapeutic Approaches in Neurodegenerative Diseases.

Protein homeostasis (proteostasis) is achieved by the interplay among various components and pathways inside a cell. Dysfunction in proteostasis leads to protein misfolding and aggregation which is ubiquitously associated with many neurodegenerative disorders, although the exact role of these aggregate in the pathogenesis remains unknown. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others are characterized by the conversion of specific protein aggregates into protein inclusions and/or plaques in degenerating brains. Apart from the conventional disease specific proteins, such as amyloid-ß, α - synuclein, huntingtin protein, and prions that are known to aggregate, a number of other proteins play a vital role in aggravating the disease condition. In this review, we discuss the disease etiology, mechanism, the role of various pathways, molecular machinery including molecular chaperones, protein degradation pathways, and the active formation of inclusions in various neurodegenerative diseases. We also highlight the approaches, strategies, and methods that have been used for the treatment of these complex diseases over the years and the efforts that have potential in the near future.