Corrigendum to 'Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics' [Genes & Diseases 10 (2023) 1367-1401].

[This corrects the article DOI: 10.1016/j.gendis.2022.02.007.].

Epigenetic Switches in Retinal Homeostasis and Target for Drug Development.

Retinal homeostasis, a tightly regulated process maintaining the functional integrity of the retina, is vital for visual function. Emerging research has unveiled the critical role of epigenetic regulation in controlling gene expression patterns during retinal development, maintenance, and response to mutational loads and injuries. Epigenetic switches, including DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in orchestrating retinal gene expression and cellular responses through various intracellular, extracellular, and environmental modulators. This review compiles the current knowledge on epigenetic switches in retinal homeostasis, providing a deeper understanding of their impact on retinal structural integrity and function and using them as potential targets for therapeutic interventions.

Derailed protein turnover in the aging mammalian brain.

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/.

Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H-/- mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/- mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.

Next Generation Mucosal Vaccine Strategy for Respiratory Pathogens.

Inducing humoral and cytotoxic mucosal immunity at the sites of pathogen entry has the potential to prevent the infection from getting established. This is different from systemic vaccination, which protects against the development of systemic symptoms. The field of mucosal vaccination has seen fewer technological advances compared to nucleic acid and subunit vaccine advances for injectable vaccine platforms. The advent of the next-generation adenoviral vectors has given a boost to mucosal vaccine research. Basic research into the mechanisms regulating innate and adaptive mucosal immunity and the discovery of effective and safe mucosal vaccine adjuvants will continue to improve mucosal vaccine design. The results from clinical trials of inhaled COVID-19 vaccines demonstrate their ability to induce the proliferation of cytotoxic T cells and the production of secreted IgA and IgG antibodies locally, unlike intramuscular vaccinations. However, these mucosal vaccines induce systemic immune responses at par with systemic vaccinations. This review summarizes the function of the respiratory mucosa-associated lymphoid tissue and the advantages that the adenoviral vectors provide as inhaled vaccine platforms.

Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity.

BACKGROUND: The accumulation of amyloid beta (Aß) peptides in fibrils is prerequisite for Alzheimer's disease (AD). Our understanding of the proteins that promote Aß fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts. METHODS: To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy. We benchmarked the success of our purifications using electron microscopy, amyloid dyes, and a large panel of Aß immunoassays. Tandem mass-spectrometry based proteomic analysis workflows provided quantitative measures of the amyloid fibril proteome. These methods allowed us to compare amyloid fibril composition from human AD brains, three amyloid mouse models, transgenic Aß42 flies, and Aß42 seeded cultured neurons. RESULTS: Amyloid fibrils are primarily composed by Aß42 and unexpectedly harbor Aß38 but generally lack Aß40 peptides. Multidimensional quantitative proteomics allowed us to redefine the fibril proteome by identifying 20 new amyloid-associated proteins. Notably, we confirmed 57 previously reported plaque-associated proteins. We validated a panel of these proteins as bona fide amyloid-interacting proteins using antibodies and orthogonal proteomic analysis. One metal-binding chaperone metallothionein-3 is tightly associated with amyloid fibrils and modulates fibril formation in vitro. Lastly, we used a transgenic Aß42 fly model to test if knock down or over-expression of fibril-interacting gene homologues modifies neurotoxicity. Here, we could functionally validate 20 genes as modifiers of Aß42 toxicity in vivo. CONCLUSIONS: These discoveries and subsequent confirmation indicate that fibril-associated proteins play a key role in amyloid formation and AD pathology.

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics.

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions.

Since long before the first approval of gene therapy for retinal disease, ocular gene therapy has captured the hopes of patients, clinicians, and scientists alike. Indeed, the retina provides a unique system for studying and treating ocular diseases, and it holds the distinction as the first tissue targeted by an approved gene therapy for inherited disorders in the United States. There are many methods for addressing genetic diseases in the eyes using a wide range of potential delivery systems and vectors. However, despite the immense progress over the last several decades, both old and new challenges remain, such as the long-term effects of treatments, immunogenicity, targeting, and manufacturing. This review provides a discussion of the history of ocular gene therapy, the various gene therapy approaches, methods to deliver a gene directly to ocular tissues (including both routes of administration and vectors), challenges to ocular gene therapy, the current clinical trial landscape, and future directions of the field.

Amyloids and brain cancer: molecular linkages and crossovers.

Amyloids are high-order proteinaceous formations deposited in both intra- and extracellular spaces. These aggregates have tendencies to deregulate cellular physiology in multiple ways; for example, altered metabolism, mitochondrial dysfunctions, immune modulation, etc. When amyloids are formed in brain tissues, the endpoint often is death of neurons. However, interesting but least understood is a close connection of amyloids with another set of conditions in which brain cells proliferate at an extraordinary rate and form tumor inside brain. Glioblastoma is one such condition. Increasing number of evidence indicate a possible link between amyloid formation and depositions in brain tumors. Several proteins associated with cell cycle regulation and apoptotic pathways themselves have shown to possess high tendencies to form amyloids. Tumor suppressor protein p53 is one prominent example that mutate, oligomerize and form amyloids leading to loss- or gain-of-functions and cause increased cell proliferation and malignancies. In this review article, we present available examples, genetic links and common pathways that indicate that possibly the two distantly placed pathways: amyloid formation and developing cancers in the brain have similarities and are mechanistically intertwined together.

Nano-assemblies enhance chaperone activity, stability, and delivery of alpha B-crystallin-D3 (αB-D3).

Crystallins, small heat shock chaperone proteins that prevent protein aggregation, are of potential value in treating protein aggregation disorders. However, their therapeutic use is limited by their low potency and poor intracellular delivery. One approach to facilitate the development of crystallins is to improve their activity, stability, and delivery. In this study, zinc addition to αB-crystallin-D3 (αB-D3) formed supramolecular nano- and micro- assemblies, induced dose-dependent changes in structure (beta-sheet to alpha-helix) and increased surface hydrophobicity and chemical stability. Further, crystallin assemblies exhibited a size-dependent chaperone activity, with the nano-assemblies being superior to micro-assemblies and 4.3-fold more effective than the native protein in preventing ß-mercaptoethanol induced aggregation of insulin. Insulin rescued by crystallin assemblies retained the activity as evidenced by glucose uptake in 3T3-L1 cells. The most active nano-assemblies enhanced protein stability, in the presence of urea, by 1.6-fold, whereas intracellular delivery was enhanced by 3.0-fold. The αB-D3 crystallin nano-assemblies exhibit uniquely enhanced stability, activity, and delivery compared to the native protein.

A comprehensive review of BBV152 vaccine development, effectiveness, safety, challenges, and prospects.

The world has responded to the COVID-19 pandemic with unprecedented speed and vigor in the mass vaccination campaigns, targeted to reduce COVID-19 severity and mortality, reduce the pressure on the healthcare system, re-open society, and reduction in disease mortality and morbidity. Here we review the preclinical and clinical development of BBV152, a whole virus inactivated vaccine and an important tool in the fight to control this pandemic. BBV152, formulated with a TLR7/8 agonist adjuvant generates a Th1-biased immune response that induces high neutralization efficacy against different SARS-CoV-2 variants of concern and robust long-term memory B- and T-cell responses. With seroconversion rates as high as 98.3% in vaccinated individuals, BBV152 shows 77.8% and 93.4% protection from symptomatic COVID-19 disease and severe symptomatic COVID-19 disease respectively. Studies in pediatric populations show superior immunogenicity (geometric mean titer ratio of 1.76 compared to an adult) with a seroconversion rate of >95%. The reactogenicity and safety profiles were comparable across all pediatric age groups between 2-18 yrs. as in adults. Like most approved vaccines, the BBV152 booster given 6 months after full vaccination, reverses a waning immunity, restores the neutralization efficacy, and shows synergy in a heterologous prime-boost study with about 3-fold or 300% increase in neutralization titers against multiple SARS-CoV-2 variants of concern. Based on the interim Phase III data, BBV152 received full authorization for adults and emergency use authorization for children from ages 6 to 18 years in India. It is also licensed for emergency use in 14 countries globally. Over 313 million vaccine doses have already been administered in India alone by April 18th, 2022.

Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases.

Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications.

Biochemical Purification and Proteomic Characterization of Amyloid Fibril Cores from the Brain.

Proteinaceous fibrillar inclusions are key pathological hallmarks of multiple neurodegenerative diseases. In the early stages of Alzheimer's disease (AD), amyloid-beta peptides form protofibrils in the extracellular space, which act as seeds that gradually grow and mature into large amyloid plaques. Despite this basic understanding, current knowledge of the amyloid fibril structure, composition, and deposition patterns in the brain is limited. One major barrier has been the inability to isolate highly purified amyloid fibrils from brain extracts. Affinity purification and laser capture microdissection-based approaches have been previously used to isolate amyloids but are limited by the small quantity of material that can be recovered. This novel, robust protocol describes the biochemical purification of amyloid plaque cores using sodium dodecyl sulfate (SDS) solubilization with sucrose density gradient ultracentrifugation and ultrasonication and yields highly pure fibrils from AD patients and AD model brain tissues. Mass spectrometry (MS)-based bottom-up proteomic analysis of the purified material represents a robust strategy to identify nearly all the primary protein components of amyloid fibrils. Previous proteomic studies of proteins in the amyloid coronae have revealed an unexpectedly large and functionally diverse collection of proteins. Notably, after refining the purification strategy, the number of co-purifying proteins was reduced by more than 10-fold, indicating the high purity of the isolated SDS insoluble material. Negative staining and immuno-gold electron microscopy allowed confirmation of the purity of these preparations. Further studies are required to understand the spatial and biological attributes that contribute to the deposition of these proteins into amyloid inclusions. Taken together, this analytical strategy is well-positioned to increase the understanding of amyloid biology.

Complex Inclusion Bodies and Defective Proteome Hubs in Neurodegenerative Disease: New Clues, New Challenges.

A healthy physiological environment of cells represents the dynamic homeostasis of crowded molecules. A subset of cellular proteome forms protein quality control (PQC) machinery to maintain an uninterrupted synthesis of new polypeptides and targeted elimination of old or defective proteins. The process of PQC may get overwhelmed under specific genetic mutations, environmental stress conditions, and aging-associated perturbances. Many of these conditions may lead to the generation of various types of aberrant protein species that may or may not accumulate as large cellular inclusions. These proteinaceous formations, referred to as inclusion bodies (IBs), could be membrane-bound or membrane-less, cytoplasmic, or nuclear. Most importantly, they could either be toxic or protective. Under acute stress conditions, the formation of aggregates may cause proteostasis failure, leading to large-scale changes in the cellular proteome compositions. However, the large insoluble IBs may act as reservoirs for many soluble proteins with high aggregation propensities, which can overwhelm the cellular chaperoning capacity and protein degradation machinery. The kinetic equilibrium between folding and unfolding, misfolding, and refolding; aggregation and degradation is perturbed in one or many neurodegenerative disorders (NDDs) associated with dementia, cognitive impairments, movement, and behavioural losses. However, a detailed interplay of IBs into the manifestation of the NDDs is unknown, and a very primitive knowledge of structural compositions of amyloid inclusions is present. The present article presents a brief evolutionary background of IBs; their functional relevance for prokaryotes, plants, and animals; and associated involvement in neuronal proteostasis.

Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases.

Cells have different sets of molecules for performing an array of physiological functions. Nucleic acids have stored and carried the information throughout evolution, whereas proteins have been attributed to performing most of the cellular functions. To perform these functions, proteins need to have a unique conformation and a definite lifespan. These attributes are achieved by a highly coordinated protein quality control (PQC) system comprising chaperones to fold the proteins in a proper three-dimensional structure, ubiquitin-proteasome system for selective degradation of proteins, and autophagy for bulk clearance of cell debris. Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery, leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions. However, modulating the expression and functional efficiency of molecular chaperones, E3 ubiquitin ligases, and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects. Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions. The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.

Neurodegeneration & imperfect ageing: Technological limitations and challenges?

Cellular homeostasis is regulated by the protein quality control (PQC) machinery, comprising multiple chaperones and enzymes. Studies suggest that the loss of the PQC mechanisms in neurons may lead to the formation of abnormal inclusions that may lead to neurological disorders and defective aging. The questions could be raised how protein aggregate formation precisely engenders multifactorial molecular pathomechanism in neuronal cells and affects different brain regions? Such questions await thorough investigation that may help us understand how aberrant proteinaceous bodies lead to neurodegeneration and imperfect aging. However, these studies face multiple technological challenges in utilizing available tools for detailed characterizations of the protein aggregates or amyloids and developing new techniques to understand the biology and pathology of proteopathies. The lack of detection and analysis methods has decelerated the pace of the research in amyloid biology. Here, we address the significance of aggregation and inclusion formation, followed by exploring the evolutionary contribution of these structures. We also provide a detailed overview of current state-of-the-art techniques and advances in studying amyloids in the diseased brain. A comprehensive understanding of the structural, pathological, and clinical characteristics of different types of aggregates (inclusions, fibrils, plaques, etc.) will aid in developing future therapies.

Cancer: An unknown territory; rethinking before going ahead.

Cancer is a disease of altered signaling and metabolism, causing uncontrolled division and survival of transformed cells. A host of molecules, factors, and conditions have been designated as underlying causes for the inception and progression of the disease. An enormous amount of data is available, system-wide interaction networks of the genes and proteins are generated over the years and have now reached up to a level of saturation, where we need to shift our focus to the more advanced and comprehensive methods and approaches of data analysis and visualization. Even with the availability of enormous literature on this one of the most pressing pathological conditions, a successful cure of the disease seems to be obscure. New treatment plans, like immunotherapy and precision medicine, are being employed for different studies. Nevertheless, their actual benefits to the patients would be known only after the evaluation of clinical data over the next few years. Therefore, we need to look at few fundamental challenges that should be addressed in more depth before we could devise better, rigorous, and comprehensive treatment plans and may successfully reach a possible cure of the disease. This article aims at bringing attention towards some fundamental gaps in our approach towards the disease that leads to failure in devising successful therapeutics.

Asymptomatic malaria infection prevailing risks for human health and malaria elimination.

There has been a consistent rise in malaria cases in the last few years. The existing malaria control measures are challenged by insecticide resistance in the mosquito vector, drug résistance in parasite populations, and asymptomatic malaria (ASM) in healthy individuals. The absence of apparent malaria symptoms and the presence of low parasitemia makes ASM a hidden reservoir for malaria transmission and an impediment in malaria elimination efforts. This review focuses on ASM in malaria-endemic countries and the past and present research trends from those geographical locations. The harmful impacts of asymptomatic malaria on human health and its contribution to disease transmission are highlighted. We discuss certain crucial genetic changes in the parasite and host immune response necessary for maintaining low parasitemia leading to long-term parasite survival in the host. Since the chronic health effects and the potential roles for disease transmission of ASM remain mostly unknown to significant populations, we offer proposals for developing general awareness. We also suggest advanced technology-based diagnostic methods, and treatment strategies to eliminate ASM.

Herpesviruses and the hidden links to Multiple Sclerosis neuropathology.

Herpesviruses like Epstein-Barr virus, human herpesvirus (HHV)-6, HHV-1, VZV, and human endogenous retroviruses, have an age-old clinical association with multiple sclerosis (MS). MS is an autoimmune disease of the nervous system wherein the myelin sheath deteriorates. The most popular mode of virus mediated immune system manipulation is molecular mimicry. Numerous herpesvirus antigens are similar to myelin proteins. Other mechanisms described here include the activity of cytokines and autoantibodies produced by the autoreactive T and B cells, respectively, viral déjà vu, epitope spreading, CD46 receptor engagement, impaired remyelination etc. Overall, this review addresses the host-parasite association of viruses with MS.

Ibuprofen-based advanced therapeutics: breaking the inflammatory link in cancer, neurodegeneration, and diseases.

Ibuprofen is a classical nonsteroidal anti-inflammatory drug (NSAID) highly prescribed to reduce acute pain and inflammation under an array of conditions, including rheumatoid arthritis, osteoarthritis, dysmenorrhea, and gout. Ibuprofen acts as a potential inhibitor for cyclooxygenase enzymes (COX-1 and COX-2). In the past few decades, research on this small molecule has led to identifying other possible therapeutic benefits. Anti-tumorigenic and neuroprotective functions of Ibuprofen are majorly recognized in recent literature and need further consideration. Additionally, several other roles of this anti-inflammatory molecule have been discovered and subjected to experimental assessment in various diseases. However, the major challenge faced by Ibuprofen and other drugs of similar classes is their side effects, and tendency to cause gastrointestinal injury, generate cardiovascular risks, modulate hepatic and acute kidney diseases. Future research should also be conducted to deduce new methods and approaches of suppressing the unwanted toxic changes mediated by these drugs and develop new therapeutic avenues so that these small molecules continue to serve the purposes. This article primarily aims to develop a comprehensive and better understanding of Ibuprofen, its pharmacological features, therapeutic benefits, and possible but less understood medicinal properties apart from major challenges in its future application.KEY POINTSIbuprofen, an NSAID, is a classical anti-inflammatory therapeutic agent.Pro-apoptotic roles of NSAIDs have been explored in detail in the past, holding the key in anti-cancer therapies.Excessive and continuous use of NSAIDs may have several side effects and multiple organ damage.Hyperactivated Inflammation initiates multifold detrimental changes in multiple pathological conditions.Targeting inflammatory pathways hold the key to several therapeutic strategies against many diseases, including cancer, microbial infections, multiple sclerosis, and many other brain diseases.