Cancer immunotherapy by immune checkpoint blockade and its advanced application using bio-nanomaterials.

Cancer is the second leading cause of death worldwide. Traditional approaches, such as surgery, chemotherapy, and radiotherapy have been the main cancer therapeutic modalities in recent years. Cancer immunotherapy is a novel therapeutic modality that potentiates the immune responses of patients against malignancy. Immune checkpoint proteins expressed on T cells or tumor cells serve as a target for inhibiting T cell overactivation, maintaining the balance between self-reactivity and autoimmunity. Tumors essentially hijack the immune checkpoint pathway in order to survive and spread. Immune checkpoint inhibitors (ICIs) are being developed as a result to reactivate the anti-tumor immune response. Recent advances in nanotechnology have contributed to the development of successful, safe, and efficient anticancer drug systems based on nanoparticles. Nanoparticle-based cancer immunotherapy overcomes numerous challenges and offers novel strategies for improving conventional immunotherapies. The fundamental and physiochemical properties of nanoparticles depend on various cancer therapeutic strategies, such as chemotherapeutics, nucleic acid-based treatments, photothermal therapy, and photodynamic agents. The review discusses the use of nanoparticles as carriers for delivering immune checkpoint inhibitors and their efficacy in cancer combination therapy.

Advancements in the Application of Nanomedicine in Alzheimer's Disease: A Therapeutic Perspective.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood-brain and blood-cerebrospinal fluid barriers are two barriers that protect the central nervous system, their presence has severely restricted the efficacy of many treatments that have been studied for AD diagnosis and/or therapy. The use of nanoparticles for the diagnosis and treatment of AD is the focus of an established and rapidly developing field of nanomedicine. Recent developments in nanomedicine have made it possible to effectively transport drugs to the brain. However, numerous obstacles remain to the successful use of nanomedicines in clinical settings for AD treatment. Furthermore, given the rapid advancement in nanomedicine therapeutics, better outcomes for patients with AD can be anticipated. This article provides an overview of recent developments in nanomedicine using different types of nanoparticles for the management and treatment of AD.

Seaweeds in the Oncology Arena: Anti-Cancer Potential of Fucoidan as a Drug-A Review.

Marine natural products are a discerning arena to search for the future generation of medications to treat a spectrum of ailments. Meanwhile, cancer is becoming more ubiquitous over the world, and the likelihood of dying from it is rising. Surgery, radiation, and chemotherapy are the mainstays of cancer treatment worldwide, but their extensive side effects limit their curative effect. The quest for low-toxicity marine drugs to prevent and treat cancer is one of the current research priorities of researchers. Fucoidan, an algal sulfated polysaccharide, is a potent therapeutic lead candidate against cancer, signifying that far more research is needed. Fucoidan is a versatile, nontoxic marine-origin heteropolysaccharide that has received much attention due to its beneficial biological properties and safety. Fucoidan has been demonstrated to exhibit a variety of conventional bioactivities, such as antiviral, antioxidant, and immune-modulatory characteristics, and anticancer activity against a wide range of malignancies has also recently been discovered. Fucoidan inhibits tumorigenesis by prompting cell cycle arrest and apoptosis, blocking metastasis and angiogenesis, and modulating physiological signaling molecules. This review compiles the molecular and cellular aspects, immunomodulatory and anticancer actions of fucoidan as a natural marine anticancer agent. Specific fucoidan and membranaceous polysaccharides from Ecklonia cava, Laminaria japonica, Fucus vesiculosus, Astragalus, Ascophyllum nodosum, Codium fragile serving as potential anticancer marine drugs are discussed in this review.

Leucine encoding codon TTG shows an inverse relationship with GC content in genes involved in neurodegeneration with iron accumulation.

We determined various forces involved in shaping codon usage of the genes linked to brain iron accumulation and infantile neuroaxonal dystrophy. The analysis paved the way for determining the forces responsible for composition, expression level, physical properties and codon bias of a gene. An interesting observation related to composition was that, on all the three codon positions, any two of the four nucleotides had similar compositions. CpG, TpA, and GpT dinucleotides were underrepresented with the overrepresentation of TpG dinucleotide. CpG and TpA containing codons ATA, CTA, TCG, and GCG were underrepresented, while TpG dinucleotide containing codon CTG was overrepresented, indicative of compositional constraints importance. GC ending codons were favored when the genome is GC rich, except leucine encoding codon TTG, which exhibits an inverse relationship with GC content. Nucleotide disproportions are found associated with the physical properties of proteins. The values of CAI and ENc are suggestive of low codon bias in genes. Considering the results of neutrality analysis, parity analysis, underrepresentation of TpA and CpG codons, and over-representation of TpG codons, the correlation between the compositional constraints and skew relationships with protein properties suggested the role of all the three selectional, mutational and compositional forces in shaping codon usage with the dominance of selectional pressure.

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer.

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.

An ELISA using a recombinant chimera of protective antigen and lethal factor for serodiagnosis of cutaneous anthrax in India.

In this study, an ELISA was developed for simultaneous detection of antibodies against both the important toxins of B. anthracis i.e. protective antigen (PA) and lethal factor (LF). A chimera of PA and LF was made by fusion and cloned and expressed in E. coli. The purified recombinant protein was used in plate ELISA for serodiagnosis of anthrax. The chimera could detect antibodies against both the toxins of Bacillus anthracis. The human serum samples (n = 98) collected from anthrax endemic and non-endemic areas were tested employing ELISA. The ELISA gave sensitivity of 100% (95% Confidence Interval [CI], 92.13 to 100) and specificity of 97.78% (95% Confidence Interval [CI], 88.23 to 99.94) with a J index of 0.97. The efficiency of ELISA was found to be 98.9% with the positive predictive value (PPV) and negative predictive value (NPV) of 97.8% and 100%, respectively. The chimera of PA and LF could be a better diagnostic antigen for serodiagnosis as the assay detects antibodies against both the toxins in early as well delayed infection cases of anthrax. Therefore, it can be a very useful tool for the surveillance as well as for confirmation of cutaneous anthrax cases.

Insight into Early Diagnosis of Multiple Sclerosis by Targeting Prognostic Biomarkers.

Multiple sclerosis (MS) is a central nervous system (CNS) immune-mediated disease that mainly strikes young adults and leaves them disabled. MS is an autoimmune illness that causes the immune system to attack the brain and spinal cord. The myelin sheaths, which insulate the nerve fibers, are harmed by our own immune cells, and this interferes with brain signal transmission. Numbness, tingling, mood swings, memory problems, exhaustion, agony, vision problems, and/or paralysis are just a few of the symptoms. Despite technological advancements and significant research efforts in recent years, diagnosing MS can still be difficult. Each patient's MS is distinct due to a heterogeneous and complex pathophysiology with diverse types of disease courses. There is a pressing need to identify markers that will allow for more rapid and accurate diagnosis and prognosis assessments to choose the best course of treatment for each MS patient. The cerebrospinal fluid (CSF) is an excellent source of particular indicators associated with MS pathology. CSF contains molecules that represent pathological processes such as inflammation, cellular damage, and loss of blood-brain barrier integrity. Oligoclonal bands, neurofilaments, MS-specific miRNA, lncRNA, IgG-index, and anti-aquaporin 4 antibodies are all clinically utilised indicators for CSF in MS diagnosis. In recent years, a slew of new possible biomarkers have been presented. In this review, we look at what we know about CSF molecular markers and how they can aid in the diagnosis and differentiation of different MS forms and treatment options, and monitoring and predicting disease progression, therapy response, and consequences during such opportunistic infections.

Neural Stem Cell-based Regenerative Therapy: A New Approach to Diabetes Treatment.

Diabetes mellitus (DM) is the most common metabolic disorder that occurs due to the loss, or impaired function of insulin-secreting pancreatic beta cells, which are of two types - type 1 (T1D) and type 2 (T2D). To cure DM, the replacement of the destroyed pancreatic beta cells of islet of Langerhans is the most widely practiced treatment. For this, isolating neuronal stem cells and cultivating them as a source of renewable beta cells is a significant breakthrough in medicine. The functions, growth, and gene expression of insulin-producing pancreatic beta cells and neurons are very similar in many ways. A diabetic patient's neural stem cells (obtained from the hippocampus and olfactory bulb) can be used as a replacement source of beta cells for regenerative therapy to treat diabetes. The same protocol used to create functional neurons from progenitor cells can be used to create beta cells. Recent research suggests that replacing lost pancreatic beta cells with autologous transplantation of insulin-producing neural progenitor cells may be a perfect therapeutic strategy for diabetes, allowing for a safe and normal restoration of function and a reduction in potential risks and a long-term cure.

A Review on the Use of Gold Nanoparticles in Cancer Treatment.

According to a 2020 WHO study, cancer is responsible for one in every six fatalities. One in four patients die due to side effects and intolerance to chemotherapy, making it a leading cause of patient death. Compared to traditional tumor therapy, emerging treatment methods, including immunotherapy, gene therapy, photothermal therapy, and photodynamic therapy, have proven to be more effective. The aim of this review is to highlight the role of gold nanoparticles in advanced cancer treatment. A systematic and extensive literature review was conducted using the Web of Science, PubMed, EMBASE, Google Scholar, NCBI, and various websites. Highly relevant literature from 141 references was chosen for inclusion in this review. Recently, the synergistic benefits of nano therapy and cancer immunotherapy have been shown, which could allow earlier diagnosis, more focused cancer treatment, and improved disease control. Compared to other nanoparticles, the physical and optical characteristics of gold nanoparticles appear to have significantly greater effects on the target. It has a crucial role in acting as a drug carrier, biomarker, anti-angiogenesis agent, diagnostic agent, radiosensitizer, cancer immunotherapy, photodynamic therapy, and photothermal therapy. Gold nanoparticle-based cancer treatments can greatly reduce current drug and chemotherapy dosages.

How Advanced are Cancer Immuno-Nanotherapeutics? A Comprehensive Review of the Literature.

Cancer is a broad term for a group of diseases involving uncontrolled cell growth and proliferation. There is no cure for cancer despite recent significant improvements in screening, treatment, and prevention approaches. Among the available treatments, immunotherapy has been successful in targeting and killing cancer cells by stimulating or enhancing the body's immune system. Antibody-based immunotherapeutic agents that block immune checkpoint proteins expressed by cancer cells have shown promising results. The rapid development of nanotechnology has contributed to improving the effectiveness and reducing the adverse effects of these anti-cancer immunotherapeutic agents. Recently, engineered nanomaterials have been the focus of many state-of-The-art approaches toward effective cancer treatment. In this review, the contribution of various nanomaterials such as polymeric nanoparticles, dendrimers, microspheres, and carbon nanomaterials in improving the efficiency of anti-cancer immunotherapy is discussed as well as nanostructures applied to combination cancer immunotherapy.

Lipid Nanocarrier-Based Drug Delivery Systems: Therapeutic Advances in the Treatment of Lung Cancer.

Although various treatments are currently being developed, lung cancer still has a very high mortality rate. Moreover, while various strategies for the diagnosis and treatment of lung cancer are being used in clinical settings, in many cases, lung cancer does not respond to treatment and presents reducing survival rates. Cancer nanotechnology, also known as nanotechnology in cancer, is a relatively new topic of study that brings together scientists from a variety of fields, including chemistry, biology, engineering, and medicine. The use of lipid-based nanocarriers to aid drug distribution has already had a significant impact in several scientific fields. Lipid-based nanocarriers have been demonstrated to help stabilize therapeutic compounds, overcome barriers to cellular and tissue absorption, and improve in vivo drug delivery to specific target areas. For this reason, lipid-based nanocarriers are being actively researched and used for lung cancer treatment and vaccine development. This review discusses the improvements in drug delivery achieved with lipid-based nanocarriers, the obstacles that still exist with in vivo applications, and the current clinical and experimental applications of lipid-based nanocarriers in lung cancer treatment and management.

Exploring the Role of Stem Cell Therapy in Treating Neurodegenerative Diseases: Challenges and Current Perspectives.

Several human neurological disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, spinal cord injury, multiple sclerosis, and brain stroke, are caused by the injury to neurons or glial cells. The recent years have witnessed the successful generation of neurons and glia cells driving efforts to develop stem-cell-based therapies for patients to combat a broad spectrum of human neurological diseases. The inadequacy of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. Attempts are thus being made to reconstruct viable neurons and glial cells from different stem cells, such as embryonic stem cells, mesenchymal stem cells, and neural stem cells. Dedicated research to cultivate stem cell-based brain transplantation therapies has been carried out. We aim at compiling the breakthroughs in the field of stem cell-based therapy for the treatment of neurodegenerative maladies, emphasizing the shortcomings faced, victories achieved, and the future prospects of the therapy in clinical settings.

3D Printing: Advancement in Biogenerative Engineering to Combat Shortage of Organs and Bioapplicable Materials.

Abstract: Organ or cell transplantation is medically evaluated for end-stage failure saving or extending the lives of thousands of patients who are suffering from organ failure disorders. The unavailability of adequate organs for transplantation to meet the existing demand is a major challenge in the medical field. This led to day-day-increase in the number of patients on transplant waiting lists as well as in the number of patients dying while on the queue. Recently, technological advancements in the field of biogenerative engineering have the potential to regenerate tissues and, in some cases, create new tissues and organs. In this context, major advances and innovations are being made in the fields of tissue engineering and regenerative medicine which have a huge impact on the scientific community is three-dimensional bioprinting (3D bioprinting) of tissues and organs. Besides this, the decellularization of organs and using this as a scaffold for generating new organs through the recellularization process shows promising results. This review discussed about current approaches for tissue and organ engineering including methods of scaffold designing, recent advances in 3D bioprinting, organs regenerated successfully using 3D printing, and extended application of 3D bioprinting technique in the field of medicine. Besides this, information about commercially available 3D printers has also been included in this article. Lay Summary: Today's need for organs for the transplantation process in order to save a patient's life or to enhance the survival rate of diseased one is the prime concern among the scientific community. Recent, advances in the field of biogenerative engineering have the potential to regenerate tissues and create organs compatible with the patient's body. In this context, major advances and innovations are being made in the fields of tissue engineering and regenerative medicine which have a huge impact on the scientific community is three-dimensional bioprinting (3D bioprinting) of tissues and organs. Besides this, the decellularization of organs and using this as a scaffold for generating new organs through the recellularization process shows promising results. This review dealt with the current approaches for tissue and organ engineering including methods of scaffold designing, recent advances in 3D bioprinting, organs regenerated successfully using 3D printing, and extended application of 3D bioprinting technique in the field of medicine. Furthermore, information about commercially available 3D printers has also been included in this article.

Codon Usage is Influenced by Compositional Constraints in Genes Associated with Dementia.

Dementia is a clinical syndrome characterized by progressive cognitive decline, and the symptoms could be gradual, persistent, and progressive. In the present study, we investigated 47 genes that have been linked to dementia. Compositional, selectional, and mutational forces were seen to be involved. Nucleotide components that influenced A- and GC-affected codon usages bias at all three codon positions. The influence of these two compositional constraints on codon usage bias (CUB) was positive for nucleotide A and negative for GC. Nucleotide A also experienced the highest mutational force, and GC-ending codons were preferred over AT-ending codons. A high bias toward GC-ending codons enhances the gene expression level, evidenced by the positive association between CAI- and GC-ending codons. Unusual behavior of the TTG codon showing an inverse relationship with the GC-ending codon and negative influence of gene expression, behavior contrary to all other GC-ending codons, shows an operative selectional force. Furthermore, parity analysis, higher translational selection value, preference of GC-ending codons over AT-ending codons, and association of gene length with gene expression refer to the dominant role of selection pressure with compositional constraint and mutational force-shaping codon usage.

Modulating the Ubiquitin-Proteasome System: A Therapeutic Strategy for Autoimmune Diseases.

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease associated with the central nervous system (CNS). Autoimmunity is caused by an abnormal immune response to self-antigens, which results in chronic inflammation and tissue death. Ubiquitination is a post-translational modification in which ubiquitin molecules are attached to proteins by ubiquitinating enzymes, and then the modified proteins are degraded by the proteasome system. In addition to regulating proteasomal degradation of proteins, ubiquitination also regulates other cellular functions that are independent of proteasomal degradation. It plays a vital role in intracellular protein turnover and immune signaling and responses. The ubiquitin-proteasome system (UPS) is primarily responsible for the nonlysosomal proteolysis of intracellular proteins. The 26S proteasome is a multicatalytic adenosine-triphosphate-dependent protease that recognizes ubiquitin covalently attached to particular proteins and targets them for degradation. Damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern many essential cellular functions, are removed by this degradation pathway. When this system is affected, cellular homeostasis is altered, resulting in the induction of a range of diseases. This review discusses the biochemistry and molecular biology of the UPS, including its role in the development of MS and proteinopathies. Potential therapies and targets involving the UPS are also addressed.

Exploring the Role of Gene Therapy for Neurological Disorders.

Gene therapy is one of the frontier fields of medical breakthroughs that poses as an effective solution to previously incurable diseases. The delivery of the corrective genetic material or a therapeutic gene into the cell restores the missing gene function and cures a plethora of diseases, incurable by the conventional medical approaches. This discovery holds the potential to treat many neurodegenerative disorders such as muscular atrophy, multiple sclerosis, Parkinson's disease (PD) and Alzheimer's disease (AD), among others. Gene therapy proves as a humane, cost-effective alternative to the exhaustive often arduous and timely impossible process of finding matched donors and extensive surgery. It also overcomes the shortcoming of conventional methods to cross the blood-brain barrier. However, the use of gene therapy is only possible after procuring the in-depth knowledge of the immuno-pathogenesis and molecular mechanism of the disease. The process of gene therapy can be broadly categorized into three main steps: elucidating the target gene, culling the appropriate vector, and determining the best mode of transfer; each step mandating pervasive research. This review aims to dissertate and summarize the role, various vectors and methods of delivery employed in gene therapy with special emphasis on therapy directed at the central nervous system (CNS) associated with neurodegenerative diseases.

Insight into Codon Utilization Pattern of Tumor Suppressor Gene EPB41L3 from Different Mammalian Species Indicates Dominant Role of Selection Force.

Uneven codon usage within genes as well as among genomes is a usual phenomenon across organisms. It plays a significant role in the translational efficiency and evolution of a particular gene. EPB41L3 is a tumor suppressor protein-coding gene, and in the present study, the pattern of codon usage was envisaged. The full-length sequences of the EPB41L3 gene for the human, brown rat, domesticated cattle, and Sumatran orangutan available at the NCBI were retrieved and utilized to analyze CUB patterns across the selected mammalian species. Compositional properties, dinucleotide abundance, and parity analysis showed the dominance of A and G whilst RSCU analysis indicated the dominance of G/C-ending codons. The neutrality plot plotted between GC12 and GC3 to determine the variation between the mutation pressure and natural selection indicated the dominance of selection pressure (R = 0.926; p < 0.00001) over the three codon positions across the gene. The result is in concordance with the codon adaptation index analysis and the ENc-GC3 plot analysis, as well as the translational selection index (P2). Overall selection pressure is the dominant pressure acting during the evolution of the EPB41L3 gene.

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments.

Sarcoidosis is a multisystem granulomatous disease with nonspecific clinical manifestations that commonly affects the pulmonary system and other organs including the eyes, skin, liver, spleen, and lymph nodes. Sarcoidosis usually presents with persistent dry cough, eye and skin manifestations, weight loss, fatigue, night sweats, and erythema nodosum. Sarcoidosis is not influenced by sex or age, although it is more common in adults (< 50 years) of African-American or Scandinavians decent. Diagnosis can be difficult because of nonspecific symptoms and can only be verified following histopathological examination. Various factors, including infection, genetic predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are difficult; however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy, high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography has improved our ability to reliably diagnose this condition and accurately forecast its prognosis. This review discusses the causes and clinical features of sarcoidosis, and the improvements made in its prognosis, therapeutic management, and the recent discovery of potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation.

Proteomics and Neurodegenerative Disorders: Advancements in the Diagnostic Analysis.

Changes in protein structure and function, alteration in protein-protein interaction, and significant difference in protein concentration inside the body could play an important role in indicating the pathological evidence of abnormalities before the development of clinical symptoms and act as a critical detection and diagnostic tool commonly known as biomarkers. Biomarkers play important roles in the diagnosis of various chronic diseases, including cancer. Neurodegenerative disorders, including Parkinson's, Alzheimer's, Huntington's, prion, and multiple sclerosis, are well characterized by neuronal deterioration, resulting in precise modifications of neuronal proteins. Nowadays, the diagnosis of neurological disorders is based on proteins or biomarkers. These biomarkers may be found in the cerebrospinal fluid, blood, serum, plasma, saliva, or urine sample. Early diagnosis is urgently needed to prevent further damage. For early diagnosis, identifying the changes in novel protein levels and their functions under the disease conditions is necessary. These can be used as specific proteomic biomarkers for diseases, and they can be possibly identified using neuroproteomics. Neuroproteomics is an emerging tool to corroborate disease-associated protein profiles. It also gives an idea about how these proteins interact with other proteins and undergo post-translational modifications. Neuroproteomics is based on bioinformatics, which provides functional characteristics and advances in technology such as mass spectroscopy, and can help in the discovery of various disease-specific biomarkers. This review gives a complete idea about the types of biomarkers, sources of biomarkers, and techniques involved in the discovery of biomarkers for early diagnosis of neurodegenerative diseases.

Enhanced production and purification of recombinant surface array protein (Sap) for use in detection of Bacillus anthracis.

Surface array protein (Sap) can be an important biomarker for specific detection of Bacillus anthracis, which is released by the bacterium during its growth in culture broth. In the present work, we have cloned and expressed Sap in Escherichia coli. The culture conditions and cultivation media were optimized and used in batch fermentation process for scale up of Sap in soluble form. The recombinant Sap was purified employing affinity chromatography followed by diafiltration. The final yield of purified protein was 20 and 46 mg/l of culture during shake flasks and batch fermentation, respectively. The protein purity and its reactivity were confirmed employing SDS-PAGE and Western blot, respectively. The antibodies raised against purified Sap were evaluated by Western blotting for detection of Sap released by B. anthracis. Our results showed that the Sap could be a novel marker for detection and confirmation of B. anthracis.