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.

Restricted X chromosome introgression and support for Haldane's rule in hybridizing damselflies.

Contemporary hybrid zones act as natural laboratories for the investigation of species boundaries and may shed light on the little understood roles of sex chromosomes in species divergence. Sex chromosomes are considered to function as a hotspot of genetic divergence between species; indicated by less genomic introgression compared to autosomes during hybridization. Moreover, they are thought to contribute to Haldane's rule, which states that hybrids of the heterogametic sex are more likely to be inviable or sterile. To test these hypotheses, we used contemporary hybrid zones of Ischnura elegans, a damselfly species that has been expanding its range into the northern and western regions of Spain, leading to chronic hybridization with its sister species Ischnura graellsii. We analysed genome-wide SNPs in the Spanish I. elegans and I. graellsii hybrid zone and found (i) that the X chromosome shows less genomic introgression compared to autosomes, and (ii) that males are underrepresented among admixed individuals, as predicted by Haldane's rule. This is the first study in Odonata that suggests a role of the X chromosome in reproductive isolation. Moreover, our data add to the few studies on species with X0 sex determination system and contradict the hypothesis that the absence of a Y chromosome causes exceptions to Haldane's rule.

Genome assembly, sex-biased gene expression and dosage compensation in the damselfly Ischnura elegans.

The evolution of sex chromosomes, and patterns of sex-biased gene expression and dosage compensation, are poorly known among early winged insects such as odonates. We assembled and annotated the genome of Ischnura elegans (blue-tailed damselfly), which, like other odonates, has a male-hemigametic sex-determining system (X0 males, XX females). By identifying X-linked genes in I. elegans and their orthologs in other insect genomes, we found homologies between the X chromosome in odonates and chromosomes of other orders, including the X chromosome in Coleoptera. Next, we showed balanced expression of X-linked genes between sexes in adult I. elegans, i.e. evidence of dosage compensation. Finally, among the genes in the sex-determining pathway only fruitless was found to be X-linked, while only doublesex showed sex-biased expression. This study reveals partly conserved sex chromosome synteny and independent evolution of dosage compensation among insect orders separated by several hundred million years of evolutionary history.

Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp).

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.

The Therapeutic Potential of the Anticancer Activity of Fucoidan: Current Advances and Hurdles.

Several types of cancers share cellular and molecular behaviors. Although many chemotherapy drugs have been designed to weaken the defenses of cancer cells, these drugs may also have cytotoxic effects on healthy tissues. Fucoidan, a sulfated fucose-based polysaccharide from brown algae, has gained much attention as an antitumor drug owing to its anticancer effects against multiple cancer types. Among the anticancer mechanisms of fucoidan are cell cycle arrest, apoptosis evocation, and stimulation of cytotoxic natural killer cells and macrophages. Fucoidan also protects against toxicity associated with chemotherapeutic drugs and radiation-induced damage. The synergistic effect of fucoidan with existing anticancer drugs has prompted researchers to explore its therapeutic potential. This review compiles the mechanisms through which fucoidan slows tumor growth, kills cancer cells, and interacts with cancer chemotherapy drugs. The obstacles involved in developing fucoidan as an anticancer agent are also discussed in this review.

Repeated sex chromosome evolution in vertebrates supported by expanded avian sex chromosomes.

Sex chromosomes have evolved from the same autosomes multiple times across vertebrates, suggesting that selection for recombination suppression has acted repeatedly and independently on certain genetic backgrounds. Here, we perform comparative genomics of a bird clade (larks and their sister lineage; Alaudidae and Panuridae) where multiple autosome-sex chromosome fusions appear to have formed expanded sex chromosomes. We detected the largest known avian sex chromosome (195.3 Mbp) and show that it originates from fusions between parts of four avian chromosomes: Z, 3, 4A and 5. Within these four chromosomes, we found evidence of five evolutionary strata where recombination had been suppressed at different time points, and show that stratum age explained the divergence rate of Z-W gametologs. Next, we analysed chromosome content and found that chromosome 3 was significantly enriched for genes with predicted sex-related functions. Finally, we demonstrate extensive homology to sex chromosomes in other vertebrate lineages: chromosomes Z, 3, 4A and 5 have independently evolved into sex chromosomes in fish (Z), turtles (Z, 5), lizards (Z, 4A), mammals (Z, 4A) and frogs (Z, 3, 4A, 5). Our results provide insights into and support for repeated evolution of sex chromosomes in vertebrates.

NBSPred: a support vector machine-based high-throughput pipeline for plant resistance protein NBSLRR prediction.

UNLABELLED: The nucleotide binding site leucine-rich repeats (NBSLRRs) belong to one of the largest known families of disease resistance genes that encode resistance proteins (R-protein) against the pathogens of plants. Various defence mechanisms have explained the regulation of plant immunity, but still, we have limited understanding about plant defence against different pathogens. Identification of R-proteins and proteins having R-protein-like features across the genome, transcriptome and proteome would be highly useful to develop the global understanding of plant defence mechanisms, but it is laborious and time-consuming task. Therefore, we have developed a support vector machine-based high-throughput pipeline called NBSPred to differentiate NBSLRR and NBSLRR-like protein from Non-NBSLRR proteins from genome, transcriptome and protein sequences. The pipeline was tested and validated with input sequences from three dicot and two monocot plants including Arabidopsis thaliana, Boechera stricta, Brachypodium distachyon Solanum lycopersicum and Zea mays. AVAILABILITY AND IMPLEMENTATION: The NBSPred pipeline is available at http://soilecology.biol.lu.se/nbs/ SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: sandeep.kushwaha@biol.lu.se.

Transcriptome profiling in the damselfly Ischnura elegans identifies genes with sex-biased expression.

BACKGROUND: Sexual dimorphism occurs widely across the animal kingdom and has profound effects on evolutionary trajectories. Here, we investigate sex-specific gene expression in Ischnura elegans (Odonata: dragonflies and damselflies), a species with pronounced sexual differences including a female-limited colour polymorphism with two female-like gynochrome morphs and one male-mimicking, androchrome morph. Whole-organism transcriptome profiling and sex-biased gene expression analysis was conducted on adults of both sexes (pooling all females as well as separating the three morphs) to gain insights into genes and pathways potentially associated with sexual development and sexual conflict. RESULTS: The de novo transcriptome assembly was of high quality and completeness (54 k transcripts; 99.6% CEGMA score; 55% annotated). We identified transcripts of several relevant pathways, including transcripts involved in sex determination, hormone biosynthesis, pigmentation and innate immune signalling. A total of 1,683 genes were differentially expressed (DE) between males and all females (1,173 were female-biased; 510 male-biased). The DE genes were associated with sex-specific physiological and reproductive processes, olfaction, pigmentation (ommochrome and melanin), hormone (ecdysone) biosynthesis and innate immunity signalling pathways. Comparisons between males and each female morph category showed that the gynochromes differed more from males than the androchrome morph. CONCLUSIONS: This is the first study to characterize sex-biased gene expression in odonates, one of the most ancient extant insect orders. Comparison between I. elegans sexes revealed expression differences in several genes related to sexual differences in behaviour and development as well as morphology. The differential expression of several olfactory genes suggests interesting sexual components in the detection of odours, pheromones and environmental volatiles. Up-regulation of pigmentation pathways in females indicates a prominent role of ommochrome pigments in the formation of the genetically controlled female colour polymorphism. Finally, the female-biased expression of several immunity genes suggests a stronger immune response in females, possibly related to the high levels of male mating harassment and recurrent matings in this species, both of which have been shown to injure females and expose them to sexually transmitted diseases and toxins contained in seminal fluids.

Gene expression under thermal stress varies across a geographical range expansion front.

Many ectothermic species are currently expanding their distributions polewards due to anthropogenic global warming. Molecular genetic mechanisms facilitating range expansion under these conditions are largely unknown, but understanding these could help mitigate expanding pests and disease vectors, or help explain why some species fail to track changing climates. Here, using RNA-seq data, we examine genomewide changes in gene expression under heat and cold stress in the range-expanding damselfly Ischnura elegans in northern Europe. We find that both the number of genes involved and levels of gene expression under heat stress have become attenuated during the expansion, consistent with a previously reported release from selection on heat tolerances as species move polewards. Genes upregulated under cold stress differed between core and edge populations, corroborating previously reported rapid adaptation to cooler climates at the expansion front. Expression of sixty-nine genes exhibited a region x treatment effect; these were primarily upregulated in response to heat stress in core populations but in response to cold stress at the range edge, suggesting that some cellular responses originally adapted to heat stress may switch to cold-stress functionality upon encountering novel thermal selection regimes during range expansion. Transcriptional responses to thermal stress involving heat-shock and neural function genes were largely geographically conserved, while retrotransposon, regulatory, muscle function and defence gene expression patterns were more variable. Flexible mechanisms of cold-stress response and the ability of some genes to shift their function between heat and cold stress might be key mechanisms facilitating rapid poleward expansion in insects.

Rhinocerebral Mucormycosis Among Diabetic Patients: An Emerging Trend.

Mucormycosis is an acute necrotic fungal infection with a fulminant course. Earlier considered a rare entity, mucormycosis is being reported with increasing frequency in recent years, possibly due to the increase in immunocompromised population especially diabetic patients. We report three cases of rhinocerebral mucormycosis among poorly controlled diabetic patients. This article emphasizes the need for further awareness of this disease, early diagnosis, and treatment to counter this opportunistic infection.

Is dosimetry still a necessity in current dental practice?

Today, dentists have a wide range of imaging modalities to choose from, the film based techniques, digital techniques, and the recent introduction of 3D volumetric or cone beam computed tomography (CBCT). The inherent design features of the new generation dental x-ray equipment has significantly improved over the years with no evidence of substandard x-ray units in operation. In dental facilities radiological workload is comparatively low, newer radiation equipments and accessories follow safety guidelines and employ better radiation protection measures for the patient and the operator. Dentists' knowledge and expertise in radiation protection measures is good, enabling them to carry out riskfree radiation procedures in their practice. Therefore, the present study is aimed at assessing the need for dosimeters in current dental scenario. 'Is there currently a significant risk from dental radiography to merit the use of personal dosimetery in dental practice. 'Dental health professionals (Oral radiologists) and radiographic assistants of fourteen dental colleges in Karnataka state participated in this questionnaire study. The questionnaire consisted of the following questions--the make, type, year of manufacture of radiographic machines used in their setup, number of radiographs made per day in the institution, type of receptors used, number of personnel at risk for radiation exposure, radiation protection measures used, regular monitoring by personal dosimeters, equivalent dosage readings for the past 12 months and whether the reading of thermoluminescent dosimeters (TLD) for any personnel had exceeded the recommended exposure value in the last 3 years. Dosimetry records of the radiology staff in the last three years shows doses no more than 1.50 mSv per year. The various institutions' dose (person mSv) was in the range of 3.70 mSv-3.90 mSv. Personal monitoring for Dentists can be omitted in the dental colleges since the estimated dose of oral radiologists contributed less than 0.01 mSv to the total average annual effective dose equivalent. Hence personal monitoring services (TLD Badges) for dentists employed in dental colleges should not be made mandatory.

De novo transcriptome of Ischnura elegans provides insights into sensory biology, colour and vision genes.

BACKGROUND: There is growing interest in odonates (damselflies and dragonflies) as model organisms in ecology and evolutionary biology but the development of genomic resources has been slow. So far only one draft genome (Ladona fulva) and one transcriptome assembly (Enallagma hageni) have been published. Odonates have some of the most advanced visual systems among insects and several species are colour polymorphic, and genomic and transcriptomic data would allow studying the genomic architecture of these interesting traits and make detailed comparative studies between related species possible. Here, we present a comprehensive de novo transcriptome assembly for the blue-tailed damselfly Ischnura elegans (Odonata: Coenagrionidae) built from short-read RNA-seq data. The transcriptome analysis in this paper provides a first step towards identifying genes and pathways underlying the visual and colour systems in this insect group. RESULTS: Illumina RNA sequencing performed on tissues from the head, thorax and abdomen generated 428,744,100 paired-ends reads amounting to 110 Gb of sequence data, which was assembled de novo with Trinity. A transcriptome was produced after filtering and quality checking yielding a final set of 60,232 high quality transcripts for analysis. CEGMA software identified 247 out of 248 ultra-conserved core proteins as 'complete' in the transcriptome assembly, yielding a completeness of 99.6%. BLASTX and InterProScan annotated 55% of the assembled transcripts and showed that the three tissue types differed both qualitatively and quantitatively in I. elegans. Differential expression identified 8,625 transcripts to be differentially expressed in head, thorax and abdomen. Targeted analyses of vision and colour functional pathways identified the presence of four different opsin types and three pigmentation pathways. We also identified transcripts involved in temperature sensitivity, thermoregulation and olfaction. All these traits and their associated transcripts are of considerable ecological and evolutionary interest for this and other insect orders. CONCLUSIONS: Our work presents a comprehensive transcriptome resource for the ancient insect order Odonata and provides insight into their biology and physiology. The transcriptomic resource can provide a foundation for future investigations into this diverse group, including the evolution of colour, vision, olfaction and thermal adaptation.

A computational investigation of potential plant-based bioactive compounds against drug-resistant Staphylococcus aureus of multiple target proteins.

Drug-resistant Staphylococcus aureus (DRSA) poses a significant global health threat, like bacteremia, endocarditis, skin, soft tissue, bone, and joint infections. Nowadays, the resistance against conventional drugs has been a prompt and focused medical concern. The present study aimed to explore the inhibitory potential of plant-based bioactive compounds (PBBCs) against effective target proteins using a computational approach. We retrieved and verified 22 target proteins associated with DRSA and conducted a screening process that involved testing 87 PBBCs. Molecular docking was performed between screened PBBCs and reference drugs with selected target proteins via AutoDock. Subsequently, we filtered the target proteins and top PBBCs based on their binding affinity scores. Furthermore, molecular dynamic simulation was carried out through GROMACS for a duration of 100 ns, and the binding free energy was calculated using the gmx_MMPBSA. The result showed consistent hydrogen bonding interactions among the amino acid residues Ser 149, Arg 151, Thr 165, Thr 216, Glu 239, Ser 240, Ile 14, as well as Asn 18, Gln 19, Lys 45, Thr 46, Tyr 109, with their respective target proteins of the penicillin-binding protein and dihydrofolate reductase complex. Additionally, we assessed the pharmacokinetic properties of screened PBBCs via SwissADME and AdmetSAR. The findings suggest that ß-amyrin, oleanolic acid, kaempferol, quercetin, and friedelin have the potential to inhibit the selected target proteins. In future research, both in vitro and in vivo, experiments will be needed to establish these PBBCs as potent antimicrobial drugs for DRSA.Communicated by Ramaswamy H. Sarma.

Oxidant and antioxidant status among tobacco users: A cross-sectional study.

Background: Smokeless and smoking tobacco use results in increased oxidative stress and lipid peroxidation, which play a major role in the causation of cancer in tobacco habituates. Malondialdehyde (MDA) is a product of lipid peroxidation, and glutathione peroxidase (GPx) and superoxide dismutase (SOD), the main enzymes in the antioxidant defense system, are assessed among tobacco users. This study gave insight into the relationship between tobacco use, oxidative stress, and antioxidant enzyme activity. Aims and Objectives: This study aimed to estimate the levels of lipid peroxidation product MDA and antioxidant enzymes SOD and GPx among tobacco users and compare them with controls. Method: A case-control study comprising 30 smokeless tobacco users, 30 smokers, and 30 controls was enrolled for the study. Serum MDA was assayed by the thiobarbituric acid method; serum SOD and GPx were assayed using Ransel antioxidant kits. The results were statistically analyzed using descriptive and inferential statistical analysis. Results: Serum MDA levels, which indicate oxidative stress, were increased among all tobacco users and significantly increased among smokeless tobacco users as compared to smokers. Serum SOD and GPx levels were decreased among both forms of tobacco users compared with controls. With an increase in duration and frequency of tobacco use, there was a significant increase in serum MDA levels among both smokers and chewers and a decrease in serum SOD and GPx levels. Conclusion: In the present day, the tobacco epidemic has attained enormous proportions with the tobacco habit starting as early as 13-14 years and leading to serious conditions with high morbidity and mortality. These biochemical parameters such as MDA, SOD, and GPx, which act as marker of oxidant and antioxidant system, can constitute important tools for evidence-based medicine for educating patients and motivating interventions in tobacco cessation therapy.

Sex matters: predator presence induces sexual dimorphism in a monomorphic prey, from stress genes to morphological defences.

Inducible defences allow prey to increase survival chances when predators are present while avoiding unnecessary costs in their absence. Many studies report considerable inter-individual variation in inducible defence expression, yet what underlies this variation is poorly understood. A classic vertebrate example of a predator-induced morphological defence is the increased body depth in crucian carp (Carassius carassius), which reduces the risk of predation from gape-size limited predators. Here, we report that among-individual variation in morphological defence expression can be linked to sex. We documented sexual dimorphism in lakes in which crucian carp coexisted with predators, where females showed shallower relative body depths than males, but not in a predator-free lake. When exposing crucian carp from a population without predators to perceived predation risk in a laboratory environment (presence/absence of pike, Esox lucius), we found that males expressed significantly greater morphological defence than females, causing sexual dimorphism only in the presence of predators. We uncovered a correlative link between the sex-specific inducible phenotypic response and gene expression patterns in major stress-related genes (POMC, MC3R, and MC4R). Together, our results highlight that sex-specific responses may be an important, yet underappreciated, component underlying inter-individual differences in the expression of inducible defences, even in species without pronounced sexual dimorphism.

Identification of a candidate dwarfing gene in Pallas, the first commercial barley cultivar generated through mutational breeding.

Many induced mutants are available in barley (Hordeum vulgare L.). One of the largest groups of induced mutants is the Erectoides (ert) mutants, which is characterized by a compact and upright spike and a shortened culm. One isolated mutant, ert-k.32, generated by X-ray treatment and registered in 1958 under the named "Pallas", was the first ever induced barley mutant to be released on the market. Its value was improved culm strength and enhanced lodging resistance. In this study, we aimed to identify the casual gene of the ert-k.32 mutant by whole genome sequencing of allelic ert-k mutants. The suggested Ert-k candidate gene, HORVU.MOREX.r3.6HG0574880, is located in the centromeric region of chromosome 6H. The gene product is an alpha/beta hydrolase with a catalytic triad in the active site composed of Ser-167, His-261 and Asp-232. In comparison to proteins derived from the Arabidopsis genome, ErtK is most similar to a thioesterase with de-S-acylation activity. This suggests that ErtK catalyzes post-translational modifications by removing fatty acids that are covalently attached to cysteine residues of target proteins involved in regulation of plant architecture and important commercial traits such as culm stability and lodging resistance.

Dietary Nutrients and Prevention of Alzheimer's Disease.

Alzheimer's disease is an irrevocable, progressive brain disorder that gradually destroys memory and cognitive skills. One of the extensively studied methods of preventing Alzheimer's disease (AD) progression is by providing a nutritional diet. Several reports have shown that intake of nutritional elements as huperzine A, ursolic acid, vitamins etc., can directly influence pathogenesis of AD. Surprisingly, the occurrence of metabolic disorders due to an unhealthy diet has been known to be a major environmental cause of AD. It has been noted that AD severity can be controlled by supplementing dietary supplements containing huge amounts of health-promoting ingredients. These elements promote cell health, regeneration, and the anti-aging process that specifically interrupt the pathogenic pathways in AD development. Fortunately, incorporating changes in the nutritional content is inexpensive, easy, acceptable, safe, effective, and in most cases, free from major adverse events. Many nutritional phytoconstituents such as flavonoids, alkaloids, and terpenoids are still being evaluated in the hope of identifying a successful therapy for AD. This review discusses the therapeutical potential of several key nutrients that have been researched for treating AD treatment and the method of their neuroprotective intervention.

The Therapeutic Potential of Algal Nanoparticles: A Brief Review.

Recently, the green synthesis of metallic nanoparticles (NPs) has received tremendous attention as a simple approach. The green pathway of biogenic synthesis of metallic NPs through microbes may provide a sustainable and environmentally friendly protocol. Green technology is the most innovative technology for various biological activities and lacks toxic effects. Reports have shown the algae-mediated synthesis of metal NPs. Algae are widely used for biosynthesis as they grow fast; they produce biomass on average ten times that of plants and are easily utilized experimentally. In the future, the production of metal NPs by different microalgae and their biological activity can be explored in diverse areas such as catalysis, medical diagnosis, and anti-biofilm applications.

Correlating multi-functional role of cold shock domain proteins with intrinsically disordered regions.

Cold shock proteins (CSPs) are an ancient and conserved family of proteins. They are renowned for their role in response to low-temperature stress in bacteria and nucleic acid binding activities. In prokaryotes, cold and non-cold inducible CSPs are involved in various cellular and metabolic processes such as growth and development, osmotic oxidation, starvation, stress tolerance, and host cell invasion. In prokaryotes, cold shock condition reduces cell transcription and translation efficiency. Eukaryotic cold shock domain (CSD) proteins are evolved form of prokaryotic CSPs where CSD is flanked by N- and C-terminal domains. Eukaryotic CSPs are multi-functional proteins. CSPs also act as nucleic acid chaperons by preventing the formation of secondary structures in mRNA at low temperatures. In human, CSD proteins play a crucial role in the progression of breast cancer, colon cancer, lung cancer, and Alzheimer's disease. A well-defined three-dimensional structure of intrinsically disordered regions of CSPs family members is still undetermined. In this article, intrinsic disorder regions of CSPs have been explored systematically to understand the pleiotropic role of the cold shock family of proteins.

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.