Oxidative stress has become a common impetus of various diseases, including neurodegenerative diseases. This review introduces the generation of reactive oxygen species (ROSs) in the nervous system, the cellular oxidative damage, and the high sensitivity of the brain to ROSs. The literature review focuses on the roles of oxidative stress in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Oxidative stress occurs when excessively produced free radicals are beyond the capability of endogenous antioxidants to scavenge, leading to the oxidation of proteins, lipids, and nucleic acids, stimulating neuroinflammatory responses, causing neuronal dysfunction, senescence, and death. The dysfunctional mitochondria and aberrant activities of metabolic enzymes are the major source of ROSs. The high vulnerability of the nervous system to ROSs underlies the critical roles of oxidative stress in neurodegenerative diseases. Gene mutations and other risk factors promote the generation of ROSs, which have been considered a crucial force causing the main pathological features of AD, PD, HD, and ALS. As a result, antioxidants hold therapeutic potential in these neurodegenerative diseases. The elucidation of the pathogenic mechanisms of oxidative stress will facilitate the development of antioxidants for the treatment of these diseases.

Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy.

Background: Diabetic sensorimotor polyneuropathy (DSP) is a common chronic diabetic complication. Traditionally, DSP was once considered irreversible with a typical loss of axon. However, the superimpose of acquired demyelination on axonal loss in DSP patients has been observed, implying that DSP may be preventable or reversible, particularly within a subgroup of patients exhibiting early-stage acquired demyelination, underscoring the critical importance of identifying early prognostic markers. Methods: We systemically review the literature on the roles of biomarkers in predicting DSP and monitoring the progress. The underlying mechanisms of biomarkers were also discussed. Results: The pathogenesis of DSP is multifaceted, with various pathological mechanisms contributing to its development. Key mechanisms include aberrant glucose metabolism and induction of oxidative stress and inflammation. Several pathological processes, such as disrupted glucose metabolism, nerve damage, impaired microcirculation, genetic variants, and microRNA dysregulation, lead to molecular and protein changes that may be detectable in blood and other biological compartments, thus serving as potential biomarkers for DSP progression. However, the utility of a biomarker depends on its predictive accuracy, practicality, and ease of measurement. Conclusions: Most biomarkers for predicting DSP have demonstrated suboptimal predictive value, and many lack established accuracy in forecasting DSP progression. Consequently, the diagnostic utility of any single biomarker remains limited. A comprehensive combination of biomarkers from various categories may hold incredible promise for accurate detection. As artificial intelligence (AI) techniques, especially machine learning, rapidly advance, these technologies may offer significant potential for developing diagnostic platforms to integrate and interpret complex biomarker data for DSP.

The aberrant expression of the transactive response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.

Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can interfere with RNA processing, while DPRs directly bind to and sequester associated proteins to disrupt processes of rRNA synthesis, mRNA translation, autophagy, and nucleocytoplasmic transport. The mutations of C9orf72 and HRE result in the loss of functional C9ORF72. Under physiological conditions, C9ORF72 binds to Smith–Magenis chromosome region 8 and WD repeat-containing protein and forms a protein complex. Loss of C9ORF72 leads to autophagic impairment, increased oxidative stress, nucleocytoplasmic transport impairment, and inflammatory response. The attempted treatments for ALS have been tried by targeting C9orf72 HRE; however, the outcomes are far from satisfactory yet. More studies should be performed on pharmacological and molecular modulators against C9orf72 HRE to evaluate their efficacy by targeting HRE.

Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes mellitus, which is a common cause of disability in individuals with diabetes mellitus. Multiple mechanisms may be involved in the development of DPN. Neuroinflammation is a critical factor contributing to nerve damage during diabetes. Inflammation can induce the development of diabetes mellitus, and long-term hyperglycemia also causes increased oxidative stress and promotes the release of inflammatory cytokines. After reading through the literature, the association of inflammation with the induction of diabetes and DPN was discussed in the review. Inflammation induces nerve damage and nerve conduction impairment. The neuropathic pain in diabetes-induced DPN is also closely associated with the inflammatory response. Given the important roles of inflammation in diabetes-induced DPN, explicit elucidation of neuroinflammation during diabetes mellitus and DPN should hold the potential for developing novel therapeutic strategies for DPN. Experimental studies and limited clinical trials support the value of anti-inflammatory reagents in treating DPN, and the positive outcomes of these investigations warrant further clinical trials.