Isma Liza Mohd Isa

Inflammation is a complex protective biological response triggered by harmful stimuli such as pathogens, chemical agents, or physical injury, and is closely associated with the development of pain and various chronic diseases. It involves a coordinated cascade of cellular and molecular events, including activation of pattern recognition receptors, release of pro-inflammatory cytokines, production of reactive oxygen species, and recruitment of immune cells. Acute inflammation is essential for host defense and tissue repair. However, persistent or dysregulated inflammation may lead to chronic inflammation, oxidative stress, and tissue damage. Inflammatory pain, a subtype of nociceptive pain, arises from the sensitization of peripheral and central nociceptive pathways by inflammatory mediators such as cytokines, prostaglandins, and nitric oxide. Herbal products have been traditionally used to manage inflammatory diseases due to their bioactive compounds, which modulate inflammatory pathways and alleviate symptoms, and gaining increasing attention due to their multi-targeted mechanisms and lower adverse effects. Polygonum minus (PM), a medicinal herb widely used in Southeast Asia, is rich in bioactive compounds including flavonoids, phenolics, polygodial and essential oils. Phytochemical studies have identified compounds such as qsiuercetin and myricetin, which exhibit strong antioxidant and anti-inflammatory properties. Experimental evidence suggested that PM exerts its anti-inflammatory effects through the inhibition of key inflammatory pathways, including cyclooxygenase (COX) and lipoxygenase (5-LOX), suppression of pro-inflammatory cytokines, and modulation of nuclear factor-kappa B (NF-κB) signaling. Additionally, its antioxidant activity contributes to the reduction in oxidative stress, thereby limiting inflammation-induced tissue damage. This review highlights the mechanisms the potential therapeutic role of PM in modulating underlying inflammation and inflammatory pain. The evidence suggested that PM may serve as a potential promising natural agent for the management of inflammation and pain. Further studies are warranted to elucidate its molecular mechanisms and to validate its efficacy and safety in clinical settings.

An organ‐on‐a‐chip platform has emerged as an advanced in vitro model that replicates organ‐level structures within physiologically relevant human microenvironments. In this review, we focus on intervertebral disc (IVD) degeneration, a leading cause of chronic low back pain, providing a comprehensive overview of the current understanding of IVD anatomy, physiology, and pathogenesis. We review conventional in vitro, ex vivo, and in vivo models, which have expanded our understanding; however, they inadequately reproduce the human phenotype, heterogeneous disc composition and anatomy, which comprises nucleus pulposus (NP) and annulus fibrosus (AF) with neovascularization and sensory innervation within the three‐dimensional (3D) degenerative microenvironment. We emphasize a disc‐on‐a‐chip platform to address these limitations, which integrates microfluidics and biomimetic ECM‐based hydrogels within a controlled microenvironment to miniaturize the disc. It offers a promising platform to simulate the pathological disc milieu by incorporating gradient control of key signaling molecules implicated in disc degeneration. These include a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMP)‐mediated extracellular matrix (ECM) degradation; tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β)‐driven inflammation via nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB); vascular endothelial growth factor (VEGF)‐promoted angiogenesis; and nerve growth factor (NGF)‐ and brain‐derived neurotrophic factor (BDNF)‐mediated sensory innervation and sensitization, thus contributing to nociception. Collectively, disc‐on‐a‐chip offers a next‐generation in vitro model for investigating mechanisms relating to ECM degradation, inflammation, innervation, vascularization, and nociception underlying IVD degeneration, enabling precision preclinical therapeutic evaluations.

Persistent and chronic hyperglycaemia in Type II diabetic mellitus (DM) is known to cause oxidative stress, which exacerbates underlying metabolic disorders, contributing to the progression of complications such as diabetic peripheral neuropathy (DPN). Palm tocotrienol-rich fraction (TRF) is renowned for its potent antioxidative and neuroprotective properties and might have the potential to halt or mitigate the severity of DPN. This study aimed to investigate the effects of palm TRF on diabetic rats with peripheral neuropathy and to identify the correlation between plasma metabolomic alterations and DPN parameters. Male Sprague Dawley (SD) rats were randomly divided into normal control and DM groups in which Type II DM was induced using a high-fat diet and a low-dose streptozotocin (STZ) (35 mg/kg). Successful diabetic rats were randomly divided and received daily oral treatments of palm olein (vehicle), metformin (70 mg/kg), TRF (60 mg/kg), or a combination of TRF and metformin for 12 weeks. Behavioural parameters, serum biomarkers, and plasma metabolomic profiling were assessed at 0 (baseline) and 12 weeks of intervention. From the behavioural parameters, improvement in the symptoms of thermal hyperalgesia and mechanical allodynia was seen with TRF interventions, either alone or in combination with metformin. A significant reduction in the neurofilament light (NEFL) chain, accompanied by a notable increase in nerve growth factor (NGF) levels in the serum of treatment groups, was also observed. From the plasma samples, findings reveal that TRF increases metabolites related to neurotransmitter pathways (acetylcholine, choline, phenylalanine, tryptophan) and decreases inflammatory metabolites (kynurenine, prostaglandin) compared to untreated diabetic rats. These metabolites, except for prostaglandin, showed positive correlations with pain sensitivity. In contrast, prostaglandin showed opposite correlations with pain and nerve damage markers, suggesting its potential role in inflammation and axonal injury.

Artificial antigen-presenting cells (aAPCs) offer a precise system for modulating immune cells, effectively addressing major challenges in immunotherapy, such as unintended effects. Diatoms have attracted considerable interest as natural templates for biomaterials owing to their surface characteristics, which can replicate those found in cellular structures. In this study, we introduced the creation of calcium-modified diatoms that act as artificial antigen-presenting cells. This innovative strategy aims to enhance immunological interactions and emulate the functions of natural antigen-presenting cells. Our findings indicate that amine polymerization on calcium-modified diatoms improved the attachment of immunomodulatory proteins (anti-CD28 and anti-CD3) to the diatom surface, thereby promoting specific antibody-antigen interactions with human T cells, as evidenced by the formation of immunological synapses, which initiate targeted immune responses. Through costimulatory signaling, we determined robust expression of T cell activation markers, not only during early activation (CD69) but also sustained at a later time point (CD25), associated with increased T cell proliferation. Metabolically, diatom-based aAPCs promote glycolysis over mitochondrial oxidative respiration to meet the elevated energy demand for immune activation and homeostasis. Our findings suggest that the immunofunctionalization of calcium-modified diatoms offers a promising strategy for the development of bioinspired, functional aAPC, which are adaptive immunomodulatory systems, and hold future potential as immunotherapeutic platforms for diseases such as cancer and autoimmunity.

Lower back pain (LBP) is a major health concern, especially in older adults. A key aetiological factor is intervertebral disc (IVD) degeneration. It is mediated by dysregulation of extracellular matrix (ECM) and inflammation. In recent years, regenerative therapies have garnered attention for their potential to restore disc function by addressing the underlying biological alterations within the IVD. This review focuses on the comprehensive understanding of the anatomy and physiology of the IVD, highlighting its life cycle from embryonic development, and maturation to degenerative phenotype. We describe current treatments for managing LBP caused by IVD degeneration. This review emphasizes on the recent advancements in hydrogel engineering, highlighting natural, synthetic, and composite hydrogels and their application in ECM-targeted regenerative therapy for IVD degeneration. By exploring innovations in hydrogel technology, including improvements in crosslinking techniques and controlled degradation rates—we discuss how these materials could enhance IVD regeneration and potentially be used for the management of LBP. With their enhanced biomimicry, hydrogel-based ECM mimics offer a promising pathway for developing effective, durable therapies that address the root causes of disc degeneration, providing new hope for individuals living with chronic LBP.

Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain, causing disability; hence, there is no regenerative nature of the current treatments. Hyaluronic acid (HA) was reported to facilitate tissue repair and alleviate pain. Herein, we determined the therapeutic effect of HA and type II collagen (COLII) hydrogel for tissue repair targeting pain in IVD degeneration. We implanted HA/COLII hydrogel following surgically induced disc injury at coccygeal levels in the rat tail model of pain. We assessed the efficacy of the HA/COLII hydrogel in reducing pain behaviour by using the von Frey assessment, protein expression of growth-associated protein (GAP) 43 for sensory nerve innervation, and disc hydration by magnetic resonance imaging (MRI). We observed the anti-nociceptive effect of the HA/COLII hydrogel in alleviating mechanical allodynia in rats. There was an inhibition of sensory hyperinnervation indicated by the GAP43 protein in the treatment group. We revealed an increase in T1ρ mapping of MRI, indicating that the hydrogel restored disc hydration in vivo. Our findings suggest the HA/COLII hydrogel alleviates pain behaviour, inhibits hyperinnervation and promotes disc hydration for tissue repair, implying that it is a potential candidate for the treatment of degenerative disc-associated low back pain.

Oxidative stress is a contributing factor that leads to the vascular complications of diabetes mellitus. Diabetic peripheral neuropathy (DPN) is one of the microvascular complications with rising concern as the disease progresses despite strict glucose control and monitoring. Thus, there is an ongoing need for an early intervention that is effective in halting or slowing the progression of DPN where antioxidants have been proposed as potential therapeutic agents. This systematic review aims to evaluate the existing evidence on the antioxidant effect in DPN and provide insight on the role of antioxidants in the progression of DPN in a rat model. A comprehensive literature search was conducted on Web of Science, EBSCOhost, and Scopus to identify the effects and role of antioxidants in DPN. Data extraction was performed and SYRCLE’s risk of bias (RoB) tool was used for risk assessment. This systematic review was written following the PRISMA 2020 statements. From the literature search, 1268 articles were screened, and a total of 101 full-text articles were further screened before 33 were analyzed. These findings collectively suggest that antioxidants can play a crucial role in managing and potentially reversing the effects of diabetic neuropathy by targeting oxidative stress and improving nerve function.