JOURNAL/nrgr/04.03/01300535-202511000-00031/figure1/v/2024-12-20T164640Z/r/image-tiff The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro . Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Microglia, the immune cells of brain, can drive neurodegenerative diseases like Parkinson's disease (PD). The resting microglia can polarize into two extremes, either proinflammatory M1 or anti-inflammatory M2 phenotype under a specific microenvironment. Different transcriptional factors and the release of various cytokines characterize these states. The released proinflammatory markers from M1 microglia lead to neuroinflammation that ultimately causes irreversible loss of dopaminergic neurons in PD patients, on the contrary, the M2 microglia possess neuroprotective activity. PD is caused by aggregation and misfolding of α-synuclein in the affected dopaminergic neurons. The misfolded α-synuclein is cytotoxic and can propagate like a prion from one cell to the other, acting like a template, that can initiate the conversion of normal proteins into abnormal conformation. The extracellular α-synuclein can interact and polarize the microglia into the M1 phenotype resulting in inflammation, thereby driving the progression of PD. The progression of neuroinflammation-mediated neurodegeneration in PD is seen higher in menopausal women; likely due to the low circulating estrogen levels. Estrogen hormones possess neuroprotective activity, and one of the ways is that they can polarize the microglia into M2 phenotypes and reduce α-synuclein-mediated microglial activation. A detailed understanding of the signaling mechanisms underlying microglial polarization between M1 and M2 phenotypes is crucial for identifying druggable targets to reduce PD symptoms, including in menopausal women.

Ischemic stroke (IS) remains a challenge in clinical treatment due to limited therapeutic options. While artemisinin (ART), an antimalarial drug, shields against acute IS via anti-inflammatory, antioxidant, and anti-apoptotic properties, the long-term benefits and specific underlying mechanisms have not been fully elucidated. Here, we investigate whether ART ameliorates IS injury and promotes neurogenesis by activating the peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 microglial polarization.

The experimental models included transient middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary microglial cultures to simulate IS. The therapeutic effects of ART were evaluated by neurological functions and infarct volume. PPARγ inhibitor T0070907 (T007) was intraperitoneally injected 24 h following MCAO/R at a dose of 2 mg/kg in vivo and a concentration of 10 μM for 30 min before OGD in vitro. We utilized real-time quantitative polymerase chain reaction (RT-qPCR) along with Western blot analyses to detect the microglia markers and PPARγ. The proliferation and differentiation of neural stem cells (NSCs) both in vivo and in vitro were assessed via immunofluorescence labeling. The neurogenic potential of ART-treated microglia was investigated by conditioned medium. The levels of brain-derived growth factor (BDNF) and insulin-like growth factor-1 (IGF-1) in microglia were measured by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).

ART treatment significantly alleviated short- and long-term neurological deficits and reduced cerebral infarct volume in rats with IS. Experiments conducted both in vivo and in vitro experiments illustrated that ART directed microglia away from the pro-inflammatory M1 state towards the anti-inflammatory M2 state, enhanced neurogenesis, and upregulated the expression of PPARγ, BDNF, and IGF-1. In addition, the conditioned medium from ART-exposed microglia stimulated the proliferation and neuronal differentiation of primary NSCs. However, these positive effects were effectively counteracted by the use of PPARγ inhibitor T0070907 (T007).

Our findings demonstrate that ART ameliorates IS injury and promotes neurogenesis mainly through PPARγ-mediated microglia M2 polarization. Therefore, ART can be considered a potential therapeutic drug for IS.

Microglia are the primary immune cells of the central nervous system that play pivotal roles in health and disease. Abnormally activated microglia secrete proinflammatory factors and play essential roles in neurodegenerative disease progression. This study investigated the potential effects of Pentadecyl, rich in odd-numbered fatty acids, such as pentadecanoic acid, isolated from Aurantiochytrium limacinum, on the lipopolysaccharide (LPS)-induced immune response of BV-2 microglial cells.

Cell viability was detected using MTT and LIVE/DEAD assays. mRNA and protein levels of inflammatory cytokines and signaling factors were assessed using real-time PCR and western blotting, respectively.

Pentadecyl did not affect MTT-reducing activity or the number of dead cells stained with ethidium homodimer-1. Pentadecyl selectively mitigated the LPS-induced overproduction of pro-inflammatory cytokines, including interleukin (IL)-6 and IL-1β, at the transcriptional and protein levels, whereas tumor necrosis factor-alpha (TNF-α) expression remained unchanged. Western blot analysis showed that Pentadecyl downregulated the LPS-induced increase in the phosphorylation of signal transducer and activator of transcription 3 (STAT3) but did not affect the phosphorylation of p65, a component of nuclear factor-kappa B, or p38 and c-Jun N-terminal kinase, both of which are mitogen-activated protein kinases. Similar to Pentadecyl, Stattic, a representative STAT3 inhibitor, preferentially suppressed the LPS-induced upregulation of IL-6 and IL-1β mRNA expression, whereas its inhibitory effect on TNF-α expression was relatively modest. These results indicate that Pentadecyl suppresses LPS-induced pro-inflammatory cytokine production without affecting cell survival by regulating the STAT3 signaling pathway in BV-2 cells.

Among nanoscale biopolymers, fungal chitin nanofibrils (ChNFs) stand out for their low carbon footprint and functional properties. However, the nanotoxicity properties of ChNFs have not been fully elucidated. To fill this knowledge gap, here we investigate the cytotoxicity and inflammatory effects of chemically modified ChNFs having gradient acid and alkaline treatments. ChNFs isolated from white mushroom exhibit a long fibrous morphology with diameters of 3-8 nm and lengths of 150-600 nm, and are composed of α-chitin in coexistence with amorphous covalently bounded β-glucans. Both alkaline (2 m NaOH) and acidic (2 m HCl) treatments impact the crystallinity, N-acetylation, zeta potential, and nitrogen content values to provide ranges of 23-to-51 %, 45-to-99 %, -5 to +26 mV, and 2.6-to-5.2 %, respectively. Nanotoxicity studies with colloidal dispersions demonstrate differences in the inflammatory response by cells after chemical post-treatments. The NaOH-treated ChNFs elicited a much lower inflammatory response, attenuating the release of nitrites and the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Alginate hydrogels with ChNFs were further fabricated and demonstrated potential to host cells in three-dimensional microenvironments, preserving a good metabolic activity, viability, and cell proliferation. These results may guide new applications of fungal nanochitin in pharmaceutical or tissue engineering.

Motor function recovery after complete spinal cord injury remained as a challenge in medical field, while one of the key approaches is promoting the local microenvironments. In this research, we performed a conjugated therapy by transplantation of neural stem cell (NSC) scaffolds and umbilical cord mesenchymal stem cell derived exosomes (ucMSC-exos) for the treatment of complete transactional spinal cord injury (SCI). We first demonstrated the anti-inflammatory effects of ucMSC-exos in vitro and found that ucMSC-exos could regulate microglia polarization from M1 to M2, an anti-inflammatory phenotype. Besides, ucMSC-exos also promoted NSC proliferation and neural differentiation during in vitro culturing. On the other hand, core-shell hydrogel microfibers were used as transplantation scaffolds for both small and large SCI defects. The core-shell microfibers could carry large amounts of NSCs in the core portion and the shell portion is highly permeable for nutrient and metabolite transportation. In in vivo experiments, we found that conjugated transplantation of ucMSC-exos and NSC microfibers could decreased inflammatory cytokines at lesion sites, gave rise to more neurons and promoted angiogenesis, thus comprehensively improved the local microenvironment while compared with transplantation of NSC scaffolds only. These beneficial results were in accordance with those in vitro experiments and further led to better locomotor function recovery. In summary, this research has demonstrated that that conjugated transplantation of ucMSC-exos and NSC microfibers could make a potential tool for complete SCI repair.

Optic neuropathy is one of the main causes of irreversible blindness in the world, and there is no effective treatment in clinic. Both primary degeneration and secondary degeneration play an important role in the injury caused by optic neuropathy. Partial optic nerve transection (PONT) model can be used to study these two kinds of degeneration simultaneously. However, there is currently no measure that can effectively intervene in both types of injuries concurrently. Here, we constructed an expanded partial optic nerve transection (EPONT) model. Nerve growth factor (NGF)-chitosan locally implanted into the injured area could simultaneously intervene in the secondary and primary degeneration, not only protecting the ventral part of the injured optic nerve, but also promoting the regeneration of the dorsal part. Visual functions, including pupillary light reflex and depth perception, were also well preserved. NGF-chitosan exerted biological effects by enhancing the expression of NGF and tyrosine kinase A (TrkA) in the optic nerve and retinal ganglion cells (RGCs). Furthermore, NGF-chitosan played a protective and repairing role by inhibiting the activation of microglia in the ventral area of the injured optic nerve and increasing the expression of mammalian target of rapamycin (mTOR) in RGCs. Our results demonstrate that the local use of NGF-chitosan in the injured area effectively repaired the optic nerve, which provides a new measure for the clinical treatment of optic nerve injury.

This study aims to assess the therapeutic effectiveness of Relaxin-2 (RLN-2) in promoting functional recovery and neuroprotection following spinal cord injury (SCI) in mice. Furthermore, continuous subcutaneous infusion of Serelaxin (0.5 mg/kg/day; human recombinant relaxin-2) improved neurological recovery, as evidenced by higher Basso-Beattie-Bresnahan (BBB) scores and reduced foot-stepping angles compared to the SCI group. Additionally, RLN-2 effectively reduced edema in the injured spinal cord, as shown by decreased water content and downregulated AQP4 expression at mRNA and protein levels. RLN-2 reduced oxidative stress markers such as malondialdehyde (MDA) and reactive oxygen species (ROS) and increased the activity of catalase (CAT). Further, RLN-2 mitigated neuroinflammation by reducing the levels of pro-inflammatory cytokines (TNF-α and IL-6) and by inhibiting the activation of M1 microglia while promoting the polarization of M2 microglia. It also inhibited the activation of the NF-κB signaling and strengthened the activation of the STAT6 signaling in the spinal cord of SCI mice. These findings suggest that RLN-2 may be a promising therapeutic agent for the treatment of spinal cord injury.

Epimedium brevicornu Maxim, a Chinese herbal medicine, is known for its efficacy in nourishing the kidneys. Icariin (ICA), the primary active ingredient in Epimedium brevicornu Maxim., possesses multiple pharmacological properties, yet its impact on Alzheimer's disease (AD) warrants further exploration.

Study aims to explore the inhibitory impact of ICA on neuroinflammation in AD via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.

SPF-grade male ICR mice were used to establish an AD model by lateral ventricle injection of Aβ1-42. Behavioral, pathological assessments, as well as immunofluorescence staining, molecular docking, and Western blot analyses, were conducted to evaluate the effects of ICA treatment on memory function, neuronal damage, neuroinflammation, and the cGAS- STING pathway in mice.

ICA significantly improved memory impairment, alleviated neuronal damage and apoptosis, and suppressed neuroinflammation in AD mice. Additionally, ICA inhibited microglial hyperactivation, promoting the transition from the M1 to the M2 phenotype. It specifically inhibited the activation of the cGAS-STING pathway and down-regulated the expression of cGAS, STING, p-TBK1/TBK1, p-IRF3/IRF3 and p-NF-κB/NF-κB. Furthermore, molecular docking revealed that the binding energy between ICA and cGAS was -7.07 kcal/mol, indicating a stable interaction. Further validation using the cGAS-selective small molecule inhibitor RU.521 confirmed the protective effects of ICA against cGAS-STING signaling on microglial transformation and neuroinflammation.

ICA exhibits therapeutic potential in AD by inhibiting microglial transformation and neuroinflammation through the cGAS-STING pathway, positioning it as a candidate drug for AD treatment targeting this pathway.

Inflammatory response plays a key role in the pathophysiological process of Ischemic stroke. Cornel iridoid glycosides (CIG), the primary components of Cornus officinalis Sieb. et Zucc., have demonstrated a wide range of anti-inflammatory pharmacological activities. This study aimed to investigate the neuroprotective effect of CIG against cerebral ischemia/reperfusion injury and to explore its anti-inflammatory mechanisms. Sprague-Dawley rats were pre-treated with CIG at doses of 1.25, 2.5, and 5 mL/kg and then subjected to transient middle cerebral artery occlusion/re-perfusion (tMCAO/R). The effectiveness of prevention was determined based on neurological function, cerebral infarction, edema, histological changes, microglia aggregation, and induction of inflammation cytokines using hematoxylin-eosin staining, TUNEL staining, and real-time quantitative PCR. Proteins involved in the canonical nuclear factor kappa B (NF-κB) signaling pathway were analyzed using immunofluorescence, western blot, and molecular docking analysis. The results showed that CIG could dose-dependently reduce the neurological deficit score, cerebral infarction and edema, and brain cells apoptosis caused by tMCAO/R injury. Additionally, CIG significantly inhibited the aggregation of microglia and decreased levels of tumor necrosis factor-α, interleukin-1β and interleukin-6 in a dose-dependent manner. Furthermore, the tMCAO/R rats pre-treated with CIG displayed inhibition of NF-κB nuclear translocation and down-regulations on TLR4, MyD88, TRAF6, and inhibitory kappa B. Molecular docking analysis revealed that the CIG components (morroniside, loganin, and cornuside I) exhibited good affinities with protein TLR4, MyD88, and TRAF6. CIG could alleviate cerebral ischemia/reperfusion injury by inhibiting microglia aggregation and reducing the neuroinflammatory response, which targets the TLR4/MyD88/NF-κB signaling pathway. Therefore, CIG might potentially serve as a new medicine candidate for the prevention of ischemic stroke.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss, neuroinflammation, and motor dysfunction. PD is a multifactorial disease, with neuroinflammation driven by NLRP3 inflammasome activation representing an important component of its pathological progression. Therefore, we aimed to evaluate the therapeutic potential of rebamipide (Mucosta®), a clinically approved anti-inflammatory agent, in PD by targeting the NLRP3 inflammasome. Specifically, we examined the effects of rebamipide on neuroinflammation, dopaminergic neuron preservation, and motor deficits using BV2 microglia cells and a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model.

Rebamipide alleviated microglial activation and downstream neuroinflammation by suppressing the NLRP3-NEK7 interaction, resulting in dopaminergic neuron protection in the MPTP-induced PD model. Rebamipide downregulated IL-1β levels in BV2 microglia cells treated with α-synuclein and MPP+. Molecular docking analysis revealed a high binding affinity between rebamipide and the NLRP3-NEK7 interaction interface. Surface plasmon resonance analysis confirmed the direct binding of rebamipide to NLRP3, with notable kinetic affinity, supporting its role as a novel NLRP3 inflammasome inhibitor. Rebamipide significantly downregulated IL-1β levels, microglial activation, and dopaminergic neuron loss in the MPTP mouse model by disrupting inflammasome activation. Rebamipide preserved dopamine levels in the striatum and improved motor deficits, including bradykinesia and motor coordination. The neuroprotective effects of rebamipide were neutralized in NLRP3 knockout mice, confirming the dependency of its action on NLRP3.

Considering its established clinical use, this study supports repurposing rebamipide for treating PD and other NLRP3 inflammasome-driven neuroinflammatory diseases.

Hibernation induces significant molecular and cellular adaptations in the retina to maintain function under reduced metabolic conditions. This study aimed to investigate the expression of neuronal, synaptic, and glial markers in the retina of Spermophilus xanthoprymnus during pre-hibernation and hibernation periods using immunohistochemical staining. Synaptophysin expression, restricted to the inner plexiform layer (IPL) and outer plexiform layer (OPL) during pre-hibernation, significantly increased in both layers during hibernation, with additional expression observed in the outer nuclear layer. NeuN immunoreactivity remained unchanged in the ganglion cell layer (GCL) but increased notably in the INL during hibernation. Calbindin-D28k expression, prominent in the INL and plexiform layers during pre-hibernation, decreased markedly in hibernation. In contrast, parvalbumin expression increased across all retinal layers, except the photoreceptor layer, during hibernation. Glial fibrillary acidic protein (GFAP) expression, observed in the NFL and GCL, was significantly reduced during hibernation. Iba-1 immunoreactivity, sparse in the IPL and OPL during pre-hibernation, showed a pronounced increase in the IPL, OPL, and INL during hibernation periods. In conclusion, the expression of synaptophysin, NeuN, calbindin-D28k, parvalbumin, GFAP, and Iba-1 was investigated for the first time in the retina of the Anatolian ground squirrel during pre-hibernation and hibernation. This study reveals region-specific shifts in retinal marker expression during pre-hibernation and hibernation, providing a basis for future research into visual system adaptations and retinal plasticity under metabolic suppression.

Oxidative stress and inflammatory responses play crucial roles in the development of secondary brain injury following traumatic brain injury (TBI). Thus, this study aimed to investigate the potential cerebroprotective effects of salvianolic acid B (SalB) in mitigating oxidative stress and inflammatory responses post-TBI through the activation of Nrf2.

This study aims to investigate the potential cerebroprotective effects of SalB in ameliorating oxidative stress and inflammatory responses following TBI by activating Nrf2, thereby laying a foundation for TBI treatment.

Controlled cortical impact and hydrogen peroxide were employed to replicate TBI in animal and cellular models, respectively.Behavioral studies predict neural function, Western Blot (WB) predicts oxidative stress, immunofluorescence and ELISA predict inflammatory response.The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.

SalB was delivered via intraperitoneal injection 1 h after TBI induction, with its neuroprotective efficacy evaluated across a range of concentrations. In the cellular assay, SalB was used to incubate cells simultaneously with H2O2. WB analysis was employed to quantify protein levels, while malondialdehyde, glutathione, superoxide intensity, and reactive oxygen radical probes were utilized to evaluate oxidative stress. Immunofluorescence and ELISA techniques were used to characterize microglia phenotype and inflammatory response. Behavioral assays were also conducted to evaluate neurological function. The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.

Animal and cellular experiments indicate that SalB can mitigate oxidative stress through the Nrf2/Peroxiredoxin 2 pathway, and reduce inflammatory response via the Nrf2/Toll-like receptor 4/Myeloid differentiation primary response protein 88 pathway in a dose-dependent manner. Consequently, SalB demonstrates efficacy in enhancing neurological function following TBI. Conversely, the inhibitory effects of ML385 counteract the antioxidant and anti-inflammatory properties of SalB.

SalB exerts its beneficial effects post-TBI through Nrf2-dependent antioxidants and as anti-inflammatory responses.

Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression. The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.

Breast cancer-related depression (BCRD) is one of the severest comorbidities, affecting the quality of life and the treatment efficacy in BC patients. Chaihu-Shugan-San (CSS), a traditional Chinese medicine presents a potential therapeutic method in BCRD.

The main purpose of the research was to investigate the effects of CSS on BCRD in a mouse model and to elucidate its mechanisms, particularly its impact on microglial polarization through the IL-17/ NF-κB pathway.

A mouse BCRD model was constructed and treated with CSS. Behavioral testing, biochemical parameters, H&E staining, and small animal imaging were used to assess the depressive-like behaviors and tumor growth in mice. RNA sequencing analysis was performed, and the data were authenticated by Western blot as well as quantitative qRT-PCR to explore the mechanisms of CSS treatment in BCRD. The BV2 microglia were stimulated with LPS in vitro and intervened by IL-17 protein, IL-17 antagonist, IMD-0354, and CSS. In addition, western blot was utilized to confirm the expression of IL-17/ NF-κB pathway-related factors. Molecular docking technique and UPLC-Q-TOF/MS were used to find out the key active components of CSS.

CSS treatment significantly improved depression-like behaviors and retarded tumor growth in mice. Through RNA sequencing analysis, it was indicated that the improvement of BCRD by CSS was highly associated with the regulation of the IL-17/ NF-κB pathway. Western blot and qRT-PCR outcomes suggested that CSS inhibited the IL-17/ NF-κB pathway, facilitating the transformation from pro-inflammatory M1 microglial phenotype to anti-inflammatory M2 phenotype, contributing to the reduction of neuroinflammation. In vitro experiments demonstrated that CSS modulated the immune reaction through the induction of phenotypic transformation of microglia from M1 toward M2 phenotype, hence reducing neuroinflammation. Notably, this therapeutic effect of CSS was highly similar to the effects of IL-17 antagonists, thus suggesting that CSS alleviates the symptoms of BCRD by targeting IL-17. Molecular docking revealed that the major bioactive compounds in CSS were Saikosaponin A, Saikosaponin C, and Saikosaponin D.

This study systematically demonstrates that CSS ameliorates BCRD by suppressing the IL-17/ NF-κB pathway as well as modulating microglial polarization and elucidates the dual function of IL-17. These results point to a new multi-target intervention strategy for BCRD treatment and fully reflect the holistic effects of CSS by its multi-component as well as multi-target actions.

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration.

Neuroinflammation is one of the main players in lesion expansion and locomotor deficits after spinal cord injury (SCI), thus treatments to control the inflammatory process emerge as novel therapeutic strategies. In this context, the anti-inflammatory effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), the main phytocannabinoids of Cannabis sativa, are increasingly recognized. The aim of this work was to investigate the effects of a standardized Cannabis sativa extract (CSE), which is mainly composed by THC/CBD in equimolar concentration, on neuroinflammation, secondary damage and locomotor outcome after SCI in rats. After acute SCI, CSE therapy increased the number of non-inflammatory (arginase-1 positive) microglial cells in the epicenter of the lesion and decreased the number of pro-inflammatory ones (arginase-1 negative) in the epicenter and in the rostral and caudal regions of the lesion. CSE also reduced the number of reactive astrocytes in the grey matter of the rostral and caudal regions. These results are consistent with the downregulation of mRNAs of inflammatory mediators (IL-1β, TNFα, IL-6, C3) and the upregulation of anti-inflammatory markers (ARG-1, MRC). In the chronic phase, CSE treatment prevented cyst expansion and also increased the volume of spared grey and white matter. Regarding locomotor outcome, CSE-treated rats showed better locomotor scores (open field test), higher latency to fall (Rotarod test) and lower number of hindlimb foot misplacements (horizontal ladder walking test) than untreated injured rats. These results suggest that this standardized CSE offers a promising perspective for reducing acute neuroinflammation and promoting functional recovery after SCI.

The optic nerve contains retinal ganglion cell (RGC) axons and functions to transmit visual stimuli to the brain. Injury to the optic nerve from ischemia, trauma, or disease leads to retrograde axonal degeneration and subsequent RGC dysfunction and death, causing irreversible vision loss. Inflammatory responses to neurological damage and axonal injuries in the central nervous system (CNS) are typically harmful to neurons and prevent recovery. However, recent evidence indicates that certain inflammatory cell types and signaling pathways are protective after optic nerve injury and promote RGC survival and axonal regeneration. The objective of this review is to examine the evidence for diverse effects of inflammatory cell types on the retina and optic nerve after injury. Additionally, we highlight promising avenues for further research.

Nardostachys jatamansi DC. (Gansong), a widely utilized herb in traditional Chinese medicine, has been historically employed in the management of various neuropsychiatric disorders. Nardosinone (Nar), a sesquiterpenoid compound, has been identified as one of the principal bioactive constituents of N. jatamansi. This study investigated the effects of ethyl acetate extract (NJ-1A) from N. jatamansi and its active constituent nardosinone on neuroinflammatory mediator release, glucose metabolic reprogramming, and T cell migration using both in vitro and in vivo experimental models.

Lipopolysaccharide(LPS)-induced BV-2 microglial cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced male C57BL/6N mouse chronic model of Parkinson's disease were applied.

Both NJ-1A and Nar could significantly suppress LPS-induced production of M1 pro-inflammatory factors or markers in microglia and could inhibit the glycolytic process and promote oxidative phosphorylation via the AKT/mTOR signaling pathway. Furthermore, they exhibited the capacity to attenuate chemokine release from activated microglia, consequently reducing T cell migration. In vivo experiments revealed that NJ-1A and Nar effectively inhibited microglial activation, diminished T cell infiltration, and mitigated the loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra of MPTP-induced mice.

NJ-1A and nardosinone exert neuroprotective effects through the modulation of microglial polarization states, regulation of metabolic reprogramming, and suppression of T cell infiltration.

Chronic stress can affect brain function through various mechanisms, leading to the development of anxiety disorders. The chronic unpredictable mild stress (CUMS) is a classic model of chronic stress. This study evaluated the effects of different durations of CUMS on anxiety-like behavior, inflammation, and tryptophan metabolism in C57BL/6N mice. The results of behavioral assessments showed that after 3 and 4 weeks of CUMS exposure, the mice exhibited significant decreases in open arms ratio and time ratio in the elevated plus maze (EPM), prolonged latency in the novelty-suppressed feeding test (NSFT), and reduced transitions in the light/dark box (LDB), all indicative of anxiety-like behavior. The inflammatory factors expressions were quantified using qPCR, showing that pro-inflammatory and anti-inflammatory markers began to rise following 1-2 weeks of CUMS exposure. After 3 weeks of stress, TNF-α significantly increased, TGF-β levels started to decrease, and by 4 weeks of CUMS, Arg-1 expression also declined. In terms of tryptophan metabolism, 5-HT content in the hippocampus of the mice began to decrease after 3 weeks of CUMS, while the levels of neuroprotective kynurenic acid (KYNA) continued to rise. Concurrently, neurotoxic substances, including 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), accumulated; after 4 weeks of CUMS, the KYNA content also started to decline. In conclusion, CUMS exposure for 3-4 weeks in male C57BL/6 N mice induces anxiety-like behavior alongside the occurrence of inflammatory responses and disturbances in tryptophan metabolism. These findings highlight the complex interplay between stress, inflammation, and metabolic pathways in the etiology of anxiety-related behaviors.

Alzheimer's disease (AD) has emerged as a global public health priority characterized by escalating prevalence and the limited efficacy of current therapeutic approaches. Although the pathological complexity of AD is well-recognized, its underlying etiology remains incompletely elucidated. Current research highlights a bidirectional gut-brain axis (GBA) interaction, wherein gut microbiome perturbations may impair intestinal barrier stability, influence immune responses, and blood-brain barrier permeability through microbial metabolite-mediated pathways, thereby contributing to AD pathophysiology. Notably, probiotics demonstrate therapeutic potential by restoring gut microbiome homeostasis, reinforcing intestinal barrier integrity, and mitigating neuroinflammatory responses via GBA. This review focuses on investigating the gut microbiome alterations in AD pathogenesis, the interaction of probiotics with GBA, and its significance in AD pathogenesis. By synthesizing current clinical evidence, this review aims to establish a scientific foundation for probiotic-based interventions as a novel therapeutic strategy in AD management.

The Coronaviridae family has again demonstrated the potential for significant neurological complications in humans during the recent pandemic. In patients, these symptoms persist throughout the infection, often lasting for months. The consequences of most of these post-infection symptoms might be linked with abnormal cytokine production and reactive oxygen species (ROS) expression, resulting in neuron damage. We investigated the effect of infection with the Mouse Hepatitis Virus (MHV) JHM strain and Sialodacryoadenitis Virus (SDAV) on a primary microglia and astrocyte culture by analysing ROS production, cytokine and chemokine expression, and cell death during one month post infection. For this purpose, confocal microscopy, flow cytometry, and a high-throughput Luminex ProcartaPlex immunopanel for 48 cytokines and chemokines were utilised. The replication of MHV-JHM and SDAV in microglia and astrocytes has increased the production of pro-inflammatory cytokines and inhibited the production of anti-inflammatory cytokines. The cytokine expression induced by the two viruses differed, as did their detection after infection. SDAV infection resulted in a much broader cytokine response compared to that of MHV-JHM. Both viruses significantly increased ROS levels and induced apoptosis in a small percentage of the cells, but without necrosis.

Anorexia nervosa (AN) is a severe psychiatric disease with a largely unknown pathophysiology. AN leads to reduced brain volume and a disbalance of the gut microbiome suggesting the involvement of the gut-brain-axis. Also, in the activity-based anorexia (ABA) animal model mimicking AN brain volume loss is observed. This study investigated the impact of chronic starvation on brain cell populations and evaluated the potential protective effects of omega-3 fatty acids (FA) and probiotics in rats. We used a chronic ABA model and provided daily oral supplementation of omega-3 FA and probiotics. Immunohistochemistry and qPCR were used to analyze GFAP-positive astrocytes, IBA1-positive microglia, OLIG1/2-positive oligodendrocytes, MAP2-positive neurons and Ki-67-positive proliferating cells in the cerebral cortex and corpus callosum. We found a significant reduction of astrocytes and microglia in all ABA groups, likely due to reduced proliferating cells. Reduced running wheel activity and reduced amount of food needed to sustain body weight were observed in animals with supplementation with omega-3 FA and probiotics but we did not observe alterations in brain cells that could be attributed to these supplementations. Our results indicate that glial cell depletion potentially underlies the diminished brain volume found in ABA rats. Omega-3 FA and probiotics show potential for reducing AN-related symptoms and merit further study as a therapeutic approach.

The Enteric Nervous System (ENS), often called the "second brain," is a complex network of neurons and glial cells within the gastrointestinal (GI) tract. It functions autonomously while maintaining close communication with the central nervous system (CNS) via the gut-brain axis (GBA). ENS dysfunction plays a crucial role in neurodegenerative and neurodevelopmental disorders, including Parkinson's disease, Alzheimer's disease, and autism spectrum disorder. Disruptions such as altered neurotransmission, gut microbiota imbalance, and neuroinflammation contribute to disease pathogenesis. The GBA enables bidirectional communication through the vagus nerve, gut hormones, immune signaling, and microbial metabolites, linking gut health to neurological function. ENS dysregulation is implicated in conditions like irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), influencing systemic and CNS pathology through neuroinflammation and impaired barrier integrity. This review highlights emerging therapeutic strategies targeting ENS dysfunction, including prebiotics, probiotics, fecal microbiota transplantation (FMT), and vagus nerve stimulation, which offer novel ways to modulate gut-brain interactions. Unlike previous perspectives that view the ENS as a passive disease marker, this review repositions it as an active driver of neurological disorders. By integrating advances in ENS biomarkers, therapeutic targets, and GBA modulation, this article presents a paradigm shift-emphasizing ENS dysfunction as a fundamental mechanism in neurodegeneration and neurodevelopmental disorders. This perspective paves the way for innovative diagnostics, personalized gut-targeted therapies, and a deeper understanding of the ENS's role in brain health and disease.

Ergothioneine (ET) is an under recognised diet-derived compound which has the potential to be a "longevity vitamin". It was found to be beneficial for cognitive function and age-related neurodegenerative disorder (ARND). Thus, this study was conducted to synthesise the existing evidence of ET's effects on cognition and ARND, emphasizing its potential as a micronutrient for healthy aging. This study also highlights the future prospects of the research regarding ET's effects on cognition and ARND that are suggested in existing literature. Three databases (Pubmed, Scopus, and Web of Science) were used to search for the studies that meet the inclusion and exclusion criteria. A total of 19 studies were included after screening in this review. The risk of bias of each study was assessed using the Office of Health Assessment and Translation (OHAT) risk of bias rating tool. All studies' characteristics and main findings were tabulated according to their type of study. Mechanisms of ET in improving cognitive function and preventing ARND were found to be through its antioxidative, anti-inflammatory and antisenescence properties. Its role in neurotransmission and neuroprotection also contributed to improving cognition and preventing ARND. In conclusion, ET is a potential compound to be explored as its role in cognition and ARND have been discovered through several studies.

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.

Microglial activation, particularly the polarization between classical (M1 phenotype) and alternative (M2 phenotype) states, plays pivotal roles in the immune pathogenesis of Parkinson's disease (PD), with the M1 phenotype exerting neurotoxic effects and the M2 phenotype conferring neuroprotection. Modulating microglial polarization toward the M2 phenotype holds therapeutic potential for PD. This study investigated the role of c-Cbl, an E3 ubiquitin ligase implicated in modulating microglial phenotypes and protecting dopaminergic neurons. Our findings revealed that c-Cbl-/- mice exhibited motor deficits, reduced striatal dopamine levels, and progressive dopaminergic neuron loss in the substantia nigra (SN). Genetic ablation of c-Cbl significantly increased proinflammatory cytokine release and microglial activation in the SN, accompanied by a phenotypic shift from M2 to M1 polarization. Furthermore, stereotaxic c-Cbl knockdown in the SN exacerbated behavioral impairments and accelerated dopaminergic neuron degeneration in the MPTP-induced mouse model of PD. At the molecular level, c-Cbl deletion promoted M1 polarization of microglia through dysregulation of the PI3K/Akt signaling pathway, thereby impairing dopaminergic neuronal survival. Collectively, this study demonstrates that c-Cbl knockout recapitulates PD-like pathology and drives microglial activation. Our results establish that c-Cbl orchestrates the transition from neurotoxic M1 to neuroprotective M2 microglial phenotypes, highlighting its central role in PD immunopathogenesis. These findings suggest c-Cbl as a promising therapeutic target for modulating microglial polarization and alleviating PD symptoms.

The dendritic cell of the CNS, the microglia (MG), is an initiation point of the immunological response within the post-blood-brain barrier (BBB) compartment. Microglia drastically changes in response to cell stress to a much different non-dendritic morphologies. This investigation postulates that if the first MG responses to toxic injury are isolated and studied in greater morphological detail, there is much to be learned about microglia's metamorphosis from and M2 to an M1 state. The organotypic hippocampal slice was the experimental setting used to investigate microglial response to toxic injury; this isolates dendritic cell to post-BBB cells dynamics from the impact of nonspecific of in vivo blood-derived signaling. Within the context of biochemically verified precise toxic cell injury/death (induced with mercury or cyanide in combination with 2-deoxy-glucose) to a specific region within the hippocampal slice, MG's morphological response was evaluated. There was up to 35% increase in microglia activation proximally to injury (CA3 region) and no changes distally (DG region) when compared to control slices treated with PBS. Maximum microglia activation consisted of a 3 plus-fold increase in the distance between the nucleus membrane and the cell membrane, which underscores an extensive and quantifiable amount of membrane rearrangement. This quantification can be applied to contemporaneous AI image analysis algorithms to demarcate and quantify relative MG activation in and around a site of injury. In between baseline and activated MG morphologies, 5 intermediate morphologies (or structural variations) are described as it relates to its cell body, nucleus, and dendrites. The result from this study reconciles details of MG's structure to its holistic characteristics in relation to parenchymal cell stress.

The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in the pathogenesis and progression of neurological diseases, although the specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide kinase involved in cellular energy metabolism and nucleotide synthesis. Recent studies suggest that CMPK2 plays a role in microglial-mediated neuroinflammation; however, its specific impact on microglial activation remains unclear. In this study, we hypothesize that CMPK2 promotes microglial-mediated neuroinflammation by activating the cGAS-STING signaling pathway. To investigate this mechanism, we employed lipopolysaccharide (LPS)-treated microglial cells to investigate the detailed mechanisms by which CMPK2 regulates neuroinflammation. Our experimental results indicate that in the BV2 and mouse primary microglial neuroinflammation model, both CMPK2 protein and transcript levels were significantly elevated, accompanied by microglial activation phenotypes such as increased cell size, shortened processes, transformation to round or rod-like shapes, and elevated CD40 expression. Concurrently, there was an increase in pro-inflammatory cytokine levels and a decrease in anti-inflammatory cytokine levels. Further investigation revealed that in the microglial, the expression of cGAS and STING was elevated, along with an increase in oxidative products and inflammatory responses. CMA stimulation further intensified these changes, while cGAS knockdown mitigated them. Finally, we demonstrated that cGAS knockdown inhibited the oxidative stress, cell activation-related changes, and neuroinflammatory responses induced by CMPK2 overexpression in the BV2 neuroinflammation model. Molecular docking experiments showed that CMPK2 stably binds to cGAS at the protein level. These findings suggest that the cGAS-STING pathway mediates CMPK2-induced microglial activation. In summary, our study demonstrates that LPS-induced CMPK2 overactivity promotes microglial activation and neuroinflammatory through the cGAS-STING pathway.

A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

Neurodegenerative diseases (NDs) have caused serious health issues worldwide. A growing body of evidence suggests a correlation between neuroinflammation and abnormal microglial activity with ND symptoms. Microglia survey play crucial roles in CNS during health and the injury. It is proposed that sex affects microglial roles during inflammation, resulting in mouse behavioural changes and expression alterations in key markers related to microglia functions.

Male and female C57BL/6 mice were injected with a single dose of LPS (5 mg/kg, i.p.) or saline. After 48 h, an open field test was conducted, followed by brain tissues collection for measuring the expression of IGF-1, IL-1β and TREM2 and Immunohistochemistry (IHC) analysis for NLRP3 level.

Males displayed greater depressive-like behaviour in the OFT, with lower levels of IGF-1, IL-1β, and NLRP3 and high TREM2 expression. Female mice did not exhibit this behaviour, in contrast to male mice, they exhibited increased IL-1β and NLRP3 expression.

This study revealed that LPS-induced sex-specific changes in genes involved in neuronal cell survival caused behavioural alterations in male mice. Moreover, females had observed inflammatory responses that had no impact on behavioural alterations. Overall, both sexes exhibited sex-specific microglial activation states.

Spinal cord injury (SCI)-induced ischemic delayed paralysis is one of the most serious side effects of aneurysms surgeries. Recent studies prove that the activation of autophagy, including macroautophagy and micro-autophagy pathways, occur during SCI-induced brain neuron damage. However, the role of chaperone mediated autophagy (CMA) during SCI remains to be unveiled. In the present work, rat model of delayed paralysis after aneurysms operation and adenovrius induced LAMP2A knockdown in microglia cells were applied in the present work to investigate the involvement of LAMP2A-mediated CMA in the aneurysm operation related SCI and delayed paralysis. The results showed that LAMP2A was upregulated in the SCI procedure, and contributed to neuron death and pro-inflammation perturbation via inducing iNOS+ polarization in microgila. We additionally observed that knockdown of LAMP2A resulted in the shift of microglia from iNOS+ to ARG1+ phenotype, as well as alleviated neuron damage during SCI. Furthermore, the analysis of BBB score, the result of immunohistological staining, and protein detection confirmed the activation of LAMP2A-mediated CMA activation and its interaction with NF-κB signaling, which leads to neuron death and motor function loss. These results prove that LAMP2A-mediated CMA contributes to the upregulation of pro-inflammatory cytokines and results in cell death in neurons during ischemic delayed paralysis via activating NF-κB signaling. Inhibition of LAMP2A promotes neurons survival during ischemic delayed paralysis.

Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic-pituitary-adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.

Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.

CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/- mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.

CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.

Recent research highlights the immune system's role in AD pathogenesis and promising prospects of natural compounds in treatment. This study explores immunity-related biomarkers and potential natural products using bioinformatics, machine learning, molecular docking, and kinetic simulation.

Differentially expressed genes (DEGs) in AD were analyzed using GSE5281 and GSE132903 datasets. Important AD module genes were identified using a weighted co-expression algorithm (WGCNA), and immune-related genes (IRGs) were obtained from the ImmPortPortal database. Intersecting these genes yielded important IRGs. Then, the least absolute shrinkage and selection operator (LASSO) and other methods screened common immune-related AD markers. Biological pathways were explored through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The accuracy of these markers was assessed by subject operator signature (ROC) curves and validated in the GSE122063 dataset. The datasets was then subjected to immunoinfiltration analysis. Multiple compound databases were used to analyze core Chinese medicines and components. Molecular docking and kinetic simulation verification were used for further verification.

A total of 1360 differential genes and 5 biomarkers (PGF, GFAP, GPI, SST, NFKBIA) were identified, showing excellent diagnostic efficiency. GSEA revealed markers associated with Oxidative phosphorylation, Nicotine addiction, and Hippo signaling pathway. Immune infiltration analysis showed dysregulation in multiple immune cell types in AD brains, with significant interactions between markers and 5 immune cell types. A total of 27 possible herbs and 7 core compounds were eventually identified. The binding environment of GPI-luteolin and GPI-stigasterol was relatively stable and showed good affinity.

PGF, GFAP, SST, GPI, and NFKBIA were identified for early AD diagnosis, associated with immune cells and pathways in AD brains. 7 promising natural compounds, including luteolin and stigmasterol, were screened for targeting these biomarkers.

Fibroblast Growth Factor 21 (FGF21), a pivotal member of the fibroblast growth factor family, exhibits multifaceted biological functions, including the modulation of pro-inflammatory cytokines and metabolic regulation. Recent research has revealed that in impaired skin tissues, FGF21 and its receptors are upregulated and play a significant role in accelerating the wound healing process. However, the clinical application of FGF21 is severely limited by its short in vivo half-life: this factor is often degraded by enzymes before it can exert its therapeutic effects. To address this limitation, the transdermal drug delivery system (TDDS) has emerged as an innovative approach that enables sustained drug release, significantly prolonging the therapeutic duration. Leveraging genetic recombination technology, research teams have ingeniously fused FGF21 with cell-penetrating peptides (CPPs) to construct recombinant FGF21 complexes. These novel conjugates can efficiently penetrate the epidermal barrier and achieve sustained and stable pharmacological activity through TDDS. This review systematically analyzes the potential signaling pathways by which FGF21 accelerates skin wound repair, summarizes the latest advancements in TDDS technology, explores the therapeutic potential of FGF21, and evaluates the efficacy of CPP fusion tags. The manuscript not only proposes an innovative paradigm for the application of FGF21 in skin injury treatment but also provides new insights into its use in transdermal delivery, marking a significant step toward overcoming existing clinical therapeutic challenges. From a clinical medical perspective, this innovative delivery system holds promise for addressing the bioavailability issues of traditional FGF21 therapies, offering new strategies for the clinical treatment of metabolism-related diseases and wound healing. With further research, this technology holds vast potential for clinical applications in hard-to-heal wounds such as diabetic foot ulcers and burns.

Recent studies have demonstrated an association between major depressive disorder (MDD) and both mitochondrial dysfunction and alterations in pro-inflammatory cytokine expression, suggesting that such changes may be key drivers of MDD pathogenesis. Mechanistically, changes in mitochondrial function are related to endoplasmic reticulum stress, reactive oxygen species production, oxidative phosphorylation, apoptosis, and disrupted calcium ion homeostasis, all of which trigger the activation of signaling cascades that affect the expression of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferons. Certain factors present in the gut microbiota ecosystem can influence communication between microorganisms and the brain through the neuroendocrine, immune, and autonomic nervous systems, thereby altering mitochondrial function and cytokine production. This review article explores the means through which mitochondria regulate immune cytokine expression and the role of mitochondrial dysfunction in the pathogenesis and treatment of MDD to provide new perspectives for the diagnosis of this disease and the development of novel therapeutic interventions with greater efficacy and improved safety profiles.

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is one of the severe complications that can occur after acute carbon monoxide poisoning (ACOP). The pathogenesis of DEACMP is complex, featuring a delitescence onset and poor prognosis. As a result, many scholars are concentrating on identifying predictors of DEACMP and evaluating their effects, including clinical characteristics, laboratory indicators, neuroelectrophysiology, imaging examination, and genetic susceptibility. However, current identified predictors lack consensus and their clinical application is limited. Therefore, we need to explore new predictors. Exosomes, the smallest extracellular vesicles (EVs) with nano-size, participate in both the physiological and pathological processes of the brain, and the changes in their content can provide valuable information for clinical diagnosis and evaluation of neurodegenerative diseases, suggesting that they may serve as a potential biomarker. However, the practicability of exosomes as biomarkers of DEACMP remains unclear. In the present review, we first introduced the pathogenesis of DEACMP and the currently identified predictors. Then, we also discussed the possibility of exosomes as the biomarkers of DEACMP, aiming to stimulate more attention and discussion on this topic, thereby providing meaningful insights for future research.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.