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This review aims to elucidate the molecular mechanisms underlying the neuroprotective effects of acupuncture in preclinical models of Parkinson's disease (PD). In PD animal models, acupuncture inhibits oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) and lipid peroxidation. It regulates autophagy either independently of mammalian target of rapamycin (mTOR) or via mTOR activation, promoting alpha-synuclein (α-synuclein) clearance. Acupuncture also suppresses apoptosis (modulating Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2)) and pyroptosis (inhibiting NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD)). It enhances neurogenesis through brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and glial cell line-derived neurotrophic factor (GDNF) signaling, promoting neural stem cell proliferation and differentiation. Furthermore, acupuncture reduces neuroinflammation by decreasing microglial activation, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It also modulates gut microbiota composition (e.g., increasing butyrate-producing bacteria like Butyricimonas and reducing pro-inflammatory Erysipelotrichaceae and Bacteroides) and influences lipid metabolism, thereby mitigating dopaminergic neuron loss and motor deficits. Preclinical evidence demonstrates that acupuncture exerts multi-target neuroprotective effects against PD through pathways involving oxidative stress, autophagy, apoptosis/pyroptosis, neurogenesis, neuroinflammation, and gut microbiota-lipid metabolism crosstalk. However, limitations include a focus on preventive rather than reversal effects, lack of long-term efficacy data, and heterogeneity in acupoint selection. Further mechanistic and standardization studies are warranted. Show less

Signal peptides (SPs) are short N-terminal sequences that direct proteins to the endoplasmic reticulum (ER). After cleavage of the SP, these proteins are mostly trafficked to the Golgi apparatus for secretion. Lipocalin-2 (LCN2), a neurotoxic secretory protein, was recently identified as a target of autophagy. The presence of an SP is a prerequisite for secretion and autophagic degradation. Based on these observations, we investigated whether the SP of LCN2 is sufficient to enable proteins to be secreted or degraded via autophagy. We fused the SP of LCN2 to a non-secretory green fluorescent protein (GFP) and found that this ER-generated GFP was either secreted or degraded via autophagy. These results indicate that the LCN2-derived SP alone is sufficient to direct proteins to the ER and subsequent secretion or autophagic degradation. This dual regulation was abolished when the SP was deleted from LCN2. Notably, the effect was preserved even when the LCN2 SP was replaced with the SP from brain-derived neurotrophic factor, another secretory protein. These results suggest that SPs with different sequences can similarly direct proteins to the ER and subsequent secretion or autophagic degradation. Furthermore, we found that even when LCN2 reached the Golgi apparatus for secretion, it could also be degraded via autophagy. Thus, we propose that SP-directed and ER-generated secretory proteins can undergo autophagic degradation during ER-Golgi transport, including at the ER, the ER-Golgi intermediate compartment, or the Golgi apparatus. Taken together, degradation of secretory proteins via autophagy suggests implications for the potential control of secretory protein homeostasis. Show less

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics. Show less

The purpose of our study was to investigate the neuroprotective effects of Nigella sativa (NSt) ethanolic extract (200 mg/kg) and/or Telmisartan(Tel) (10 mg/kg) against fipronil (Fip) (9.7 mg/kg)-induced neurobehavioral toxicity in rats, besides exploring the underlying mechanistic signaling pathways. Our results showed that the phytochemical analysis of NSt ethanolic extract by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS) revealed 43 compounds, mainly alkaloids, phenolics, terpenoids, fatty acids and flavonoids. While in our in vivo model of neurotoxicity, the combination of NSt and Tel effectively restored neurobehavioral alterations in rotarod, open field and T-maze tests. Additionally, the cotreatments of NSt and Tel significantly decreased acetylcholine, tumor necrosis factors-α, interleukin (IL)-6, IL-1β, MDA, BAX, P62, LC3B and IBA-1. Conversely, they significantly upregulated GABA, brain-derived neurotrophic factor, superoxide dismutase, catalase, glutathione peroxidase and antiapoptotic BCl2, P70S6K and miRNA137-5P without significant change in mTOR expression in hippocampus. Also, they ameliorated pathological alterations as detected by H&E staining, reduced glial fibrillary acidic protein and caspase-3 immunoreactivity. Electron microscopic examination of the combination group revealed the restoration of nuclear and mitochondrial structures with less glial activation and multivesicular bodies. In conclusion, the combination of NSt and Tel are notable agents in mitigating hippocampal neuronal necrosis and astrogliosis and reduced Fip-induced neurotoxicity. Show less