A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

Glucagon-like peptide-1 and impaired counterregulatory responses to hypoglycemia in type 1 diabetes

This letter comments on a study by Jin et al,published recently in the World Journal of Diabetes.Hypoglycemia is a significant complication of diabetes,with primary defense mechanisms involving the stimulation of glucagon secretion inα-cells and the inhibition of insulin secretion in pancreaticβ-cells,which are often compromised in type 1 diabetes mellitus(T1DM)and advanced type 2 diabetes mellitus.Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness,a condition underpinned by complex pathophysiological processes,encompassing central nervous system adaptations and several hormonal interactions,including a potential role for glucagon-like peptide-1(GLP-1)in paracrine and endocrine vias.Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreaticδ-cells,which inhibits glucagon secretion from neighboringα-cells.However,current trials evaluating GLP-1 receptor agonists(GLP-1 RAs)in T1DM patients have shown promising benefits in reducing insulin requirements and body weight,without increasing the risk of hypoglycemia.Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex,and their impact on hypoglycemia unawareness in T1DM patients.

Exploring the therapeutic potential of glucagon-like peptide 1agonists in metabolic disorders

This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use of glucagon-like peptide 1 receptor agonists,especially when used in combination therapy.However,despite their notable efficacy,these drugs were not initially designed to target MASLD directly.In a groundbreaking development,the Food and Drug Administration has recently approved resmetirom,the first treatment specifically aimed at reducing liver fibrosis in metabolic-associated steatohepatitis.Resmetirom,an orally administered,liver-directed thyroid hormone beta-selective agonist,acts directly on intrahepatic pathways,enhancing its therapeutic potential and marking the beginning of a new era in the treatment of MASLD.Furthermore,the integration of lifestyle modifications into liver disease management is an essential component that should be considered and reinforced.By incorporating dietary changes and regular physical exercise into treatment,patients may achieve improved outcomes,reducing the need for pharmacological interventions and/or improving treatment efficacy.As a complement to medical therapies,lifestyle factors should not be overlooked in the broader strategy for managing MASLD.

Anti-skin aging effects and bioavailability of collagen tripeptide and elastin peptide formulations in young and middle-aged women

Background:Collagen peptides(CP),including tripeptides and elastin peptides(EP),are known for their in vitro and in vivo anti-skin aging effects.Despite positive results in animal models,the combination effects of CP and EP and the bioavailability of CP in human studies,particularly in young and middle-aged women,remain underexplored.Objective:To evaluate the effects of an orally administered collagen drink combining CP and EP on the skin health of young and middle-aged women.Materials and Methods:A single-center,randomized,double-blind,parallel-controlled trial was conducted,utilizing the WONDERLABR fish collagen tripeptide beverage.Participants consumed the drink over an 8-week period.Results:Compared to the placebo group,the collagen drink group showed significant improvements in skin hydration(39.19%increase),transepidermal water loss(33.45%decrease),skin elasticity(25.37%increase),dermal collagen content(21.64%increase),pore size(7.94%decrease),wrinkle length(18.09%decrease),skin smoothness(2.85%improvement),and skin roughness(15.32%decrease).Overall pore volume decreased by 60%,and visual assessments indicated a decrease in skin luminosity by 15.20%and smoothness index by 22.55%.Mass spectrometry demonstrated a significant increase in collagen efficacy components,including blood pH and GPH levels(P<0.05).Conclusion:The study confirmed the combination nourishing and anti-skin aging effects of EP and CP on the skin of young and middle-aged women,demonstrating significant improvements in various skin parameters and good bioavailability of collagen peptides.

Calcium-chelating peptides from rabbit bone collagen:characterization,identification and mechanism elucidation

This study aimed to characterize and identify calcium-chelating peptides from rabbit bone collagen and explore the underlying chelating mechanism.Collagen peptides and calcium were extracted from rabbit bone by instant ejection steam explosion(ICSE)combined with enzymatic hydrolysis,followed by chelation reaction to prepare rabbit bone peptide-calcium chelate(RBCP-Ca).The chelating sites were further analyzed by liquid chromatography-tandem mass(LC-MS/MS)spectrometry while the chelating mechanism and binding modes were investigated.The structural characterization revealed that RBCP successfully chelated with calcium ions.Furthermore,LC-MS/MS analysis indicated that the binding sites included both acidic amino acids(Asp and Glu)and basic amino acids(Lys and Arg),Interestingly,three binding modes,namely Inter-Linking,Loop-Linking and Mono-Linking were for the first time found,while Inter-Linking mode accounted for the highest proportion(75.1%),suggesting that chelation of calcium ions frequently occurred between two peptides.Overall,this study provides a theoretical basis for the elucidation of chelation mechanism of calcium-chelating peptides.

Dock-able linear and homodetic di, tri, tetra and pentapeptide library from canonical amino acids: SARS-CoV-2 Mpro as a case study

Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low toxicity.Although noncanonical residues can always be used,employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico screening.Towards this goal,the dataset comprising all possible di-,tri-,and tetra-peptide combinations of the canonical residues has been previously reported.However,with increasing computational power,the comprehensive set of pentapeptides is now also feasible for screening as the comprehensive set of cyclic peptides comprising four or five residues.Here,we provide both the complete and prefiltered libraries of all di-,tri-,tetra-,and penta-peptide sequences from 20 canonical amino acids and their homodetic(N-to-C-terminal)cyclic homologues.The FASTA,simplified molecular-input line-entry system(SMILES),and structure-data file(SDF)-three dimension(3D)libraries can be readily used for screening against protein targets.We also provide a simple method and tool for conducting identity-based filtering.Access to this dataset will accelerate small peptide screening workflows and encourage their use in drug discovery campaigns.As a case study,the developed library was screened against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main protease to identify potential small peptide inhibitors.

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy

Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

Molecular and cellular mechanisms of neuroprotection by oligopeptides from snake venoms

Venom snake-derived peptides have multiple biochemical,pharmacological,and toxicological profiles,allowing for the discovery of new medicinal products and therapeutic applications.This review specifically examines the fundamental elements of neuroprotection offered by different oligopeptides derived from snake venom.It also includes a brief evaluation of short peptides that are being considered as potential therapeutic agents.Proline-rich peptides and tryptophyllin family peptides isolated from the crude venom of Viperidae family snakes,specifically Bothrops atrox,Bothrops jararaca,and Bothrops moojeni,have been shown to have pro-survival properties,the ability to reduce oxidative stress,and the ability to promote cell viability and mitochondrial functions.Three significant mechanisms are related to the neuroprotection mediated by snake venom oligopeptides:(1)Activation of the L-arginine metabolite pathway,such as polyamines from ornithine metabolism,which reduces N-methyl-D-aspartate(NMDA)-type glutamate receptor activity;(2)Enhancement of cell viability by activating the nerve growth factor-signaling pathway;and(3)Activation of the Muscarinic acetylcholine receptor subtype M1(mAChR-M1).These small peptides show promise as neuroprotective agents against a variety of neurodegenerative disorders.

Glucagon-like-peptide-1 receptor agonists and the management of type 2 diabetes-backwards and forwards

This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Novel umami peptides from two Termitomyces mushrooms and molecular docking to the taste receptor T1R1/T1R3

Wild edible Termitomyces mushrooms are popular in Southwest China and umami is important flavor qualities of edible mushrooms.This study aimed to understand the umami taste of Termitomyces intermedius and Termitomyces aff.bulborhizus.Ten umami peptides from aqueous extracts were separated using a Sephadex G-15 gel filtration chromatography.The intense umami fraction was evaluated by both sensory evaluation and electronic tongue.They were identified as KLNDAQAPK,DSTDEKFLR,VGKGAHLSGEH,MLKKKKLA,SLGFGGPPGY,TVATFSSSTKPDD,AMDDDEADLLLLAM,VEDEDEKPKEK,SPEEKKEEET and PEGADKPNK.Seven peptides,except VEDEDEKPKEK,SPEEKKEEET and PEGADKPNK were selectively synthesized to verify their taste characteristics.All these 10 peptides had umami or salt taste.The 10 peptides were conducted by molecular docking to study their interaction with identified peptides and the umami taste receptor T1R1/T1R3.All these 10 peptides perfectly docked the active residues in the T1R3 subunit.Our results provide theoretical basis for the umami taste and address the umami mechanism of two wild edible Termitomyces mushrooms.

Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease

In this editorial,we comment on Yin et al’s recently published Letter to the editor.In particular,we focus on the potential use of glucagon-like peptide 1 receptor agonists(GLP-1RAs)alone,but even more so in combination therapy,as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease(MASLD),the new definition of an old condition,non-alcoholic fatty liver disease,which aims to better define the spectrum of steatotic pathology.It is well known that GLP-1RAs,having shown outstanding performance in fat loss,weight loss,and improvement of insulin resistance,could play a role in protecting the liver from progressive damage.Several clinical trials have shown that,among GLP-1RAs,semaglutide is a safe,well-studied therapeutic choice for MASLD patients;however,most studies demonstrate that,while semaglutide can reduce steatosis,including steatohepatitis histological signs(in terms of inflammatory cell infiltration and hepatocyte ballooning),it does not improve fibrosis.Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease.In particular,GLP-1RAs associated with antifibrotic drug therapy,dual glucose-dependent insulinotropic polypeptide(GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis,liver biochemistry,and non-invasive fibrosis tests than monotherapy.Therefore,although to date there are no definitive indications from international drug agencies,there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD,one that will certainly include the use of GLP-1RAs as combination therapy.

Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.

Exploring the taste presentation and receptor perception mechanism of salty peptides from Stropharia rugosoannulata based on molecular dynamics and thermodynamics simulation

The taste presentation and receptor perception mechanism of the salty peptide of Stropharia rugosoannulata were predicted and verified using peptide omics and molecular interaction techniques.The combination of aspartic acid(D)and glutamic acid(E),or peptide fragments composed of arginine(R),constitute the characteristic taste structural basis of salty peptides of S.rugosoannulata.The taste intensity of the salty peptide positively correlates with its concentration within a specific concentration range(0.25–1.0 mg/mL).The receptor more easily recognizes the first amino acid residue at the N-terminal of salty peptides and the aspartic acid residue in the peptides.GLU513,ASP707,and VAL508 are the critical amino acid residues for the receptor to recognize salty peptides.TRPV1 is specifically the receptor for recognizing salty peptides.Hydrogen bonds and electrostatic interactions are the main driving forces for the interactions between salty peptides and TRPV1 receptors.KSWDDFFTR has the most potent binding capacity with the receptor and has tremendous potential for application in sodium salt substitution.This study confirmed the taste receptor that specifically recognizes salty peptides,analyzed the receptor-peptide binding interaction,and provided a new idea for understanding the taste receptor perception of salty peptides.

Three novel umami peptides derived from the alcohol extract of the Pacific oyster(Crassostrea gigas):identification,characterizations and interactions with T1R1/T1R3 taste receptors

Oyster(Crassostrea gigas),the main ingredient of oyster sauce,has a strong umami taste.In this study,three potential umami peptides,FLNQDEEAR(FR-9),FNKEE(FE-5),and EEFLK(EK-5),were identified and screened from the alcoholic extracts of the oyster using nano-HPLC-MS/MS analysis,i Umami-Scoring Card Method(i Umami-SCM)database and molecular docking(MD).Sensory evaluation and electronic tongue analysis were further used to confirm their tastes.The threshold of the three peptides ranged from 0.38 to 0.55 mg/m L.MD with umami receptors T1R1/T1R3 indicated that the electrostatic interaction and hydrogen bond interaction were the main forces involved.Besides,the Phe592 and Gln853 of T1R3 were the primary docking site for MD and played an important role in umami intensity.Peptides with two Glu residues at the terminus had stronger umami,especially at the C-terminus.These results contribute to the understanding of umami peptides in oysters and the interaction mechanism between umami peptides and umami receptors.

Andrias davidianus bone peptides alleviates hyperuricemia-induced kidney damage in vitro and in vivo

Hyperuricemia(HUA)is a vital risk factor for chronic kidney diseases(CKD)and development of functional foods capable of protecting CKD is of importance.This paper aimed to explore the amelioration effects and mechanism of Andrias davidianus bone peptides(ADBP)on HUA-induced kidney damage.In the present study,we generated the standard ADBP which contained high hydrophobic amino acid and low molecular peptide contents.In vitro results found that ADBP protected uric acid(UA)-induced HK-2 cells from damage by modulating urate transporters and antioxidant defense.In vivo results indicated that ADBP effectively ameliorated renal injury in HUA-induced CKD mice,evidenced by a remarkable decrease in serum UA,creatinine and blood urea nitrogen,improving kidney UA excretion,antioxidant defense and histological kidney deterioration.Metabolomic analysis highlighted 14 metabolites that could be selected as potential biomarkers and attributed to the amelioration effects of ADBP on CKD mice kidney dysfunction.Intriguingly,ADBP restored the gut microbiome homeostasis in CKD mice,especially with respect to the elevated helpful microbial abundance,and the decreased harmful bacterial abundance.This study demonstrated that ADBP displayed great nephroprotective effects,and has great promise as a food or functional food ingredient for the prevention and treatment of HUA-induced CKD.

Advancing energy storage with nitrogen containing biomaterials utilizing amino acid, peptide and protein: Current trends and future directions

As the climate crisis continues to escalate, there has been a growing emphasis on the development of electrode materials that are environmentally friendly and sustainable. Biomolecules, such as proteins,peptides, and amino acids, have emerged as promising alternatives to metal oxide and metal hydroxide-based energy storage systems. These biomolecules offer several advantages, such as high safety, non-toxicity, abundant raw material sources, and ease of device fabrication. In this review, we highlighted the recent advancements in amino acid, peptide, and protein-based materials for lithiumion batteries, supercapacitors, and fuel cells. We delve into the synthetic strategies employed and their impact on factors such as active potential window, solubility in the electrolyte, and electrochemical performance. Our focus is on the development, composition, and performance of biomolecules, as well as the various approaches taken for their application in batteries, supercapacitors, and fuel cells. Finally, we discuss key considerations that must be taken into account to promote the design, synthesis and development for future practical applications of lithium-ion batteries, supercapacitors, and fuel cells.

Food-derived bio-functional peptides for the management of hyperuricemia and associated mechanism

Hyperuricemia,a metabolic disorder related to uric acid metabolism dysregulation,has become a common metabolic disease worldwide,due to changes in lifestyle and dietary structure.In recent years,owing to their high activity and few adverse effects,food-derived active peptides used as functional foods against hyperuricemia have attracted increasing attention.This article aims to focus on the challenge associated with peptide-specific preparation methods development,functional components identification,action mechanism(s)clarification,and bioavailability improvement.The current review proposed recent advances in producing the food-derived peptides with high anti-hyperuricemia activity by protein source screening and matched enzymatic hydrolysis condition adjusting,increased the knowledge about strategies to search antihyperuricemia peptides with definite structure,and emphasized the necessity of combining computer-aided approaches and activity evaluations.In addition,novel action mechanism mediated by gut microbiota was discussed,providing different insights from classical mechanism.Moreover,considering that little attention was paid previously on the structure-activity relationships of anti-hyperuricemia peptides,we collected the sequences from published studies and make a preliminary summary about the structure-activity relationships,which in turn provided guides for enzymatic hydrolysis optimization and bioavailability improvement.Hopefully,this article could promote the development,application and commercialization of food-derived anti-hyperuricemia peptides in the future.

Toward Artificial Peptide Nanocapsules

HIGHLIGHTS The formation of peptide nanocapsules is facilitated by a gradient interface,where the differential solvent concentration drives the peptides to preferentially localize and assemble.The peptide nanocapsules,characterized by their hollow structures,demonstrated potential as carriers for targeted drug delivery.1 Introduction Peptide nanocapsules are a type of nanoscale delivery system that encapsulates active substances within a shell composed of peptides,leveraging the unique properties of peptides such as biocompatibility and biodegradability[1].Historically,the development of peptide nanocapsules was inspired primordially by the natural biological processes.

Cath-KP,a novel peptide derived from frog skin,prevents oxidative stress damage in a Parkinson’s disease model

Parkinson’s disease(PD)is a neurodegenerative condition that results in dyskinesia,with oxidative stress playing a pivotal role in its progression.Antioxidant peptides may thus present therapeutic potential for PD.In this study,a novel cathelicidin peptide(Cath-KP;GCSGRFCNLF NNRRPGRLTLIHRPGGDKRTSTGLIYV)was identified from the skin of the Asiatic painted frog(Kaloula pulchra).Structural analysis using circular dichroism and homology modeling revealed a uniqueαββconformation for Cath-KP.In vitro experiments,including free radical scavenging and ferric-reducing antioxidant analyses,confirmed its antioxidant properties.Using the 1-methyl-4-phenylpyridinium ion(MPP^(+))-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,Cath-KP was found to penetrate cells and reach deep brain tissues,resulting in improved MPP^(+)-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1(Sirt1)/Nuclear factor erythroid 2-related factor 2(Nrf2)pathway activation.Both focal adhesion kinase(FAK)and p38 were also identified as regulatory elements.In the MPTP-induced PD mice,Cath-KP administration increased the number of tyrosine hydroxylase(TH)-positive neurons,restored TH content,and ameliorated dyskinesia.To the best of our knowledge,this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress.These findings expand the known functions of cathelicidins,and hold promise for the development of therapeutic agents for PD.