搜索结果：Molecular biology reports

Plants rely on complex signaling networks to interact with beneficial plant growth-promoting rhizobacteria (PGPR). Among these microbes, Caulobacter RHG1 is recognized by Arabidopsis thaliana roots via specific receptor-like kinases (RLKs), but the molecular mechanisms underlying the plant growth-promotion effect remain largely unknown. To investigate these mechanisms, we used an integrative approach combining proteomics and phosphoproteomics. Our phosphoproteome analysis revealed that RHG1 triggers a range of signaling events, involving two RLKs (LysM RLK1-INTERACTING KINASE 1 [LIK1] and an uncharacterized RLK, AT5G49770). Notably, via the proteome analysis, we revealed that upon RHG1 treatment, defense proteins are downregulated early. Later on, developmental processes, such as ribosome biogenesis and maturation, might lead to enhanced cell division and/or activity to promote growth. Our findings suggest that RHG1 triggered phosphorylation-based signaling pathways, resulting in the timely modulation of defense and developmental processes, which eventually lead to plant growth promotion. Our data, combined with that of previous reports, suggest that RHG1 activates a broad network of regulatory mechanisms that extend beyond a single pathway. Understanding the mechanisms behind such beneficial plant-microbe interactions can pave the way for more effective commercialization of PGPR-based agricultural products.

Neurogenesis in adult mammalian brain persists in restricted areas, especially the subgranular zone (SGZ) of the hippocampus and the ventricular-subventricular zone (V-SVz), where neural stem cells (NSCs) occupy neurogenic niches. These NSC niches provide signals that regulate stem cell behavior. Among extrinsic modulators, Growth Differentiation Factor 11 (GDF11 or BMP11) which is a transforming growth factor-β (TGF-β) superfamily member, was shown to play key role in the NSC biology and brain aging. In this review, the most recent molecular mechanisms of GDF11 signaling in the regulation of NSC will be addressed. GDF11 plays mainly through activin type II receptors (ActRIIA/B) and ALK4/ALK5, activating classical Smad2/3 pathways that impact transcriptional networks controlling neural cell behavior. Moreover, GDF11 stimulates non-Smad signaling pathways - including ERK, p38, JNK, and PI3K/AKT - providing context-dependent integration of proliferative and anti-proliferative signals. Furthermore, GDF11 functions as a feedback regulator limiting the number of progenitor cells and organizing neurogenic timing. In the adult brain, GDF11 plays important role in neurovascular remodeling, glial inflammatory states, and extracellular matrix interactions. Despite its recognized roles, the effect of GDF11 on aging remains a subject of intense debate, characterized by conflicting reports regarding its circulating levels, tissue-specific dynamics, and dose-dependent effects. Recent evidence suggests that GDF11 acts as a context-dependent modulator, integrating systemic, vascular, and cellular cues to maintain NSC homeostasis and neurogenic potential. Therefore, elucidating the exact cellular and molecular mechanisms by which GDF11 controls NSC behavior is vital to advancing novel therapeutic strategies for neurodegenerative disorders and age-related cognitive decline.

Lenalidomide (Len) is the standard of care for red blood cell transfusion-dependent (TD) patients with myelodysplastic syndromes (MDS) and del(5q). A Phase III clinical trial (SintraRev) demonstrated better efficacy of early treatment with Len in anemic del(5q) MDS patients prior to TD, but clonal evolution with this approach remained unexplored. We evaluated changes in mutational profiles of non-TD del(5q) MDS patients treated with Len to assess whether early administration of Len could reduce or worsen the mutational burden in those patients. The molecular profile of patients included in the SintraRev trial was analyzed by targeted sequencing. Median follow up of patients was 60.6 months (interquartile range [IQR] 32.3-73.9). Next-generation sequencing (NGS) was available in a total of 51 patients. SF3B1 (25.5%) and TP53 (21.3%) were the most frequently mutated genes. Clonal evolution during treatment among patients receiving Len or placebo (Pcb) was markedly different, with a 41.2% reduction in predominating clones in the Len arm, while remaining stable/increase in 100% of Pcb patients after 2 years. Mutations in SF3B1 and TP53 decreased/remained stable in the Len cohort, while only DNMT3A mutations increased under cytogenetic response. Regarding disease progression, only 20% of Len patients carrying TP53 mutations developed acute myeloid leukemia (AML), similar to the Pcb group (20%). Treatment with low-dose Len in transfusion-independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53-mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.

Nanoparticles (NPs) have attracted increasing attention because of their antimicrobial properties. This study aimed to evaluate the antibacterial and antibiofilm activities of nickel oxide (NiO) nanoparticles against representative uropathogenic Escherichia coli (UPEC) O-serotypes isolated from patients with urinary tract infections (UTIs) and characterized by ERIC-PCR typing. A total of 153 UPEC isolates were characterized by PCR-based O-serogrouping and ERIC-PCR typing. NiO nanoparticles were synthesized using the sol-gel method. The antibacterial and antibiofilm activities of NiO nanoparticles were evaluated against one representative biofilm-forming isolate from each ERIC type using the broth microdilution and microtiter plate methods, respectively. Among the 153 UPEC isolates, seven O-serogroups, O2, O4, O6, O8, O15, O16, and O25, were detected, with O25 being the most prevalent. ERIC-PCR analysis classified the isolates into 19 distinct clusters (E1-E19) at an 80% similarity threshold, comprising 13 common types (each containing ≥ 2 isolates) and 6 unique (singleton) types. No significant association was observed between O-serogroups and ERIC-PCR clusters (p > 0.05). NiO nanoparticles exhibited antibacterial and antibiofilm activity against 19 representative UPEC isolates, with MIC values ranging from 250 to 500 µg/mL and significant inhibition of biofilm formation at concentrations of 125-500 µg/mL (p = 0.001). Biofilm inhibition was also observed at sub-MIC concentrations. NiO nanoparticles demonstrated in vitro antibacterial and antibiofilm activity against 19 representative UPEC isolates. However, broader isolate screening and comprehensive toxicity and in vivo studies are required to further evaluate the antimicrobial activity and potential applicability of NiO nanoparticles.

Atypical endometrial hyperplasia and endometrial adenocarcinoma are successive stages of malignant transformation of the uterine epithelium. Usually genomic instability and tumor mutation burden progressively increase during carcinogenesis. In case of endometrial cancer, the presence of a mutation in the exonuclease domain of the POLE gene and/or a DNA mismatch repair deficiency (dMMR) leads to genomic instability at early stages of tumor development. This paper describes a clinical case of a 49-year-old female patient with synchronous presence of several stages of the endometrium malignant transformation: glandular polyp without signs of atypia, atypical hyperplasia and highly differentiated endometrioid adenocarcinoma. In all substrates, the POLE p.Pro286Arg mutation was detected. In the glandular polyp sample, it was detected with a minimal variant allele frequency (1%). At the same time, in the tissue of atypical hyperplasia and adenocarcinoma, this mutation led to an explosive accumulation of oncogenic genetic variants. This observation indicates role of mutation in the POLE gene as an early driver of carcinogenesis and emphasizes the importance of its determination in atypical endometrial proliferations. Атипическая гиперплазия эндометрия и эндометриальная аденокарцинома представляют собой последовательные этапы злокачественного перерождения эпителия тела матки. В процессе канцерогенеза геномная нестабильность и мутационная нагрузка прогредиентно нарастают, однако в случае рака эндометрия наличие мутации в экзонуклеазном домене гена POLE и/или дефицита системы репарации ошибочно спаренных нуклеотидов ДНК (dMMR) приводит к геномной нестабильности на ранних этапах развития опухоли. В данной работе описывается клиническое наблюдение пациентки 49 лет, в гистологическом материале которой были выявлены одновременно 3 стадии злокачественной трансформации эндометрия: железистый полип без признаков атипии, атипическая гиперплазия и высокодифференцированная эндометриоидная аденокарцинома. Во всех субстратах была выявлена мутация POLE p.Pro286Arg, которая в образце железистого полипа обнаруживалась с минимальным значением доли альтернативного аллеля (1%). При этом в ткани атипической гиперплазии и аденокарциномы такая мутация приводила к взрывному накоплению онкогенных генетических вариантов. Данное наблюдение указывает на роль мутации в гене POLE как раннего драйвера канцерогенеза и подчеркивает важность ее определения в атипичных эндометриальных пролиферациях.

SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the blood-brain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G>C (G561R) variant of Slc6a8, which corresponds to a variant identified in SLC6A8 in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G>C point mutation into the mouse Slc6a8 gene using the CRISPR/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.Significance Statement Creatine transporter deficiency (CTD) causes cerebral creatine depletion and intellectual disability; however, the developmental mechanisms linking creatine loss to brain dysfunction remain unclear. We performed developmental proteomic profiling of the hippocampus and cerebral cortex using a mouse model carrying a pathogenic Slc6a8 variant identified in patients with CTD. Creatine transporter dysfunction induces distinct region- and stage-dependent molecular responses during postnatal brain maturation. The hippocampus shows early alterations in cytoskeleton-dependent membrane trafficking pathways, consistent with impaired synaptic and circuit maturation, whereas the cerebral cortex exhibits progressive metabolic and mitochondrial adaptations. These findings suggest that impaired creatine-dependent energy buffering disrupts distinct developmental programs across brain regions, potentially contributing to cognitive dysfunction by hindering early hippocampal circuit maturation.

This study reports the complete mitochondrial genome (15,610 bp) of Stauroderus scalaris, a grasshopper species from Xinjiang, China, which comprises 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region. Phylogenetic analysis confirms its close evolutionary relationship with the genera Gomphocerus and Gomphocerippus, supporting its placement within the tribe Gomphocerini. These findings enrich the available mitochondrial genome resources for grasshoppers and provide valuable molecular data for subsequent research on the phylogeny and evolutionary history of the subfamily Gomphocerinae.

Gliomas are molecularly heterogeneous central nervous system tumors with variable treatment responsiveness and survival outcomes. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an important biomarker because it is associated with reduced DNA repair capacity and increased sensitivity to alkylating agents, particularly temozolomide (TMZ). However, its clinical meaning is not uniform across glioma subtypes and should not be interpreted as a universal prognostic marker. In IDH-wildtype glioblastoma, MGMT promoter methylation has the strongest evidence as a predictive biomarker for benefit from TMZ-containing therapy, although survival advantages in treated cohorts should be interpreted mainly as treatment-associated effects unless treatment-independent prognostic value is demonstrated. In IDH-mutant astrocytoma, MGMT methylation may partly reflect IDH-associated global hypermethylation and appears to have limited independent clinical value. In IDH-mutant, 1p/19q-codeleted oligodendroglioma, MGMT methylation may provide supportive, treatment-context-dependent information, particularly in patients receiving alkylating chemotherapy. In pediatric-type and rare molecularly defined gliomas, including histone-altered tumors, MGMT status remains exploratory and should be interpreted alongside methylation class, lineage-defining alterations, tumor location, and treatment history. Technical factors, including assay platform, CpG-site selection, cutoff definition, tissue quality, tumor-cell content, and intratumoral heterogeneity, further complicate interpretation. Because MGMT methylation is biologically continuous, this review further argues that borderline results should be reported as gray-zone or intermediate categories when validated, and that quantitative methylation values should be integrated into subtype-aware multivariable models rather than being reduced exclusively to binary calls. This review summarizes the biological and clinical relevance of MGMT promoter methylation across glioma subtypes and proposes a subtype-aware, treatment-conditional, and assay-aware framework for interpreting its predictive and survival-related significance.

Yam is a medicinal plant and previous studies have demonstrated that the yam glycoprotein (GLP1) possessed immunomodulatory bioactivity. However, how GLP1 exerted immunomodulatory effect and the molecular mechanism is unclear. To investigate the underlying mechanisms, the immunoregulation of GLP1 on macrophages are examined. The composition of GLP1 was investigated using high-performance liquid chromatography (HPLC) and UV visible spectrophotometer (UV-Vis). The activity of macrophages was detected, and the effects of GLP1 on macrophages were studied using immunofluorescence, flow cytometry, Enzyme-linked immunosorbent assay (ELISA), and Western blotting. Results indicated that GLP1, as a biomolecule, contained abundant monosaccharides and possessed O-glycopeptide bonds. GLP1 bound to pattern recognition receptors (PRRs) and was internalized by macrophages via toll-like receptor 4 (TLR4), thereby exerting its immunomodulatory effects. Further experimental studies revealed that GLP1 promoted RAW264.7 cells proliferation by advancing cells from G0/G1 phase to S phase. Additionally, GLP1 stimulated the secretion of reactive oxygen species (ROS) from mitochondria and induced macrophage polarization toward the M1 phenotype. GLP1 is a functional protein and has the capacity to regulate macrophages immune responses via the TLR4/NF-κB pathway. The findings highlighted the potential of GLP1 might as a dietary immunostimulant at the molecular level.

The emergence of highly virulent and multidrug-resistant Salmonella strains continues to pose a major global public health concern. Building on our previous investigation of 80 Salmonella isolates obtained from avian and human sources in northeastern Algeria (Annaba and Constantine) over a three-year period (2017-2019), in which their resistance profiles to 15 antimicrobial agents were assessed, the present study further explores the molecular features of virulence by targeting two additional plasmid-encoded genes, spvB and spvR. All isolates were subjected to polymerase chain reaction (PCR) amplification using gene-specific primers. The results revealed that spvB was detected in 86.25% of isolates, while spvR was identified in 73.75%, suggesting a strong association with strains capable of causing severe systemic infections. When compared with previous reports, notable geographical variations were observed, which may reflect differences in host reservoirs, ecological conditions, and selective pressures arising from antimicrobial use. The coexistence of spv virulence genes and multidrug-resistant (MDR) phenotypes in our isolates underscores the substantial risk of dissemination of highly pathogenic and resistant Salmonella strains between animals and humans. These findings highlight the need to integrate virulence gene surveillance into existing antimicrobial resistance monitoring programs to better understand and manage the zoonotic transmission dynamics of Salmonella in Algeria.

Brain metastases occur in 30-55% of patients with HER2-positive metastatic breast cancer, presenting significant therapeutic challenges. Circulating tumor DNA (ctDNA) monitoring has emerged as a potentially useful tool for earlier molecular detection of disease activity. We report a 35-year-old woman with HER2-positive metastatic breast cancer diagnosed during pregnancy who achieved pathological complete response after standard therapy. Given her young age, de novo stage IV disease, and atypical pregnancy-associated presentation, baseline comprehensive genomic profiling was performed at diagnosis. Serial ctDNA monitoring detected positivity approximately three months prior to radiologic evidence of brain metastases. Genomic profiling revealed newly emergent alterations potentially contributory to evolving disease biology, including MET amplification and HER2 V777L mutation. Treatment with trastuzumab deruxtecan plus pyrotinib, informed by ctDNA dynamics and the molecular profile, was associated with intracranial disease control over 17 months of follow-up. Drug-induced hepatotoxicity was managed through dose modifications and supportive care without treatment interruption. This case illustrates the feasibility of incorporating ctDNA monitoring into treatment decisions and provides a hypothesis-generating observation regarding combination therapy in managing HER2-positive brain metastases. The temporal relationship between molecular and radiologic findings observed here suggests potential value for earlier detection of disease activity, although whether such lead time translates into improved clinical outcomes requires prospective validation. The findings support prospective evaluation of this approach, including the ongoing TROPHY trial investigating this therapeutic approach.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, which disrupt thymidine metabolism. This study aimed to characterize a novel homozygous TYMP variant and provide insights into its potential structural and functional consequences through bioinformatic analyses. We identified a homozygous TYMP variant (c.131G>C, p.R44P) in a proband with MNGIE using whole-exome sequencing and Sanger sequencing. Computational structural analyses and molecular modeling were performed to predict the impact of the R44P substitution on thymidine phosphorylase (TP) stability, homodimerization, catalytic activity, and substrate binding. The homozygous TYMP c.131G>C variant was confirmed in the proband. Computational analyses suggested that the p.R44P substitution may destabilize TP and potentially impair homodimerization. Molecular modeling further predicted altered thymidine binding and disrupted active-site geometry. These predicted perturbations are hypothesized to contribute to defective nucleotide metabolism, thymidine accumulation, and deoxynucleotide triphosphate pool imbalance, which may ultimately result in mitochondrial genomic instability manifesting as mitochondrial DNA deletions and depletion. Our findings report the TYMP c.131G>C variant in a homozygous configuration, extending beyond a recently described compound heterozygous case. The bioinformatic predictions support the classification of this variant as likely pathogenic in MNGIE, though functional studies are warranted to validate these findings.

This study aims to mine and analyze adverse event (AE) signals for trastuzumab deruxtecan (T-DXd) using the FAERS database, particularly focusing on AEs that are not fully described in clinical trials and early market surveillance. The study selected data from the first quarter of 2020 to the third quarter of 2023, searching with T-DXd as the primary suspected drug. Four advanced signal mining and analysis methods were employed: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), to comprehensively assess the AE signals in the FAERS database. The study collected 6,703,410 AE reports, of which 4,055 reports involved T-DXd. Through comprehensive analysis, 118 PT signals involving 26 SOCs were identified. The study revealed various newly discovered AEs associated with T-DXd treatment, including immune dysregulation events like Gastroenteritis listeria and Coronavirus pneumonia, hepatobiliary disorders like Pseudocirrhosis and Hepatic failure, and hematological issues like Neutropenia and Thrombocytopenia. Additionally, new safety signals for cardiovascular and ocular problems were found. This study confirmed known AEs and identified a range of new AEs, aiding clinicians in making more informed decisions when using T-DXd.

Molecular tumor boards are supported by clinical decision support system (CDSS) tools for the interpretation of complex molecular data towards personalized treatments. Current CDSS tools are genomics-focused and characterized by tight couplings between data ingestion, guideline-based reasoning logic and curated knowledgebases. Next-generation CDSS solutions should integrate multimodal data and learn from outcomes in an interoperable ecosystem, leveraging explainable, trustworthy output from AI models through rigorous clinical validation processes.

Fruit cuticle thickness and biochemical composition have traditionally been regarded as the primary determinants of postharvest water loss in fleshy fruits. However, several reports indicate that some tomato mutants with thinner fruit cuticles or less cutin and waxes do not always show increased transpiration, suggesting that additional surface features influence postharvest water loss. Here, we show that fruit trichome density is a previously underappreciated determinant of postharvest water loss in tomatoes. Using two independent mutants, cr-slhdziv7 and cr-slhdziv9, which exhibit reduced fruit trichome density, we found that both mutants displayed reduced water loss rates and extended shelf life during postharvest storage despite having thinner cuticles and reduced levels of key cutin monomers. Further molecular analyses, including RNA-seq, yeast one-hybrid (Y1H), and dual-luciferase reporter assays, revealed that these two HD-ZIP IV proteins not only regulate fruit trichome formation but also directly or indirectly modulate the expression of multiple cutin biosynthesis genes. Collectively, our results demonstrate that the benefit of reducing trichome-associated microchannels can outweigh the negative effects of cuticle thinning on postharvest water loss. This study establishes fruit trichome density as an important and previously underestimated target for improving postharvest fruit quality and shelf life.

To enhance its pathogenic potential, Neisseria gonorrhoeae (Gc) pirates zinc from human metal sequestration proteins using TonB-dependent outer membrane transport systems. However, cytoplasmic mechanisms by which Gc adapts to zinc limitation are still uncharacterized. rpmE2 and rpmJ2 transcripts, encoding alternative L31 and L36 ribosomal proteins, respectively, which are not predicted to bind zinc, are significantly more abundant in zinc-limited Gc. In other bacterial species, alternative ribosomal proteins replace canonical zinc-binding ribosomal proteins when zinc availability is low, enabling growth under metal limitation. We found that Gc rpmE2 and rpmJ2 are in an operon and transcriptionally induced under zinc limitation by derepression via the zinc uptake regulator Zur, while genes encoding canonical proteins rpmE and rpmJ are not zinc-regulated. In contrast to other bacteria, ribosomes in zinc-limited Gc contained both RpmE2 and RpmE. Furthermore, Gc deleted for RpmE2 and RpmJ2 grew better than the wild-type parent under zinc limitation. Gc engineered to produce only RpmE2 exhibited a growth defect relative to RpmE-only Gc, regardless of zinc availability. Moreover, ribosomes from RpmE2-only Gc had reduced translation in vitro. Thus, unlike other bacteria, the alternative L31 protein RpmE2 is not functionally equivalent to the canonical RpmE in Gc. Instead, the ribosomes of zinc-limited Gc are heterogeneous, containing either alternative or canonical ribosomal proteins. We propose that L31 ribosomal protein alternation allows Gc to withstand zinc limitation by reducing translation and slowing growth, to prolong its survival when encountering host-imposed nutritional immunity. Zinc acquisition is crucial for growth and infectivity of Neisseria gonorrhoeae (Gc). However, research on Gc adaptation to zinc limitation has primarily focused on outer and inner membrane zinc transporters. Here, we implicate ribosomal protein alternation in the Gc response to zinc limitation. Ribosomes containing the non-zinc-binding, alternative ribosomal protein RpmE2 are less translationally active, and RpmE2-producing bacteria grow more slowly. This contrasts with reports from other bacteria, where ribosomal protein alternation facilitates growth in zinc-limited conditions. This work uncovers a new way in which ribosomal protein alternation enables bacterial resistance to nutritional immunity.

The human chemokine receptor 8 (CCR8) plays a role in various autoimmune disorders, such as multiple sclerosis and inflammatory bowel disease, spurring the interest in CC8 agonism as a potential therapeutic strategy. Triazolyl substituted phenoxybenzylpiperidine analogues have been previously synthesized and were shown to act as CCR8 agonists although with moderate potency. In this study, their structure-activity relationship was expanded by the synthesis of a series of 1,4-disubstituted 1,2,3-triazole analogues with structural modifications of the phenoxybenzylpiperidinyl and phenyl moieties. Evaluation in cell-based assays revealed potent and selective CCR8 agonistic activity of several derivatives. Molecular docking was applied to shed a light on their binding mode. Despite its suboptimal pharmacokinetic behaviour, a representative CCR8 agonist from this series, showed activity in a humanized model mimicking xenogeneic graft-versus-host disease.

Cardiovascular and neurodegenerative disorders remain major contributors to global morbidity and mortality, underpinned by overlapping pathogenic processes including chronic inflammation, oxidative stress, endothelial dysfunction, and mitochondrial impairment. Therapeutic strategies capable of simultaneously modulating these interconnected pathways are increasingly recognized as essential for improving clinical outcomes. Curcumin (CUR), a pleiotropic polyphenolic compound derived from Curcuma longa, and statins, widely prescribed lipid-lowering agents, exhibit a broad spectrum of anti-inflammatory, antioxidant, and cytoprotective effects that extend beyond their canonical pharmacological actions. This review critically examines the molecular and pharmacological synergy between CUR and statins, with particular emphasis on their coordinated regulation of key signaling cascades, including NF-κB, iNOS, MAPK, and Nrf2-mediated antioxidant responses. Evidence from in vitro, in vivo, and emerging clinical studies indicates that CUR-statin co-administration may elicit additive or synergistic protective effects across diverse pathological contexts, such as atherosclerosis, myocardial ischemia-reperfusion injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, Myopathy, wound healing, and anti-cancer effects. Unfortunately, the majority of available experiments are preclinical and fewer clinical studies have been performed until now. At the cellular and tissue levels, this combinatorial approach appears to restore vascular homeostasis, preserve mitochondrial function, enhance neuronal survival, and suppress sustained inflammatory signaling. Collectively, the available data underscore a compelling pharmacological rationale for CUR-statin combination therapy as a multitarget intervention for complex cardiometabolic, neurodegenerative diseases, and a wide variety of disorders. Future investigations should focus on optimizing dosing regimens, improving CUR bioavailability, elucidating pharmacokinetic-pharmacodynamic interactions, and validating therapeutic efficacy through well-designed clinical trials.

Spinal cord injury (SCI) is characterized by irreversible loss of motor and sensory function, imposing a substantial burden on patients and their families. Tetramethylpyrazine (TMP), a bioactive compound derived from traditional Chinese medicine, possesses a wide range of pharmacological activities and has demonstrated potential therapeutic effects in the treatment of SCI. Therefore, this article provides a comprehensive review of the mechanisms by which TMP promotes spinal cord repair. This review compiles a large body of in vitro, in vivo, and clinical studies, including a total of 86 publications documenting the effects of TMP on SCI. The results indicate that the mechanisms by which TMP exerts its effects in SCI treatment include promoting nerve regeneration, improving vascular dysfunction, exerting anti-inflammatory effects, inhibiting neuronal apoptosis, reducing oxidative stress, regulating iron metabolism, maintaining ion homeostasis, alleviating pyroptosis, and modulating autophagy. Through these mechanisms, TMP contributes to the restoration of spinal cord morphology, motor function, and electrophysiological parameters in experimental animal models. Clinical reports on the use of TMP injection for SCI are relatively limited, and its clinical efficacy requires further investigation. The combined application of nanotechnology or hydrogels provides an efficient targeted delivery and sustained-release system for TMP in the spinal cord, thereby significantly enhancing its bioavailability. Overall, TMP shows promising potential in SCI treatment and may serve as a valuable adjunctive therapeutic strategy.