Serum brain-derived neurotrophic factor levels in type 2 diabetes mellitus patients and its association with cognitive impairment: A meta-analysis.

OBJECTIVE: To compare the serum levels of brain-derived neurotrophic factor (BDNF) in type 2 diabetes mellitus (T2DM) patients with healthy controls (HC) and evaluate the BDNF levels in T2DM patients with/without cognitive impairment. METHODS: PubMed, EMBASE, and the Cochrane Library databases were searched for the published English literature on BDNF in T2DM patients from inception to December 2022. The BDNF data in the T2DM and HC groups were extracted, and the study quality was evaluated using the Agency for Healthcare Research and Quality. A meta-analysis of the pooled data was conducted using Review Manager 5.3 and Stata 12.0 software. RESULTS: A total of 18 English articles fulfilled with inclusion criteria. The standard mean difference of the serum BDNF level was significantly lower in T2DM than that in the HC group (SMD: -2.04, z = 11.19, P <0.001). Besides, T2DM cognitive impairment group had a slightly lower serum BDNF level compared to the non-cognitive impairment group (SMD: -2.59, z = 1.87, P = 0.06). CONCLUSION: BDNF might be involved in the neuropathophysiology of cerebral damage in T2DM, especially cognitive impairment in T2DM.

Development of a wound epithelialization healing model: reducing the impact of contraction healing on the wound surface.

Animal experiments are important in trauma-related studies because they simulate in vivo effects. Rodents are a good choice for preparing trauma models; however, contractile healing in rodents results in a healing pattern that differs considerably from that in humans. Therefore, this study developed a new rodent model that avoids contractile healing of the skin around the wound using an anti-contraction ring, and the skin in the wound's center remains intact and acts as a source for epithelialized diffusion healing. Cell proliferation, migration, revascularization, and collagen secretion did not differ between the novel and conventional full-skin defect trauma models. However, the healing rate at various stages significantly differed between the two groups owing to differences in the healing patterns. And without effective treatment, the experimental group cannot heal. The stabilities of the novel and conventional methods were good regardless of operator or batch. In summary, this new animal trauma model provides a stable experimental environment similar to that in humans, which may promote trauma-related research.

13C6-Glucose Labeling Associated with LC-MS: Identification of Plant Primary Organs in Secondary Metabolite Synthesis.

This paper presents a novel and efficient method for certifying primary organs involved in secondary metabolite synthesis. As the most important secondary metabolite in Parispolyphylla var. yunnanensis (Franch.) Hand. -Mzt. (PPY), Paris saponin (PS) has a variety of pharmacological activities and PPY is in increasing demand. This study established leaf, rhizome, and stem-vascular-bundle 13C6-Glucose feeding and non-feeding four treatments to precisely certify the primary organs involved in Paris saponins VII (PS VII) synthesis. By combining liquid chromatography-mass spectrometry (LC-MS), the 13C/12C ratios of leaf, rhizome, stem, and root in different treatments were quickly and accurately calculated, and four types of PS isotopic ion peak(M-) ratios were found: (M+1) -/M-, (M+2) -/M-, (M+3) -/M- and (M+4) -/M-. The results showed that the ratio of 13C/12C in the rhizomes of the stem-vascular-bundle and rhizome feeding treatments was significantly higher than that in the non-feeding treatment. Compared to the non-feeding treatment, the ratio of PS VII molecules (M+2) -/M- in the leaves increased significantly under leaf and stem-vascular-bundle feeding treatments. Simultaneously, compared to the non-feeding treatment, the ratio of PS VII molecules (M+2) -/M- in the leaves under rhizome treatment showed no significant difference. Furthermore, the ratio of PS VII molecules (M+2) -/M- in the stem, root, and rhizome showed no differences among the four treatments. Compared to the non-feeding treatment, the ratio of the Paris saponin II (PS II) molecule (M+2) -/M- in leaves under leaf feeding treatment showed no significant difference, and the (M+3) -/M- ratio of PS II molecules in leaves under leaf feeding treatment were lower. The data confirmed that the primary organ for the synthesizing of PS VII is the leaves. It lays the foundation for future identification of the primary organs and pathways involved in the synthesis of secondary metabolites in medicinal plants.

Mesenchymal Stem Cells-Involved Strategies for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration and poor targeting, traditional anti-rheumatic drugs have unsatisfactory treatment efficacy and strong side effects, including myelosuppression, liver or kidney function damage, and malignant tumors. Consequently, mesenchymal stem cells (MSCs)-involved therapy is proposed for RA therapy as a benefit of their immunosuppressive and tissue-repairing effects. This review summarizes the progress of MSCs-involved RA therapy through suppressing inflammation and promoting tissue regeneration and predicts their potential clinical application.

Overview of ectopic pancreas.

This editorial discusses the article written by Zheng et al that was published in the latest edition of the World Journal of Gastrointestinal Surgery. Our primary focus is on the causes, location, diagnosis, histological classification, and therapy of ectopic pancreas. Ectopic pancreas refers to the presence of pancreatic tissue that is situated in a location outside its usual anatomical placement, and is not connected to the normal pancreas in terms of blood supply or anatomical structure. Currently, the embryological origin of ectopic pancreas remains uncertain. The most prevalent form of ectopic pancreatic is gastric ectopic pancreas. Endoscopic ultrasonography examination can visualize the morphological characteristics of the ectopic pancreatic lesion and pinpoint its anatomical location. The histological categorization of ectopic pancreas evolves. Endoscopic treatment has been widely advocated in ectopic pancreas.

Add-on sirolimus for the treatment of mild or moderate systemic lupus erythematosus via T lymphocyte subsets balance.

OBJECTIVE: The efficacy of sirolimus in treating severe or refractory systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, few studies focused on mild or moderate SLE. Therefore, in this study we elucidated clinical efficacy of add-on sirolimus in patients with mild or moderate SLE. METHODS: Data of 17 consecutive patients with SLE were retrospectively collected. SLE Disease Activity Index-2000 (SLEDAI-2K), clinical manifestation, laboratory data and peripheral T lymphocyte subsets with cytokines were collected before and 6 months after sirolimus add-on treatment. T cell subsets were detected by flow cytometry and cytokines were determined by multiplex bead-based flow fluorescent immunoassay simultaneously. Twenty healthy controls matched with age and sex were also included in our study. RESULTS: (1) The numbers of peripheral blood lymphocytes, T cells, T helper (Th) cells, regulatory T (Treg) cells, Th1 cells, Th2 cells and Treg/Th17 ratios in patients with SLE were significantly lower, while the numbers of Th17 cells were evidently higher than those of healthy control (p<0.05). (2) After 6 months of sirolimus add-on treatment, urinary protein, pancytopenia, immunological indicators and SLEDAI-2K in patients with SLE were distinctively improved compared with those before sirolimus treatment (p<0.05). (3) The numbers of peripheral blood lymphocytes, T cells, Th cells, Treg cells, Th2 cells and the ratios of Treg/Th17 in patients with SLE after treatment were clearly higher than those before (p<0.05). (4) The levels of plasma interleukin (IL)-5, IL-6 and IL-10 in patients with SLE decreased notably, conversely the IL-4 levels increased remarkably compared with pretreatment (p<0.05). CONCLUSIONS: (1) Patients with SLE presented imbalanced T cell subsets, especially the decreased ratio of Treg/Th17. (2) Sirolimus add-on treatment ameliorated clinical involvement, serological abnormalities and disease activity without adverse reactions in patients with SLE. (3) The multi-target therapy facilitates the enhanced numbers of Treg cells, Treg/Th17 imbalance and anti-inflammatory cytokines, simultaneously, reducing inflammatory cytokines.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Myofibroblastic cancer-associated fibroblast subtype heterogeneity in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a fibrotic stroma that has both tumor-promoting and tumor-restraining properties. Different types of cancer-associated fibroblasts (CAFs) have been described. Here, we investigated whether CAFs within the same subtype exhibit heterogeneous functions. METHODS: We evaluated the gene and protein expression differences in two myofibroblastic CAF (myCAF) lines using single-cell and bulk RNA-sequencing. We utilized proliferation and migration assays to determine the effect of different CAF lines on a tumor cell line. RESULTS: We found that myCAF lines express an activated stroma subtype gene signature, which is associated with a shorter survival in patients. Although both myCAF lines expressed α-smooth muscle actin (α-SMA), platelet-derived growth factor-α (PDGFR-α), fibroblast-activated protein (FAP), and vimentin, we observed heterogeneity between the two lines. Similarly, despite being consistent with myCAF gene expression overall, heterogeneity within specific genes was observed. We found that these differences extended to the functional level where the two myCAF lines had different effects on the same tumor cell line. The myCAF216 line, which had slightly increased inflammatory CAF-like gene expression and higher protein expression of α-SMA, PDGFR-α, and FAP was found to restrain migration of tumor cells. CONCLUSIONS: We found that two myCAF lines with globally similar expression characteristics had different effects on the same tumor cell line, one promoting and the other restraining migration. Our study highlights that there may be unappreciated heterogeneity within CAF subtypes. Further investigation and attention to specific genes or proteins that may drive this heterogeneity will be important.

Enabling Broadband Solar-Blind UV Photodetection by a Rare-Earth Doped Oxyfluoride Transparent Glass-Ceramic.

Oxyfluoride transparent glass-ceramics (GC) are widely used as the matrix for rare-earth (RE) ions due to their unique properties such as low phonon energy, high transmittance, and high solubility for RE ions. Tb3+ doped oxyfluoride glasses exhibit a large absorption cross section for ultraviolet (UV) excitation, high stability, high photoluminescence quantum efficiency, and sensitive spectral conversion characteristics, making them promising candidate materials for use as the spectral converter in UV photodetectors. Herein, a Tb3+ doped oxyfluoride GC is developed by using the melt-quenching method, and the microstructure and optical properties of the GC sample are carefully investigated. By combining with a Si-based photo-resistor,a solar-blind UV detector is fabricated, which exhibits a significant photoelectric response with a broad detection range from 188 to 400 nm. The results indicate that the designed UV photodetector is of great significance for the development of solar-blind UV detectors.

Bioactive prosthesis interface compositing variable-stiffness hydrogels regulates stem cells fates to facilitate osseointegration through mechanotransduction.

Fluid hydrogel is proper to be incorporated with rigid porous prosthesis interface, acting as a soft carrier to support cells and therapeutic factors, to enhance osseointegration. In the previous study, we innovatively utilized self-healing supramolecular hydrogel as 3D cell culture platform to incorporate with 3D printed porous titanium alloy scaffold, constructing a novel bioactive interface. However, the concrete relationship and mechanism of hydrogel stiffness influencing cellular behaviors of bone marrow mesenchymal stem cells (BMSCs) within the interface are still inconclusive. Herein, we synthesized a series of supramolecular hydrogels with variable stiffness as extracellular matrix (ECM) to enhance the osseointegration of 3D printed prosthesis interface. BMSCs exposed to stiff hydrogel received massive environmental mechanical stimulations, subsequently transducing biophysical cues into biochemical signal through mechanotransduction process. The mRNA-sequencing analysis revealed that the activated FAK-MAPK pathway played significant roles in promoting osteogenic differentiation, thus contributing to a strong osseointegration. Our work preliminarily demonstrated the relationship of ECM stiffness and osteogenic differentiation trend of BMSCs, and optimized stiffness of hydrogel within a certain range benefitting for osteogenic differentiation and prosthesis interface osseointegration, providing a valuable insight into the development of orthopaedic implants equipped with osteogenic mechanotransduction ability.

Mean square exponential stabilization analysis of stochastic neural networks with saturated impulsive input.

The exponential stabilization of stochastic neural networks in mean square sense with saturated impulsive input is investigated in this paper. Firstly, the saturated term is handled by polyhedral representation method. When the impulsive sequence is determined by average impulsive interval, impulsive density and mode-dependent impulsive density, the sufficient conditions for stability are proposed, respectively. Then, the ellipsoid and the polyhedron are used to estimate the attractive domain, respectively. By transforming the estimation of the attractive domain into a convex optimization problem, a relatively optimum domain of attraction is obtained. Finally, a three-dimensional continuous time Hopfield neural network example is provided to illustrate the effectiveness and rationality of our proposed theoretical results.

Digestive interaction between dietary nitrite and dairy products generates novel nitrated linolenic acid products.

Nitrated fatty acids are important anti-inflammatory and protective lipids formed in the gastric compartment, with conjugated linoleic acid (rumenic acid, RA, 9Z,11E-18:2) being the primary substrate for lipid nitration. The recently reported identification of nitrated rumelenic acid (NO2-RLA) in human urine has led to hypothesize that rumelenic acid (RLA, 9Z,11E,15Z-18:3) from dairy fat is responsible for the formation of NO2-RLA. To evaluate the source and mechanism of NO2-RLA formation, 15N labeled standards of NO2-RLA were synthesized and characterized. Afterward, milk fat with different RA and RLA levels was administered to mice in the presence of nitrite, and the appearance of nitrated fatty acids in plasma and urine followed. We confirmed the formation of NO2-RLA and defined the main metabolites in plasma, urine, and tissues. In conclusion, RLA obtained from dairy products is the main substrate for forming this novel electrophilic lipid reported to be present in human urine.

Double-edged role of mechanical stimuli and underlying mechanisms in cartilage tissue engineering.

Mechanical stimuli regulate the chondrogenic differentiation of mesenchymal stem cells and the homeostasis of chondrocytes, thus affecting implant success in cartilage tissue engineering. The mechanical microenvironment plays fundamental roles in the maturation and maintenance of natural articular cartilage, and the progression of osteoarthritis Hence, cartilage tissue engineering attempts to mimic this environment in vivo to obtain implants that enable a superior regeneration process. However, the specific type of mechanical loading, its optimal regime, and the underlying molecular mechanisms are still under investigation. First, this review delineates the composition and structure of articular cartilage, indicating that the morphology of chondrocytes and components of the extracellular matrix differ from each other to resist forces in three top-to-bottom overlapping zones. Moreover, results from research experiments and clinical trials focusing on the effect of compression, fluid shear stress, hydrostatic pressure, and osmotic pressure are presented and critically evaluated. As a key direction, the latest advances in mechanisms involved in the transduction of external mechanical signals into biological signals are discussed. These mechanical signals are sensed by receptors in the cell membrane, such as primary cilia, integrins, and ion channels, which next activate downstream pathways. Finally, biomaterials with various modifications to mimic the mechanical properties of natural cartilage and the self-designed bioreactors for experiment in vitro are outlined. An improved understanding of biomechanically driven cartilage tissue engineering and the underlying mechanisms is expected to lead to efficient articular cartilage repair for cartilage degeneration and disease.

Prevalence of Presbyphonia in Older Adults With Dysphonia: A Systematic Review and Meta-Analysis.

PURPOSE: This study aims to investigate the prevalence of presbyphonia among older adults who report voice complaints. METHOD: We conducted a systematic search of five medical databases to identify studies that reported on presbyphonia as the cause of voice disorders in older adults. The pooled prevalence was calculated using random-effects models and presented as percentages with 95% confidence intervals (CI). The degree of heterogeneity among studies was assessed using I2 statistics. Subgroup analyses were performed to identify the sources of heterogeneity. RESULTS: Out of 764 abstracts from five libraries, 11 studies were included in this systematic review. The pooled prevalence of presbyphonia among older adults with voice disorders is 17.78% (95% CI [12.69, 23.51]). We conducted a subgroup analysis on studies that used laryngeal visualization to confirm the diagnosis for all patients and found that the prevalence of presbyphonia was lower in studies with unrestrictive inclusion criteria (12.84%, 95% CI [8.38, 18.08]) compared to studies with restricted inclusion criteria (22.59%, 95% CI [14.49, 31.88]). CONCLUSIONS: This study suggests that voice disorders in older adults have multiple causes, not predominantly presbyphonia. Overestimation of presbyphonia prevalence occurs if certain diagnoses are excluded at recruitment. This study emphasizes the importance of recognizing the diverse underlying etiologies of dysphonia in older adults; therefore, comprehensive examination and accurate diagnosis are crucial. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24263029.

Efficacy of non-conventional synthetic DMARDs for patients with rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). METHODS: PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant articles from inception to 1 June 2022. The results obtained from the analysis were expressed as mean difference (MD), effect size and 95% CI. RESULTS: A total of 17 studies, including 1315 patients with RA-ILD, were eligible. The ncs-DMARDs included abatacept, rituximab, tocilizumab, tumour necrosis factor and Janus kinase inhibitors. Compared with the baseline, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) values in the pooled data after ncs-DMARD treatment (alone or combined with conventional therapy) (p=0.36 for FVC; p=0.96 for FEV1 and p=0.46 for DLCO). Of note, FVC was obviously increased in rituximab subgroup (MD=-4.62, 95% CI -8.90 to -0.33, p=0.03). Also, high-resolution CT non-progression rate and fatality rate due to ILD progression in patients with RA-ILD were 0.792 (95% CI 0.746 to 0.834, p=0.015) and 0.049 (95% CI 0.035 to 0.065, p=0.000), respectively. CONCLUSION: ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment for stabilising or improving ILD in patients with RA-ILD. PROSPERO REGISTRATION NUMBER: CRD42022356816.

Modified Stabilization Test to Diagnose Chronic Syndesmotic Injuries Based on Posture Control.

BACKGROUND: To propose and validate a modified noninvasive method for the diagnosis of chronic syndesmotic injuries. METHODS: This study included 16 patients with chronic ankle instability. Herein, we propose the Modified Stabilization Test, a new measurement for use in the diagnosis of chronic syndesmotic injury, as determined by wearing a 60-kPa pneumatic brace. The test combines the center of pressure and sensory organization test to measure postural control. For comparison, we also measured the tibiofibular clear space, tibiofibular overlap, and medial clear space using anteroposterior radiograph; a line marked horizontally above the tibial plaque using computed tomography (CT) to measure the syndesmotic gap and fibular rotation angle; and magnetic resonance imaging (MRI) scans to determine the presence of the λ sign. The distance of syndesmosis was confirmed in 16 individuals through arthroscopy, and the results of the examination were used to determine the diagnostic efficacy of each index. RESULTS: Receiver operating characteristic curve analysis revealed that the optimal cut-off value, sensitivity, and specificity of the Modified Stabilization Test for the diagnosis of chronic syndesmotic injuries were 0.80, 100%, and 87.5%, respectively. The area under the curve (AUC) of the Modified Stabilization Test was 0.906 (95% CI 0.656, 0.993; P < .001), which was superior to imaging indices such as radiography, CT, and MRI (AUC = 0.516-0.891). CONCLUSION: We developed the Modified Stabilization Test-a noninvasive diagnostic tool for the screening of chronic syndesmotic injuries. The test showed high sensitivity and specificity for the identification of chronic syndesmotic injuries and is helpful in the identification of chronic syndesmotic injuries. LEVEL OF EVIDENCE: Level II, diagnostic-investigating a diagnostic test.

Effect of Sophorolipid Adsorption on the Coal Microstructure: Experimental and Wettability Mathematical Model Discussion.

Green biosurfactants are emerging as a promising area of research. However, there is a limited focus on the adsorption and wetting characteristics of biosurfactants on coal dust. This study explores the effects of sophorolipid (SL) biosurfactants on the microstructure and wettability of different coalification degree coal. The microstructure parameters of SL adsorbed on coal dust were measured using a surface tensiometer, contact angle analyzer, and particle size analyzer. The results indicate that SL has the lowest critical surface tension, leading to a 9.25° decrease in the contact angle for low-rank bituminous coal (YZ-LRBC). Furthermore, SL significantly altered the particle size distribution of lignite (NM-LC) and YZ-LRBC. The pore size structure of SL-infiltrated coal dust was quantified using a specific surface area analyzer, revealing a decrease in the specific surface area and an increase in the average pore size. The infrared analysis demonstrated that SL permeation significantly increased the percentage of hydrophilic functional groups (hydroxyl structures) while reducing the hydrophobic functional groups (aliphatic hydrocarbon and aromatic structure). Based on the measured microstructure parameters, a regression equation for contact angle was established: [contact angle (°)] = 73.800 - 0.860 × [D10 (nm)] + 4.280 × [specific surface area (m2/g)]. Notably, the characteristic particle size D10 had a significant negative effect on the contact angle, while the specific surface area had a significant positive effect. These findings provide a theoretical foundation for the application of biosurfactants in water injection to reduce dust and improve the wetting efficiency.

Plasmonic nanobipyramids with photo-enhanced catalytic activity under near-infrared II window for effective treatment of breast cancer.

Nanozyme-based catalytic therapy is an effective method for cancer treatment, but insufficient catalytic activity presents a challenge in achieving optimal therapeutic outcomes. External light can provide an innovative approach to modulate nanozyme catalytic activity. Herein, we report on plasmonic gold nanobipyramid@cuprous oxide (Au NBP@Cu2O) nanozyme for the effective phototherapy of breast cancer. In the tumor microenvironment, Cu+-mediated Fenton-like reaction catalyzes the generation of toxic hydroxyl radicals (•OH) from endogenous hydrogen peroxide to induce apoptosis. Additionally, the Au NBP@Cu2O nanostructure improves the absorption performance of Au NBPs in the near-infrared II region through near-field enhancement of equipartite exciters and achieves a high photothermal conversion efficiency value of 58%. Remarkably, the Au NBP@Cu2O nanoheterostructure can capture hot electrons induced by equipartition excitations and promote electron-hole separation under 1064 nm laser irradiation, facilitating the production of more reactive oxygen species (ROS). The mechanism behind this enhanced catalytic activity was unraveled using femtosecond transient absorption spectroscopy. Both in vitro and in vivo investigations have demonstrated the efficacious tumor therapeutic potential of Au NBP@Cu2O nanozyme, particularly under 1064 nm laser irradiation. Furthermore, the proposed therapeutic approach has been proved to effectively block tumor metastasis, providing a promising strategy for the development of multifunctional nanotherapeutics to tackle metastatic tumors. STATEMENT OF SIGNIFICANCE: A highly effective plasmonic nanozyme has been developed to improve catalytic therapy for breast cancer. When exposed to 1064 nm laser irradiation, Au NBP@Cu2O nanozyme can promote the separation of hot electrons and holes thereby facilitating the production of reactive oxygen species. Hot electrons transfer behavior is unveiled by femtosecond transient absorption spectroscopy technique. This enhanced catalytic activity, along with the intrinsic photothermal effect, effectively kills tumor cells.

Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies.

Nitro fatty acids (NO2-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO2-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB). CP-6 specifically targets Cys319, essential in RAD51-controlled HR-mediated DNA DSB repair in cells. A nitroalkene library screen identified two structurally different nitroalkenes, a non-natural fatty acid [(E) 8-nitro-nonadec-7-enoic acid (CP-8)] and a dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP-23)] superior to CP-6 in TNBC cells killing, synergism with three different inhibitors of the poly ADP-ribose polymerase (PARP) and γ-IR. CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR in a GFP-reported assay but did not affect benign human epithelial cells or cell cycle phases. In vivo, CP-8 and CP-23's efficacies diverged as only CP-8 showed promising anticancer activities alone and combined with the PARP inhibitor talazoparib in an HR-proficient TNBC mouse model. As preliminary preclinical toxicology analysis also suggests CP-8 as safe, our data endorse CP-8 as a novel anticancer molecule for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.