[RHD Genotyping Characteristics of RhD-Negative Blood Donors in Wuhu Area].

OBJECTIVE: To investigate the molecular mechanism and distribution characteristics of RhD negative phenotypes in Han population of blood donors in Wuhu city. METHODS: A total of 210 RhD- samples from August 2021 to August 2022 were screened by serological test and collected from Wuhu Central Blood Station for the voluntary blood donor population. Exons 1 and 10 of the RHD gene were amplificated by PCR to determine whether the samples had the RHD gene. Exons 1-10 of the RHD gene were amplificated by PCR and zygosity analysis were performed in 82 samples containing D gene, and Sanger sequencing was performed on 55 samples containing all RHD exons to determine the genotype. RESULTS: Among 210 RhD- specimens, 128 cases (60.38%) had RHD gene deletion. 27 cases had partial exons of RHD, including 2 cases with RHD*DVI.3/RHD*01N.01, 24 cases with RHD*01N.04/RHD*01N.01, and 1 case with RHD-CE(2-10)/RHD*01N.01. 55 cases had retained all of 10 exons, including 4 cases with RHD*01/RHD*01N.01, 6 cases with RHD*15/RHD*01N.01, 1 case with RHD*01W.72/RHD*01N.01, 1 case with RHD*15/RHD*01EL.01, 39 cases with RHD*01EL.01/RHD*01N.01, and the remaining 4 cases were determined to have no RHD gene deletion by zygosity analysis and sequencing showed the presence of 1227G>A mutation loci. CONCLUSION: There is polymorphism in the molecular mechanism of RhD- D gene in Wuhu blood donor population, among which RHD*01EL.01 and RHD*15 are the main variants in this region. The results of this study provide a theoretical basis for RhD blood group identification and clinical blood transfusion in this region.

Diabetes and susceptibility to COVID-19: Risk factors and preventive and therapeutic strategies.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diabetes is a well-known risk factor for infectious diseases with high prevalence and increased severity. Here, we elucidated the possible factors for the increased vulnerability of diabetic patients to SARS-CoV-2 infection and the more severe COVID-19 illness. The worsened prognosis of patients with both COVID-19 and diabetes may be attributable to host receptor angiotensin-converting enzyme 2-assisted viral uptake. Moreover, insulin resistance is often associated with impaired mucosal and skin barrier integrity, resulting in mic-robiota dysbiosis, which increases susceptibility to viral infections. It may also be associated with higher levels of pro-inflammatory cytokines resulting from an impaired immune system in diabetics, inducing a cytokine storm and excessive inflammation. This review describes diabetes mellitus and its complications, explains the risk factors, such as disease characteristics and patient lifestyle, which may contribute to the high susceptibility of diabetic patients to COVID-19, and discusses preventive and therapeutic strategies for COVID-19-positive diabetic patients.

Combined prevention and treatment measures are essential to control nosocomial infections during the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus-2 is a highly contagious positive-sense, single-stranded RNA virus that has rapidly spread worldwide. As of December 17, 2023, 772838745 confirmed cases including 6988679 deaths have been reported globally. This virus primarily spreads through droplets, airborne transmission, and direct contact. Hospitals harbor a substantial number of confirmed coronavirus disease 2019 (COVID-19) patients and asymptomatic carriers, accompanied by high population density and a larger susceptible population. These factors serve as potential triggers for nosocomial infections, posing a threat during the COVID-19 pandemic. Nosocomial infections occur to varying degrees across different countries worldwide, emphasizing the urgent need for a practical approach to prevent and control the intra-hospital spread of COVID-19. This study primarily concentrated on a novel strategy combining preventive measures with treatment for combating COVID-19 nosocomial infections. It suggests preventive methods, such as vaccination, disinfection, and training of heathcare personnel to curb viral infections. Additionally, it explored therapeutic strategies targeting cellular inflammatory factors and certain new medications for COVID-19 patients. These methods hold promise in rapidly and effectively preventing and controlling nosocomial infections during the COVID-19 pandemic and provide a reliable reference for adopting preventive measures in the future pandemic.

Integrative analysis of transcriptome and metabolome reveal the differential tolerance mechanisms to low and high salinity in the roots of facultative halophyte Avicennia marina.

Mangroves perform a crucial ecological role along the tropical and subtropical coastal intertidal zone where salinity fluctuation occurs frequently. However, the differential responses of mangrove plant at the combined transcriptome and metabolome level to variable salinity are not well documented. In this study, we used Avicennia marina (Forssk.) Vierh., a pioneer species of mangrove wetlands and one of the most salt-tolerant mangroves, to investigate the differential salt tolerance mechanisms under low and high salinity using inductively coupled plasma-mass spectrometry, transcriptomic and metabolomic analysis. The results showed that HAK8 was up-regulated and transported K+ into the roots under low salinity. However, under high salinity, AKT1 and NHX2 were strongly induced, which indicated the transport of K+ and Na+ compartmentalization to maintain ion homeostasis. In addition, A. marina tolerates low salinity by up-regulating ABA signaling pathway and accumulating more mannitol, unsaturated fatty acids, amino acids' and L-ascorbic acid in the roots. Under high salinity, A. marina undergoes a more drastic metabolic network rearrangement in the roots, such as more L-ascorbic acid and oxiglutatione were up-regulated, while carbohydrates, lipids and amino acids were down-regulated in the roots, and, finally, glycolysis and TCA cycle were promoted to provide more energy to improve salt tolerance. Our findings suggest that the major salt tolerance traits in A. marina can be attributed to complex regulatory and signaling mechanisms, and show significant differences between low and high salinity.

Clinical outcomes and predictors of bleomycin polidocanol foam sclerotherapy treatment response in venous malformations.

OBJECTIVE: To evaluate the safety and efficacy of bleomycin polidocanol foam (BPF) sclerotherapy for venous malformations (VMs) and analyze the associated clinical outcomes and predictors. METHODS: We retrospectively assessed BPF sclerotherapy outcomes in 138 patients with VMs. We analyzed pain levels, lesion volume reduction, and subjective perception of response. Logistic regression analysis was performed to identify potential predictors of treatment outcome. Additionally, we carefully monitored and recorded complications. RESULTS: There was a notable average reduction in lesion volume by 78.50% ± 15.71%. The pain numerical rating scale (NRS) score decreased from 4.17 ± 2.63 prior to treatment to 1.05 ± 1.54 afterward, and 70.3% of the patients experienced effective relief after a single BPF treatment. Multivariate analysis revealed that a high baseline NRS (odds ratio [OR]: 4.026) and elevated activated partial thromboplastin time (APTT, OR: 1.200) were positive predictors of pain reduction. Additionally, a high baseline NRS score (OR: 1.992) and elevated thrombocytocrit (PCT, OR: 2.543) were positive predictors of incomplete postoperative pain relief. Minor complications occurred in 31 (22.46%) patients. CONCLUSION: BPF sclerotherapy is safe and effective for VMs, resulting in significant reduction in lesion volume, improved symptoms, and minimal complications. APTT and PCT levels are important predictors of pain outcomes following BPF treatment.

Identification of key pyroptosis-related genes and microimmune environment among peripheral arterial beds in atherosclerotic arteries.

Atherosclerosis is a chronic inflammatory disease characterized with innate and adaptive immunity but also involves pyroptosis. Few studies have explored the role of pyroptosis in advanced atherosclerotic plaques from different vascular beds. Here we try to identify the different underlying function of pyroptosis in the progression of atherosclerosis between carotid arteries and femoral. arteries. We extracted gene expression levels from 55 advanced carotid or femoral atherosclerotic plaques. The pyroptosis score of each sample was calculated by single-sample-gene-set enrichment analysis (ssGSEA). We then divided the samples into two clusters: high pyroptosis scores cluster (PyroptosisScoreH cluster) and low pyroptosis scores cluster (PyroptosisScoreL cluster), and assessed functional enrichment and immune cell infiltration in the two clusters. Key pyroptosis related genes were identified by the intersection between results of Cytoscape and LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Finally, all key pyroptosis related genes were validated in vitro. We found all but one of the 29 carotid plaque samples belonged to the PyroptosisScoreH cluster and the majority (19 out of 26) of femoral plaques were part of the PyroptosisScoreL cluster. Atheromatous plaque samples in the PyroptosisScoreL cluster had higher proportions of gamma delta T cells, M2 macrophages, myeloid dendritic cells (DCs), and cytotoxic lymphocytes (CTLs), but lower proportions of endothelial cells (ECs). Immune full-activation pathways (e.g., NOD-like receptor signaling pathway and NF-kappa B signaling pathway) were highly enriched in the PyroptosisScoreH cluster. The key pyroptosis related genes GSDMD, CASP1, NLRC4, AIM2, and IL18 were upregulated in advanced carotid atherosclerotic plaques. We concluded that compared to advanced femoral atheromatous plaques, advanced carotid atheromatous plaques were of higher grade of pyroptosis. GSDMD, CASP1, NLRC4, AIM2, and IL18 were the key pyroptosis related genes, which might provide a new sight in the prevention of fatal strokes in advanced carotid atherosclerosis.

Structural, developmental and functional analyses of leaf salt glands of mangrove recretohalophyte Aegiceras corniculatum.

Salt secretion is an important strategy used by the mangrove plant Aegiceras corniculatum to adapt to the coastal intertidal environment. However, the structural, developmental and functional analyses on the leaf salt glands, particularly the salt secretion mechanism, are not well documented. In this study, we investigated the structural, developmental and degenerative characteristics and the salt secretion mechanisms of salt glands to further elucidate the mechanisms of salt tolerance of A. corniculatum. The results showed that the salt gland cells have a large number of mitochondria and vesicles, and plenty of plasmodesmata as well, while chloroplasts were found in the collecting cells. The salt glands developed early and began to differentiate at the leaf primordium stage. We observed and defined three stages of salt gland degradation for the first time in A. corniculatum, where the secretory cells gradually twisted and wrinkled inward and collapsed downward as the salt gland degeneration increased and the intensity of salt gland autofluorescence gradually diminished. In addition, we found that the salt secretion rate of the salt glands increased when the treated concentration of NaCl increased, reaching the maximum at 400 mM NaCl. The salt-secreting capacity of the salt glands of the adaxial epidermis is significantly greater than that of the abaxial epidermis. The real-time quantitative PCR results indicate that SAD2, TTG1, GL2 and RBR1 may be involved in regulating the development of the salt glands of A. corniculatum. Moreover, Na+/H+ antiporter, H+-ATPase, K+ channel and Cl- channel may play important roles in the salt secretion of salt glands. In sum mary, this study strengthens the understanding of the structural, developmental and degenerative patterns of salt glands and salt secretion mechanisms in mangrove recretohalophyte A. corniculatum, providing an important reference for further studies at the molecular level.

Comparison of bleomycin polidocanol foam vs electrochemotherapy combined with polidocanol foam for treatment of venous malformations.

OBJECTIVE: This study aims to investigate the difference in safety and efficacy between two treatments for venous malformations (VMs), electrochemotherapy combined with polidocanol foam (ECP) and bleomycin polidocanol foam (BPF), providing alternative therapies for VMs. METHODS: We conducted a retrospective review of 152 patients with VMs treated with ECP and BPF. Pre- and post-treatment magnetic resonance images (MRIs) were collected, and clinical follow-up assessments were performed. Imaging results were used to calculate lesion volume changes. Clinical outcomes included changes in pain and improvements in perceived swelling. Patients were followed up at 1 week and 6 months after surgery. All emerging complications were documented in detail. RESULTS: Of the 152 patients, 87 (57.2%) received BPF treatment, and 65 (42.8%) received ECP treatment. The most common location of VMs was the lower extremities (92/152; 60.2%), and the most common symptom was pain (108/152; 71.1%). Forty-three patients had previously undergone therapy in the BPF group (43/87; 49.4%), whereas 30 patients had received prior treatment in the ECP group (30/65; 46.2%). The study found that the percentage of lesion volume reduction in the BPF group was not significantly different from that in the ECP group (75.00% ± 17.85% vs 74.69% ± 8.48%; P = .899). ECP was more effective when the initial lesion volume was greater than 30 mL (67.66% ± 12.34% vs 73.47% ± 8.00%; P = .048). Patients treated with BPF had significantly less posttreatment pain than those treated with ECP, in different baseline lesion size. In the overall sample, pain relief was significantly higher in the BPF group than in the ECP group (4.21 ± 1.19 vs 3.57 ± 0.76; P = .002). However, there was no difference in pain relief between the two groups for the treatment of initially large VMs (4.20 ± 0.94 vs 3.70 ± 0.87; P = .113). The ECP group was significantly more likely to develop hyperpigmentation (5/87; 5.75% vs 11/65; 16.92%; P = .026) and swelling (9/87; 10.34% vs 16/65; 24.62%; P = .019) 1 week after surgery than the BPF group. CONCLUSIONS: Our study demonstrates that both BPF and ECP are effective treatments for VMs, with BPF being a safer option. ECP is a better choice for patients with the initial lesion volume greater than 30 mL, but it is more likely to lead to early swelling and hyperpigmentation.

Targeting Keap1 with Inulae Herba activated the Nrf2 receptor to alleviate LPS-mediated acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Inulae Herba (IH) is known as Jinfeicao recorded in Chinese Pharmacopoeia with effects of lowering qi and eliminating phlegm, and used for the treatment of pulmonary diseases. However, its protective mechanism on pulmonary diseases, especially acute lung injury (ALI), is still undefined. AIM OF THE STUDY: This study aimed to explore anti-inflammatory and anti-oxidation effects of IH and its underlying mechanism for treating ALI. MATERIALS AND METHODS: We constructed a lipopolysaccharide (LPS)-ALI mouse model to reveal the therapeutical effect of IH. Western blot, real-time quantitative PCR, flow cytometry, small RNA interference, immunohistochemical staining, and the dual-luciferase experiment were performed to study the mechanism of IH for treating ALI. RESULTS: IH attenuated LPS-mediated pathological changes (e.g. pneumonedema and pulmonary congestion) through inactivation of macrophages in an ALI mouse model. The result of flow cytometry demonstrated that IH regulated the homeostasis of M1 (CD80+CD206-) and M2 (CD80+CD206+) phenotype macrophages. Furthermore, IH suppressed mRNA expressions of M1 phenotype markers, such as iNOS and IL-6, whereas promoted mRNA expressions of M2 phenotype markers, such as ARG1 and RETNLA in LPS-mediated mice. Notably, IH targeted Keap1 to activate the Nrf2 receptor, exerting its anti-inflammatory and anti-oxidation effects proved by using immunohistochemical staining, dual-luciferase, and Keap1 knockdown technologies. CONCLUSION: These findings suggested that targeting Keap1 with IH alleviated LPS-mediated ALI, and it could serve as a herbal agent for developing anti-ALI drugs.

Combined metabolome and transcriptome analysis reveals a critical role of lignin biosynthesis and lignification in stem-like pneumatophore development of the mangrove Avicennia marina.

MAIN CONCLUSION: Transcriptional and metabolic regulation of lignin biosynthesis and lignification plays crucial roles in Avicennia marina pneumatophore development, facilitating its adaptation to coastal habitats. Avicennia marina is a pioneer mangrove species in coastal wetland. To cope with the periodic intertidal flooding and hypoxia environment, this species has developed a complex and extensive root system, with its most unique feature being a pneumatophore with a distinct above- and below-ground morphology and vascular structure. However, the characteristics of pneumatophore lignification remain unknown. Studies comparing the anatomy among above-ground pneumatophore, below-ground pneumatophore, and feeding root have suggested that vascular structure development in the pneumatophore is more like the development of a stem than of a root. Metabolome and transcriptome analysis illustrated that the accumulation of syringyl (S) and guaiacyl (G) units in the pneumatophore plays a critical role in lignification of the stem-like structure. Fourteen differentially accumulated metabolites (DAMs) and 10 differentially expressed genes involved in the lignin biosynthesis pathway were targeted. To identify genes significantly associated with lignification, we analyzed the correlation between 14 genes and 8 metabolites and further built a co-expression network between 10 transcription factors (TFs), including 5 for each of MYB and NAC, and 23 enzyme-coding genes involved in lignin biosynthesis. 4-Coumarate-CoA ligase, shikimate/quinate hydroxycinnamoyl transferase, cinnamyl alcohol dehydrogenase, caffeic acid 3-O-methyltransferase, phenylalanine ammonia-lyase, and peroxidase were identified to be strongly correlated with these TFs. Finally, we examined 9 key candidate genes through quantitative real-time PCR to validate the reliability of transcriptome data. Together, our metabolome and transcriptome findings reveal that lignin biosynthesis and lignification regulate pneumatophore development in the mangrove species A. marina and facilitate its adaptation to coastal habitats.

Multi-locus phylogenetic analyses reveal eight novel species of Distoseptispora from southern China.

IMPORTANCE: Distoseptispora as a single genus in Distoseptisporaceae was introduced by morphological and phylogenetic analyses. Members of this genus occur mainly as asexual morphs, forming effuse, hairy colonies on decaying wood, plant stems, bamboo culms, and fallen leaves and shafts in terrestrial and freshwater habitats. In the present study, saprobic hyphomycetes from plant debris were investigated, and eight new Distoseptispora species were introduced based on morphology and phylogenetic analyses of LSU, ITS, TEF1, and RPB2 sequence data. This study provides important data on the species diversity, ecological environment, and geographical area of Distoseptispora, greatly updates the classification of Distoseptispora, and improves our understanding of the taxonomy of Distoseptispora.

Inventory of cadmium-transporter genes in the root of mangrove plant Avicennia marina under cadmium stress.

Mangrove Avicennia marina has the importantly potential for cadmium (Cd) pollution remediation in coastal wetlands. Unfortunately, the molecular mechanisms and transporter members for Cd uptake by the roots of A. marina are not well documented. In this study, photosynthetic and phenotypic analysis indicated that A. marina is particularly tolerant to Cd. The content and flux analysis indicated that Cd is mainly retained in the roots, with greater Cd influx in fine roots than that in coarse roots, and higher Cd influx in the root meristem zone as well. Using transcriptomic analysis, a total of 5238 differentially expressed genes were identified between the Cd treatment and control group. Moreover, we found that 54 genes were responsible for inorganic ion transport. Among these genes, AmHMA2, AmIRT1, and AmPCR2 were localized in the plasma membrane and AmZIP1 was localized in both plasma membrane and cytoplasm. All above gene encoding transporters showed significant Cd transport activities using function assay in yeast cells. In addition, the overexpression of AmZIP1 or AmPCR2 in Arabidopsis improved the Cd tolerance of transgenic plants. This is particularly significant as it provides insight into the molecular mechanism for Cd uptake by the roots of mangrove plants and a theoretical basis for coastal wetland phytoremediation.

Dietary phytochemical and metabolic disease prevention: Focus on plant proteins.

Plant-based functional foods have attracted increasing research interest to validate their use in preventing metabolic disease. Since it is increasingly recognized that inflammation, oxidative stress, and circadian rhythm play vital roles in various metabolic diseases, including diabetes, obesity and non-alcoholic liver disease, plant proteins, protein hydrolysates, and food extracts that intervene in these biological processes are promising dietary supplements to prevent metabolic diseases. Here, we reviewed the recent research on plant-based foods used for metabolic disease prevention and provided new perspectives regarding the current study gaps and future directions in this field.

Morphology and Multigene Phylogeny Revealed Three New Species of Helminthosporium (Massarinaceae, Pleosporales) from China.

Saprobic hyphomycetes are highly diverse on plant debris. Over the course of our mycological surveys in southern China, three new Helminthosporium species, H. guanshanense sp. nov., H. jiulianshanense sp. nov. and H. meilingense sp. nov., collected on dead branches of unidentified plants, were introduced by morphological and molecular phylogenetic analyses. Multi-loci (ITS, LSU, SSU, RPB2 and TEF1) phylogenetic analyses were performed using maximum-likelihood and Bayesian inference to infer their taxonomic positions within Massarinaceae. Both molecular analyses and morphological data supported H. guanshanense, H. jiulianshanense and H. meilingense as three independent taxa within Helminthosporium. A list of accepted Helminthosporium species with major morphological features, host information, locality and sequence data was provided. This work expands our understanding of the diversity of Helminthosporium-like taxa in Jiangxi Province, China.

Hydrogen sulfide upregulates the alternative respiratory pathway in mangrove plant Avicennia marina to attenuate waterlogging-induced oxidative stress and mitochondrial damage in a calcium-dependent manner.

Hydrogen sulfide (H2 S) is considered to mediate plant growth and development. However, whether H2 S regulates the adaptation of mangrove plant to intertidal flooding habitats is not well understood. In this study, sodium hydrosulfide (NaHS) was used as an H2 S donor to investigate the effect of H2 S on the responses of mangrove plant Avicennia marina to waterlogging. The results showed that 24-h waterlogging increased reactive oxygen species (ROS) and cell death in roots. Excessive mitochondrial ROS accumulation is highly oxidative and leads to mitochondrial structural and functional damage. However, the application of NaHS counteracted the oxidative damage caused by waterlogging. The mitochondrial ROS production was reduced by H2 S through increasing the expressions of the alternative oxidase genes and increasing the proportion of alternative respiratory pathway in the total mitochondrial respiration. Secondly, H2 S enhanced the capacity of the antioxidant system. Meanwhile, H2 S induced Ca2+ influx and activated the expression of intracellular Ca2+ -sensing-related genes. In addition, the alleviating effect of H2 S on waterlogging can be reversed by Ca2+ chelator and Ca2+ channel blockers. In conclusion, this study provides the first evidence to explain the role of H2 S in waterlogging adaptation in mangrove plants from the mitochondrial aspect.

In silico analysis of NAC gene family in the mangrove plant Avicennia marina provides clues for adaptation to intertidal habitats.

NAC (NAM, ATAF1/2, CUC2) transcription factors (TFs) constitute a plant-specific gene family. It is reported that NAC TFs play important roles in plant growth and developmental processes and in response to biotic/abiotic stresses. Nevertheless, little information is known about the functional and evolutionary characteristics of NAC TFs in mangrove plants, a group of species adapting coastal intertidal habitats. Thus, we conducted a comprehensive investigation for NAC TFs in Avicennia marina, one pioneer species of mangrove plants. We totally identified 142 NAC TFs from the genome of A. marina. Combined with NAC proteins having been functionally characterized in other organisms, we built a phylogenetic tree to infer the function of NAC TFs in A. marina. Gene structure and motif sequence analyses suggest the sequence conservation and transcription regulatory regions-mediated functional diversity. Whole-genome duplication serves as the driver force to the evolution of NAC gene family. Moreover, two pairs of NAC genes were identified as positively selected genes of which AmNAC010/040 may be imposed on less constraint toward neofunctionalization. Quite a few stress/hormone-related responsive elements were found in promoter regions indicating potential response to various external factors. Transcriptome data revealed some NAC TFs were involved in pneumatophore and leaf salt gland development and response to salt, flooding and Cd stresses. Gene co-expression analysis found a few NAC TFs participates in the special biological processes concerned with adaptation to intertidal environment. In summary, this study provides detailed functional and evolutionary information about NAC gene family in mangrove plant A. marina and new perspective for adaptation to intertidal habitats.

Major Limb Amputation in Parkes-Weber Syndrome With Refractory Ulceration: A Case Report and Literature Review.

Parkes-Weber syndrome (PWS) is a rare congenital vascular syndrome consisting of capillary, venous, lymphatic, and arteriovenous malformation. There are many complications of PWS, such as ulceration, bleeding, infection, and cardiac failure. Among them, skin ulceration is one of the thorniest problems in PWS, requiring multidisciplinary approaches for the management. In this article, we presented the case of an elderly patient with refractory ulceration who received numerous treatments with no effect and finally underwent a major amputation to improve the quality of life. Moreover, we reviewed 23 previously reported cases to improve our understanding of the management for PWS patients with ulceration.

A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer.

Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs, PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed "NN3″, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover, NN3 degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders, NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.

Reduction in Allergenicity and Induction of Oral Tolerance of Glycated Tropomyosin from Crab.

Tropomyosin (TM) is an important crustacean (Scylla paramamosain) allergen. This study aimed to assess Maillard-reacted TM (TM-G) induction of allergenic responses with cell and mouse models. We analyzed the difference of sensitization and the ability to induce immune tolerance between TM and TM-G by in vitro and in vivo models, then we compared the relationship between glycation sites of TM-G and epitopes of TM. In the in vitro assay, we discovered that the sensitization of TM-G was lower than TM, and the ability to stimulate mast cell degranulation decreased from 55.07 ± 4.23% to 27.86 ± 3.21%. In the serum of sensitized Balb/c mice, the level of specific IgE produced by TM-G sensitized mice was significantly lower than TM, and the levels of interleukins 4 and interleukins 13 produced by Th2 cells in spleen lymphocytes decreased by 82.35 ± 5.88% and 83.64 ± 9.09%, respectively. In the oral tolerance model, the ratio of Th2/Th1 decreased from 4.05 ± 0.38 to 1.69 ± 0.19. Maillard reaction masked the B cell epitopes of TM and retained some T cell epitopes. Potentially, Maillard reaction products (MRPs) can be used as tolerance inducers for allergen-specific immunotherapy.