Spinal myeloid sarcoma presenting as initial symptom in acute promyelocytic leukemia with a rare cryptic PLZF::RARα fusion gene: a case report and literature review.

Background: Acute promyelocytic leukemia (APL) is rarely caused by the PLZF::RARα fusion gene. While APL patients with PLZF::RARα fusion commonly exhibit diverse hematologic symptoms, the presentation of myeloid sarcoma (MS) as an initial manifestation is infrequent. Case presentation: A 61-year-old patient was referred to our hospital with 6-month history of low back pain and difficulty walking. Before this admission, spine magnetic resonance imaging (MRI) conducted at another hospital revealed multiple abnormal signals in the left iliac bone and vertebral bodies spanning the thoracic (T11-T12), lumbar (L1-L4), and sacral (S1/S3) regions. This led to a provisional diagnosis of bone tumors with an unknown cause. On admission, complete blood count (CBC) test and peripheral blood smear revealed a slightly increased counts of monocytes. Immunohistochemical staining of both spinal and bone marrow (BM) biopsy revealed positive expression for CD117, myeloperoxidase (MPO), and lysozyme. BM aspirate showed a significant elevation in the percentage of promyelocytes (21%), which were morphologically characterized by round nuclei and hypergranular cytoplasm. Multiparameter flow cytometry of BM aspirate revealed that blasts were positive for CD13, CD33, CD117, and MPO. Through the integrated application of chromosome analysis, fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and Sanger sequencing, it was determined that the patient possessed a normal karyotype and a rare cryptic PLZF::RARα fusion gene, confirming the diagnosis of APL. Conclusion: In the present study, we report the clinical features and outcome of a rare APL patient characterized by a cryptic PLZF::RARα fusion and spinal myeloid sarcoma (MS) as the initial presenting symptom. Our study not only offers valuable insights into the heterogeneity of APL clinical manifestations but also emphasizes the crucial need to promptly consider the potential link between APL and MS for ensuring a timely diagnosis and personalized treatments.

MYB24, MYB144, and MYB168 positively regulate suberin biosynthesis at potato tuber wounds during healing.

The essence of wound healing is the accumulation of suberin at wounds, which is formed by suberin polyphenolic (SPP) and suberin polyaliphatic (SPA). The biosynthesis of SPP and SPA monomers is catalyzed by several enzyme classes related to phenylpropanoid metabolism and fatty acid metabolism, respectively. However, how suberin biosynthesis is regulated at the transcriptional level during potato (Solanum tuberosum) tuber wound healing remains largely unknown. Here, 6 target genes and 15 transcription factors related to suberin biosynthesis in tuber wound healing were identified by RNA-seq technology and qRT-PCR. Dual luciferase and yeast one-hybrid assays showed that StMYB168 activated the target genes StPAL, StOMT, and St4CL in phenylpropanoid metabolism. Meanwhile, StMYB24 and StMYB144 activated the target genes StLTP, StLACS, and StCYP in fatty acid metabolism, and StFHT involved in the assembly of SPP and SPA domains in both native and wound periderms. More importantly, virus-induced gene silencing in S. tuberosum and transient overexpression in Nicotiana benthamiana assays confirmed that StMYB168 regulates the biosynthesis of free phenolic acids, such as ferulic acid. Furthermore, StMYB24/144 regulated the accumulation of suberin monomers, such as ferulates, α, ω-diacids, and ω-hydroxy acids. In conclusion, StMYB24, StMYB144, and StMYB168 have an elaborate division of labor in regulating the synthesis of suberin during tuber wound healing.

USP7 promotes cervical cancer progression by stabilizing MTDH expression through deubiquitination.

BACKGROUND: Metadherin (MTDH) and ubiquitin specific protease 7 (USP7) have been identified to involve in the tumorigenesis of cervical cancer (CC). USP7 is one of the deubiquitinating enzymes. Here, this study aimed to explore whether USP7 affected CC progression via interacting with MTDH and regulating its stability via deubiquitination. METHODS: qRT-PCR and western blotting assays detected the levels of genes and proteins. Functional analysis was conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays, respectively. Proteins between USP7 and MTDH were identified by co-immunoprecipitation assay. A mouse xenograft model was established for in vivo analysis. RESULTS: MTDH was highly expressed in CC tissues and cells, silencing of MTDH suppressed CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization. Mechanistically, USP7 directly bound to MTDH, and maintained its stability by removing ubiquitination on MTDH. CC tissues and cells showed high USP7 expression, and USP7 knockdown also inhibited CC cell proliferation, migration, invasion, angiogenesis and macrophage M2 polarization, and these effects mediated by USP7 knockdown were reversed by MTDH overexpression. Moreover, USP7 knockdown impeded CC growth in vivo by regulating MTDH. CONCLUSION: Collectively, USP7 promoted CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization in vitro, as well as tumor growth in vivo by regulating MTDH.

Inhibitory effects of black phosphorus nanosheets on tumor cell proliferation through downregulation of ADIPOQ and downstream signaling pathways.

Exposure to environmental pollutants, including nanomaterials, has a significant impact on tumor progression. The increased demand for black phosphorus nanosheets (BPNSs), driven by their exceptional properties, raises concerns about potential environmental contamination. Assessing their toxicity on tumor growth is essential. Herein, we employed a range of biological techniques, including cytotoxicity measurement, bioinformatics tools, proteomics, target gene overexpression, Western blot analysis, and apoptosis detection, to investigate the toxicity of BPNSs across A549, HepG-2, MCF-7, and Caco-2 cell lines. Our results demonstrated that BPNSs downregulated the expression of ADIPOQ and its associated downstream pathways, such as AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (Nrf2), and other unidentified pathways. These downregulated pathways ultimately led to mitochondria-dependent apoptosis. Notably, the specific downstream pathways involved varied depending on the type of tumors. These insightful findings not only confirm the consistent inhibitory effects of BPNSs across different tumor cells, but also elucidate the cytotoxicity mechanisms of BPNSs in different tumors, providing valuable information for their safe application and health risk assessment.

Immunomodulation of nutritional formula containing epigallocatechin-3-gallate, ginseng extract, and polydextrose on inflammation and macrophage polarization.

Single nutrient likes polyphenol or dietary fiber have been exhaustively investigated to validate their positive intervention in health or disease. Meanwhile, the common interaction of inner systems with the nutrient complex has not been well elucidated, which raises the scientific issue of the modulatory effect of the nutrient complex on immunity. The representative prebiotics of epigallocatechin-3-gallate (EGCG), ginseng extract, and polydextrose (PDX) were selected on behalf of the classification of polyphenol, flavone or polysaccharides, and dietary fiber to generally cover the daily food intake in this study to explore their intervention in inflammation and macrophage polarization. The intervention of selected nutrients on inflammation and macrophage polarization has been evaluated against macrophages to unveil their comprehensive effects. The synergistic effect of selected nutrients was demonstrated by inhibiting M1 macrophage polarization and the promotion of M2 macrophage polarization. Then, the nutrient formula was set up to verify the intervention effect, and the results revealed the significant inhibition of cell inflammation and the effect on cell proliferation through promoting the cell cycle in the G2 phase. The nutrient complex could inhibit M1 macrophage polarization to inhibit M1-mediated inflammation and promote M2 macrophages for anti-inflammatory effect and enhance cell phagocytosis. Moreover, the varied intervention effects of the nutrient complex with different formulas could be summarized. In general, the formula containing EGCG, ginseng extract, and PDX was demonstrated to possess an enhanced immunomodulatory effect on cell inflammation and macrophage polarization, which could potentially inspire the investigation of complex nutrients in health and diseases.

Adult-type granulosa cell tumor associated with elevated luteinizing hormone: Two rare case reports.

INTRODUCTION: Adult-type granulosa cell tumors (AGCTs), which account for 2% to 5% of all malignant ovarian tumors, are rare sex cord-stromal tumors that usually secrete excess estrogens, but they can also secrete androgens. PATIENT CONCERNS: We report 2 patients of childbearing age with AGCT who presented with the complaint of abnormal menstruation and elevated luteinizing hormone (LH), and mildly elevated testosterone. DIAGNOSIS: The ovarian tumors had hormonal activity. INTERVENTIONS: The 2 patients underwent laparoscopic left adnexectomy. The second patient underwent 4 cycles of chemotherapy with paclitaxel and carboplatin as adjuvant treatments. OUTCOMES: Their postoperative pathology confirmed AGCTs. Also, their menstrual cycle returned to normal, with normal serum LH and testosterone levels. There was no sign of recurrence. CONCLUSION: The cases suggest that elevated serum LH levels may be a sign of unknown tumors in cases of oligomenorrhea or secondary amenorrhea. It is useful to evaluate the serum levels of inhibin B and anti-Müllerian hormone to improve the early recognition of ovarian granulosa cell tumors.

An asymptomatic perforation of the gastrointestinal tract caused by ingestion of foreign body: A case report.

Ingestion of foreign bodies is very common in clinical practice. However, gastrointestinal perforation caused by a foreign body is rare, as most foreign bodies can pass the alimentary tract spontaneously or be removed endoscopically. Ingesting a foreign body causes gastrointestinal tract perforation in less than 1% of cases that require surgery. In the past, the literature about gastrointestinal tract perforation caused by foreign bodies had been widely reported worldwide. However, the case of foreign bodies causing gastrointestinal perforation without significant abdominal infection was rarely documented. A 47-year-old woman presented with intermittent left lower abdominal pain associated with a mass for 1 month and had no other symptoms. Laparotomy was performed after clinical assessment. During the operation, a local inflammatory mass that adhered to the abdominal wall, part of the small intestine, and sigmoid colon was found in the left lower quarter of the abdominal cavity. The surrounding intestinal wall was edematous. There were two bony foreign bodies in it. Postoperative pathology suggested an inflammatory mass. A foreign body rarely migrates into the abdominal cavity without symptoms that may be related to the omentum's slow perforation process and good function. The best treatment is surgery and using appropriate antibiotics.

Sorption enhancement of Cr(VI) from aqueous solution by polyaniline confined in three-dimensional network of composite porous hydrogel.

Hexavalent chromium Cr(VI) is a typical harmful pollutant, which is carcinogenic or mutagenic to aquatic animals and humans. In this study, sepiolite/humic acid/polyvinyl alcohol@ polyaniline (SC/HA/PVA@PANI) composite porous hydrogel adsorbent was synthesized by Pickering emulsion template in situ chemical oxidative polymerization for adsorption of Cr(VI) from aqueous solution. The in situ polymerization of aniline at the Pickering emulsion interface and the unique three-dimensional network structure of the hydrogel act as an effective "confinement" for the growth of the polymer. The porous structure of the material acts as a water channel, which effectively accelerates the binding of the adsorbate to the adsorption sites, and significantly improves the adsorption rate and adsorption capacity. The adsorption capacity of PANI for Cr(VI) confined in three-dimensional network of composite porous SC/HA/PVA@PANI hydrogel reached 1180.97 mg/g-PANI, which increased about 27-fold compared the adsorption capacity of pure PANI (43.48 mg/g). It is shown that the experimental design effectively avoids the agglomeration of PANI and improves its potential adsorption performance. In addition, the analysis of FESEM-EDX, FT-IR, and XPS spectra before and after adsorption confirmed that the main adsorption mechanisms of Cr(VI) on SC/HA/PVA@PANI included ion exchange, electrostatic attraction, and redox reaction. In conclusion, SC/HA/PVA@PANI has good stability and excellent adsorption performance, which is a new type of Cr(VI) ion adsorbent with great potential.

Primary alveolar rhabdomyosarcoma in the stomach of an adult: A case report.

Alveolar rhabdomyosarcoma (ARMS) is more common in children and rare in adults. A small number of cases in the stomach of an adult have been documented. The present study describes a case of primary gastric ARMS in a 20-year-old healthy female. The patient was admitted to Handan Central Hospital (Handan, China) with intermittent abdominal pain for >1 month, which was noticeable and progressively worsened after meals, with black stools. Gastroscopy revealed a 2.5-cm ulcer on the side of the greater curvature of the gastric body, and a pathological biopsy revealed a neuroendocrine neoplasm. An enhanced abdominal computed tomography (CT) scan indicated a thickening and an ulcerated mass measuring ~4.5×2.0 cm at the gastric body, with the tumor showing poor enhancement. Finally, a laparoscopic distal gastrectomy was performed. The postoperative pathology combined with immunohistochemical staining indicated that the patient had primary alveolar RMS of the stomach. The present case suggests that an early diagnosis of gastric adenoid RMS is extremely difficult. However, this disease must be investigated in any young person who presents with a gastric mass. The current study presents a rare case of primary ARMS occurring in the stomach; however, more research on this disease is necessary to improve the clinical diagnosis and treatment.

Distinctive anti-inflammatory effects of resveratrol, dihydroresveratrol, and 3-(4-hydroxyphenyl)-propionic acid on DSS-induced colitis in pseudo-germ-free mice.

Resveratrol is a dietary polyphenol that interacts with gut microbiota to possess various biological activities. To identify the microbial metabolites of resveratrol, fresh feces from 12 volunteers were cultured in vitro. Their urine samples were collected after taking a commercial capsule containing 600 mg of resveratrol. Metabolites were characterized and quantified by UPLC-Q-Exactive plus orbitrap MS/MS. The results showed that dihydroresveratrol, 3-(4-hydroxyphenyl)-propionic acid, and lunularin were the major microbial metabolites of RSV with interindividual differences. 3-(4-Hydroxyphenyl)-propionic acid significantly attenuated the inflammatory response of LPS-treated RAW264.7 cells and DSS-induced colitis in antibiotics-treated pseudo-germ-free mice by regulating MAPK and NF-κB pathways. In contrast, dihydroresveratrol did not exhibit significant anti-inflammatory effects, and lunularin exhibited pro-inflammatory effects in cells. This study may help to better understand the health effects of resveratrol and its microbial metabolites.

Structures, biosynthesis, and bioactivities of prodiginine natural products.

Prodiginines are a large family of microbial secondary metabolites with a core structure of tripyrrole rings. They exhibit not only diverse chemical structures but also rich biological activities, such as anti-cancer, anti-microbial, anti-algae, anti-parasitic, pesticides, and UV radiation resistance. The preferred cytotoxicity to cancer cells rather than normal cells indicates a good biological selectivity and safety, which makes the prodiginines promising candidates for drug development and novel additives for food processing. Until now, 33 prodiginine natural products have been identified in various bacteria, including Serratia, Hahella, Pseudoalteromonas, Vibrio, Zooshikella, Streptomyces, and Actinomadura. However, most efforts are still focused on the star molecule prodigiosin, while little yet is known about other prodiginine members, which retards the research and application of prodiginine compounds. To gain insight into the prodiginine family, we reviewed the recent discoveries on their chemical structures, biosynthesis, biological activities, and mechanisms of action. We believe this article will provide a guideline for new research on prodiginines, such as the discovery of new congeners and drug development. KEY POINTS: • The prodiginines are a large family of natural products with a core structure of tripyrrole rings and exhibit various bioactivities. • The prodiginines have a widespread distribution among many environmental microbes and diverse biosynthetic pathways, indicating important ecological roles and a great potential for new congeners. • The potent biological activities and good selectivity of action make prodiginines good lead compounds for drug development.

Differential Protective Effect of Resveratrol and Its Microbial Metabolites on Intestinal Barrier Dysfunction is Mediated by the AMPK Pathway.

The effectiveness of resveratrol (RES) on intestinal barrier dysfunction and colitis has been extensively studied. However, the specific effects of its microbial metabolites on gut barrier function remain unclear. Hence, we compared the protective effects of RES and its microbial metabolites dihydroresveratrol (DHR) and 3-(4-hydroxyphenyl)-propionic acid (4HPP) against intestinal barrier injury and colitis. Only 4HPP and RES significantly reduced paracellular permeability and the secretion of proinflammatory cytokines in lipopolysaccharides (LPS)-treated intestinal Caco-2 cells, which was consistent with the upregulation in tight junction (TJ) proteins. Furthermore, RES and 4HPP ameliorated intestinal barrier dysfunction and colonic inflammation in colitis mice, while DHR did not. In particular, the expressions of intestinal TJ proteins and Muc2 were restored by RES and 4HPP. The molecular mechanism involved the adenosine monophosphate-activated protein kinase (AMPK)-mediated activation of CDX2 and the regulation of the SIRT1/NF-κB pathway. These findings provide new insights into understanding the protective effects of RES against intestinal barrier damage and colitis.

A Prognostic Survival Model of Pancreatic Adenocarcinoma Based on Metabolism-Related Gene Expression.

Accurately predicting the survival prospects of patients suffering from pancreatic adenocarcinoma (PAAD) is challenging. In this study, we analyzed RNA matrices of 182 subjects with PAAD based on public datasets obtained from The Cancer Genome Atlas (TCGA) as training datasets and those of 63 subjects obtained from the Gene Expression Omnibus (GEO) database as the validation dataset. Genes regulating the metabolism of PAAD cells correlated with survival were identified. Furthermore, LASSO Cox regression analyses were conducted to identify six genes (XDH, MBOAT2, PTGES, AK4, PAICS, and CKB) to create a metabolic risk score. The proposed scoring framework attained the robust predictive performance, with 2-year survival areas under the curve (AUCs) of 0.61 in the training cohort and 0.66 in the validation cohort. Compared with the subjects in the low-risk cohort, subjects in the high-risk training cohort presented a worse survival outcome. The metabolic risk score increased the accuracy of survival prediction in patients suffering from PAAD.

Brassinosteroid Accelerates Wound Healing of Potato Tubers by Activation of Reactive Oxygen Metabolism and Phenylpropanoid Metabolism.

Wound healing could effectively reduce the decay rate of potato tubers after harvest, but it took a long time to form typical and complete healing structures. Brassinosteroid (BR), as a sterol hormone, is important for enhancing plant resistance to abiotic and biotic stresses. However, it has not been reported that if BR affects wound healing of potato tubers. In the present study, we observed that BR played a positive role in the accumulation of lignin and suberin polyphenolic (SPP) at the wounds, and effectively reduced the weight loss and disease index of potato tubers (cv. Atlantic) during healing. At the end of healing, the weight loss and disease index of BR group was 30.8% and 23.1% lower than the control, respectively. Furthermore, BR activated the expression of StPAL, St4CL, StCAD genes and related enzyme activities in phenylpropanoid metabolism, and promoted the synthesis of lignin precursors and phenolic acids at the wound site, mainly by inducing the synthesis of caffeic acid, sinapic acid and cinnamyl alcohol. Meanwhile, the expression of StNOX was induced and the production of O2- and H2O2 was promoted, which mediated oxidative crosslinking of above phenolic acids and lignin precursors to form SPP and lignin. In addition, the expression level of StPOD was partially increased. In contrast, the inhibitor brassinazole inhibited phenylpropanoid metabolism and reactive oxygen metabolism, and demonstrated the function of BR hormone in healing in reverse. Taken together, the activation of reactive oxygen metabolism and phenylpropanoid metabolism by BR could accelerate the wound healing of potato tubers.

Neuroprotective effects of novel compound Tozan on cognition, neurogenesis and apoptosis in diabetes.

BACKGROUND: Cognitive impairment is a serious complication of diabetes that manifests as an impairment of spatial memory and learning ability. Its pathogenesis is unclear, and effective therapeutic drugs are very limited. Our group designed and synthesized a novel compound named 3-p-tolyl-9H-xanthen-9-one (Tozan). In this study, we sought to investigate the effects and mechanism of Tozan on diabetic cognitive impairment. METHODS: Methylglyoxal (MG)-induced SH-SY5Y cells and streptozotocin (STZ)-induced type 1 diabetic mice were treated with Tozan. Methyl thiazolul tetrazolium (MTT) and lactate dehydrogenase (LDH) were used to test cytotoxicity. Morris water maze (MWM) and Y-maze tests were used to evaluate cognitive function. Immunofluorescence and western blot analyses were used to evaluate neurogenesis, apoptosis, and signal transduction pathway-related proteins. In addition, Lentivirus (LV)-estrogen receptor beta (ERß)-ribonucleic acid interference (RNAi) was used to knockdown the ERß gene in SH-SY5Y cells. RESULTS: We found that Tozan ameliorated MG-induced cytotoxicity in SH-SY5Y cells, improved cognitive dysfunction in STZ-induced type 1 diabetic mice, increased neurogenesis, and prevented apoptotic responses in vitro and in vivo. Importantly, Tozan (2, 4, and 8 mg/kg) mediated phosphatidylinositol-3-kinase and protein kinase B cAMP-response element binding protein (PI3K/Akt-CREB) signaling by activating membrane ERß, and a high dose of Tozan (8 mg/kg) mediated CREB signaling by activating nuclear ERß in the hippocampus. Notably, Tozan did not have an anti-apoptosis and regeneration protective role in ERß gene knockdown cells. CONCLUSIONS: Our study demonstrates Tozan's contributions to and role in cognition, neurogenesis, and apoptosis in diabetes, and lays an experimental foundation for the development of new anti-diabetic cognitive impairment drugs.

Black phosphorus assisted polyionic micelles with efficient PTX loading for remotely controlled release and synergistic treatment of drug-resistant tumors.

Nanomedicines have been widely used in the effective delivery of chemotherapeutic drugs due to their advantages such as increasing the half-life of drugs, selectively targeting tumor tissues, and thus reducing systemic toxicity. However, the low drug entrapment rate and the difficulty of real-controlled release at tumor sites hinder their further clinical translations. Here we have developed biodegradable polyionic micelles (PD-M) to facilitate black phosphorus (BP) encapsulation (PD-M@BP) for improved drug loading. With the introduction of BP, PTX-loaded PD-M@BP (PD-M@BP/PTX) with sizes of 124-162 nm exhibited superior encapsulation efficiency over 94% and excellent colloidal stability. Meanwhile, PD-M well protected BP from fast degradation to show the good photothermal performance under near-infrared (NIR) irradiation, thus achieving the remotely controlled fast PTX release due to micelle core melting and dissociation, accompanied by the synergistic photothermal tumor therapy. The in vivo results demonstrated that the PD-M@BP/PTX nanosystem not only realized significant inhibition of multi-drug resistant (MDR) cervical tumors (HeLa/PTXR tumor) by remote NIR-regulation, but also reduced the potential damage of chemotherapeutic drugs to the whole body, rendering these hybrid nanosystems as great tools to treat MDR tumors synergistically.

Environmental stability and cytotoxicity of layered black phosphorus modified with Polyvinylpyrrolidone and Zeolitic Imidazolate Framework-67.

Layered black phosphorus (LBP) is regarded as a promising two-dimensional nanomaterial in various application fields. As bare LBP is unstable in humid environment, many modification methods have been developed recently. However, environmental risks of modified LBP nanomaterials are largely unknown. Herein, by sonication and in-situ surface-confined synthesis, polyvinylpyrrolidone (PVP) coated LBP (LBP/PVP), and zeolitic imidazolate framework-67 (ZIF-67) modified LBP (LBP/PVP-ZIF-67) nanomaterials were synthesized. Environmental stability and toxicity of the modified nanomaterials were compared with bare LBP. Results show that LBP/PVP-ZIF-67 exhibits excellent photothermal performance, and higher potential in electrochemical hydrogen evolution than bare LBP or LBP/PVP. Characteristic visible light absorbance at 593 nm was introduced into the nanomaterial by ZIF-67. LBP/PVP has stability in aqueous environment or cytotoxicity similar to LBP. LBP/PVP-ZIF-67 is completely stable in water within 120 h, in contrast to over 30% degradation of LBP or LBP/PVP. More than 50% of LBP in the LBP/PVP-ZIF-67 can degrade to dissolvable phosphorus in oxygenated water after 17 days, indicating the nanomaterial will not be persistent in the environment. Moreover, modification with ZIF-67 can reduce cytotoxicity of LBP. Therefore, this study develops a safe strategy to modify LBP and provides basic information for ecological risk assessment of LBP based materials.

Margination and adhesion dynamics of tumor cells in a real microvascular network.

In tumor metastasis, the margination and adhesion of tumor cells are two critical and closely related steps, which may determine the destination where the tumor cells extravasate to. We performed a direct three-dimensional simulation on the behaviors of the tumor cells in a real microvascular network, by a hybrid method of the smoothed dissipative particle dynamics and immersed boundary method (SDPD-IBM). The tumor cells are found to adhere at the microvascular bifurcations more frequently, and there is a positive correlation between the adhesion of the tumor cells and the wall-directed force from the surrounding red blood cells (RBCs). The larger the wall-directed force is, the closer the tumor cells are marginated towards the wall, and the higher the probability of adhesion behavior happen is. A relatively low or high hematocrit can help to prevent the adhesion of tumor cells, and similarly, increasing the shear rate of blood flow can serve the same purpose. These results suggest that the tumor cells may be more likely to extravasate at the microvascular bifurcations if the blood flow is slow and the hematocrit is moderate.

((E)-N-(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aß1-42-Induced Alzheimer's Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis.

Our study investigated the protective effects of ((E)-N-(4-(((2-amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) 9b, a novel glycogen synthase kinase-3ß (GSK-3ß) inhibitor, on the learning and memory function of rats with amyloid-ß1-42 (Aß1-42)-induced Alzheimer's disease (AD) and explored the possible mechanisms. Sixty male Sprague-Dawley (SD) rats were randomly divided into five groups: the control, Aß, donepezil, and low-dose and high-dose 9b groups. The rats in the Aß, donepezil, and two 9b intervention groups received a single microinjection of 10 µg of Aß1-42 into the hippocampus followed by intragastric administration of 0.5% sodium carboxymethyl cellulose (CMC-Na), 12 (mg/kg)/d donepezil hydrochloride and 6 or 18 (mg/kg)/d compound 9b for 28 days, while the rats in the control group were treated with the vehicles. Learning and memory impairment were attenuated, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), acetylcholinesterase (AChE), and adenosine triphosphatase (ATPase) in the brain tissue were significantly increased (p < 0.05), and the concentrations of Aß1-42, phospho-tau (p-tau), and malondialdehyde (MDA) in the brain tissue were significantly decreased (p < 0.05) in the compound 9b group compared to the Aß group. In addition, compound 9b regulated the imbalance in the concentrations of neurotransmitters and alleviated severe damage and apoptosis in the brains of the rats exposed to Aß1-42. The novel GSK-3ß inhibitor 9b could improve learning and memory dysfunction caused by Aß1-42 through its antioxidant and antiapoptotic effects.

The lipoprotein NlpD in Cronobacter sakazakii responds to acid stress and regulates macrophage resistance and virulence by maintaining membrane integrity.

Cronobacter sakazakii, an emerging opportunistic pathogen, is implicated in severe foodborne outbreak infections in premature and full-term infants. Generally, acid tolerance is vital for the pathogenesis of foodborne pathogens; however, its role in C. sakazakii virulence remains largely unknown. To screen out acid-tolerance determinants from transposon mutants, anovel counterselection method using gentamicin and acid was developed. Using the counterselection method and growth assay, we screened several acid-sensitive mutants and found that nlpD encodes an acid-resistance factor in C. sakazakii.  Compared to the wild-type strain, the nlpD mutant exhibited attenuated virulence in a rat model. Using macrophage THP-1 cells and a pH probe, we verified that nlpD enables bacteria to resist macrophages by resisting acidification. Finally, we confirmed that nlpD maintains C. sakazakii membrane integrity in acid using propidium iodide permeabilization assays via flow cytometry. Our results confirm that nlpD is a novel virulence factor that permits C. sakazakii to survive under acid stress conditions. Considering that NlpD is a conserved lipoprotein located in the bacterial outer membrane, NlpD could be used as a target for drug development.