Bioactive solanidane steroidal alkaloids from Solanum lyratum.

Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A-F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.

N-acetylcysteine protects against neurodevelopmental injuries induced by methylmercury exposure during pregnancy and lactation.

As an extremely dangerous environmental contaminant, methylmercury (MeHg) results in detrimental health effects in human brain nervous system, one of its main targets. However, as a developmental toxicant, the brain of offspring is vulnerable to MeHg during pregnancy and lactation exposure. Unfortunately, mechanisms of neurodevelopmental injuries induced by MeHg have not been fully elucidated. N-acetylcysteine (NAC) has been used for several decades as an antioxidant to antagonize oxidative stress. However, the molecular mechanisms of NAC alleviating MeHg-induced neurodevelopmental toxicity are not clear. Here, for evaluation of the dose-dependent effects of MeHg exposure on neurodevelopmental injuries of offspring, and the possible protective effects of NAC, the pregnant female mice were exposed to MeHg (4, 8, 12 mg/L, respectively) and NAC (50, 100, 150 mg/kg, respectively) from gestational day 1 (GD1) to postnatal day 21 (PND21). Our results indicated that administering MeHg caused behavioral impairment and neuronal injuries in the cerebral cortex of newborn mice. MeHg dose-dependently caused reactive oxygen species (ROS) overproduction and oxidative stress aggravation, together with expression of Nrf2, HO-1, Notch1, and p21 up-regulation, and CDK2 inhibition. NAC treatment dose-dependently antagonized MeHg-induced oxidative stress that may contribute to alleviating neurobehavioral and neurodevelopmental impairments. These results give insight into that NAC can protect against MeHg-induced neurodevelopmental toxicity by its antioxidation capacity.

Emodin suppresses adipogenesis of bone marrow derived mesenchymal stem cells from aplastic anemia via increasing TRIB3 expression.

BACKGROUND: Increasing evidence indicate that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) could contribute to the adiposity alteration in marrow microenvironment of aplastic anemia (AA). Identifying small molecule drugs with role in inhibiting adipogenesis of BM-MSCs may represent a novel direction in AA therapy by improving BM-MSCs mediated marrow microenvironment. METHODS: For the purpose, we isolated AA BM-MSCs through whole bone marrow cell culture, evaluated a series of small molecule drugs using the in vitro adipogenic differentiation model of BM-MSCs, and finally focused on emodin, a natural anthraquinone derivative. Subsequently, we systematically investigated the molecular mechanism of emodin in attenuating adipogenic process by means of microarray profiling, bioinformatics analysis and lentivirus-mediated functional studies and rescue assay. RESULTS: We found that emodin presented significantly suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Further mechanistic investigation revealed that emodin could increase the expression of Tribbles homolog 3 (TRIB3) which exhibited remarkably decreased expression in AA BM-MSCs compared with the normal counterparts and was subsequently demonstrated as a negative regulator in adipogenesis of AA BM-MSCs. Besides, TRIB3 depletion alleviated the suppressive effect of emodin on the adipogenic differentiation of AA BM-MSCs. CONCLUSION: Our findings propose that emodin mediated TRIB3 up-regulation alleviates the adipogenic capacity of AA BM-MSCs, and emodin could serve as a potential therapeutic regimen for AA therapy.

Apicidin confers promising therapeutic effect on acute myeloid leukemia cells via increasing QPCT expression.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by abnormal cell proliferation, apoptosis repression and myeloid differentiation blockade of hematopoietic stem/progenitor cells. Developing and identifying novel therapeutic agents to reverse the pathological processes of AML are of great significance. Here in this study, we found that a fungus-derived histone deacetylase inhibitor, Apicidin, presents promising therapeutic effect on AML by inhibiting cell proliferation, facilitating apoptosis and inducing myeloid differentiation of AML cells. Mechanistic investigation revealed that QPCT is identified as a potential downstream target of Apicidin, which exhibits significantly decreased expression in AML samples compared with the normal controls and is remarkably up-regulated in AML cells upon Apicidin management. Functional study and rescue assay demonstrated that QPCT depletion further promotes cell proliferation, inhibits apoptosis and impairs myeloid differentiation of AML cells, alleviating the anti-leukemic effect of Apicidin on AML. Our findings not only provide novel therapeutic target for AML, but also lay theoretical and experimental foundation for the clinical application of Apicidin in AML patients.

Chidamide suppresses adipogenic differentiation of bone marrow derived mesenchymal stem cells via increasing REEP2 expression.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation at the expense of osteogenesis has been implicated in obesity, diabetes, and age-related osteoporosis as well as various hematopoietic disorders. Defining small molecules with role in rectifying the adipo-osteogenic differentiation imbalance is of great significance. Here, we unexpectedly found that Chidamide, a selective histone deacetylases inhibitor, exhibited remarkably suppressive effect on the in vitro induced adipogenic differentiation of BM-MSCs. Multifaceted alterations in the spectrum of gene expression were observed in Chidamide-managed BM-MSCs during adipogenic induction. Finally, we focused on REEP2, which presented decreased expression in BM-MSCs-mediated adipogenesis and was restored by Chidamide treatment. REEP2 was subsequently demonstrated as a negative regulator of adipogenic differentiation of BM-MSCs and mediated the suppressive effect of Chidamide on adipocyte development. Our findings provide the theoretical and experimental foundation for the clinical application of Chidamide for disorders associated with excessive marrow adipocytes.

Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11.

Programed cell death plays a key role in promoting human development and maintaining homeostasis. Ferroptosis is a recently identified pattern of programmed cell death that is closely associated with the onset and progression of neurodegenerative diseases. Ferroptosis is mainly caused by the intracellular accumulation of iron-dependent lipid peroxides. The cysteine/glutamate antibody Solute carrier family 7 member 11 (SLC7A11, also known as xCT) functions to import cysteine for glutathione biosynthesis and antioxidant defense. SLC7A11 has a significant impact on ferroptosis, and inhibition of SLC7A11 expression promotes ferroptosis. Moreover, SLC7A11 is also closely associated with neurodegenerative diseases. In this paper, we summarize the relationship between ferroptosis and neurodegenerative diseases and the role of SLC7A11 during this process. The various regulatory mechanisms of SLC7A11 are also discussed. In conclusion, we are looking forward to a theoretical basis for further understanding the occurrence and development of ferroptosis in SLC7A11 and neurodegenerative diseases, and to seek new clues for the treatment of neurodegenerative diseases.

Simple Fabrication of Polyvinylidene Fluoride/Graphene Composite Membrane with Good Lipophilicity for Oil Treatment.

Graphene (GE) is an emerging type of two-dimensional functional nanoparticle with a tunable passageway for oil molecules. Herein, polyvinylidene fluoride (PVDF)/GE composite membranes with controllable pore structure were fabricated with a simple non-solvent-induced phase separation method. The change of crystallinity and crystal structure (α, ß, γ, etc.) generated is due to the addition of GE, which benefits the design of a suitable pore structure for oil channels. Meanwhile, the hydrophobicity and thermal stability of the composite membrane were obviously enhanced. With 3 wt % GE, the contact angle was 124.6°, which was increased greatly compared to that of the GE-0 sample. Moreover, the rate of the phase transition process was affected by the concentration of casting solution, temperature, and composition of the coagulation bath. For example, the composite membrane showed better oil-water separation properties when the coagulation bath was dioctyl phthalate. In particular, the oil flux and separation efficiencies were up to 2484.08 L/m2·h and 99.24%, respectively. Consequently, PVDF/GE composite membranes with excellent lipophilicity may have good prospects for oily wastewater treatment.

Combination of low-dose rituximab, bortezomib and dexamethasone for the treatment of autoimmune hemolytic anemia.

ABSTRACT: Autoimmune hemolytic anemia (AIHA) therapy may be associated with severe complications such as diabetes, hypertension, obesity, osteoporosis, peptic ulcers, infection, and some other diseases. To reduce those effects, we used low-dose rituximab, bortezomib and dexamethasone (LowR-BD regimen) to treat AIHA. The purpose of this study was to evaluate the efficacy and safety of this regimen.Seven patients with warm AIHA (wAIHA) admitted from March 2020 to October 2020 were treated with LowR-BD regimen: Rituximab 100 mg by intravenous infusion on day 1 combined with bortezomib 1.3 mg/m2 by subcutaneous injection on day 2 plus dexamethasone 20 mg by intravenous infusion on days 2, 3. Clinical efficacy and safety were assessed at the regular reexamination of relevant indicators and follow-up.After 4 cycles of the LowR-BD regimen, the overall response rate (ORR) was 85.71% with a complete response (CR) of 28.57% and a partial response (PR) of 57.14%. After a median follow-up of 12 (range 7-13) months, 5 patients achieved CR and 2 patients had PR status, including 1 patient who did not respond to LowR-BD treatment and reached CR after using methylprednisolone combined with cyclophosphamide. One patient relapsed and achieved PR after retreatment of 2 cycles LowR-BD regimen. The patients tolerated the treatment well and did not complain of apparently adverse reactions except a patient with Sjogren's syndrome and bronchiectasis who developed a severe infection during treatment.Low-dose rituximab combined with bortezomib and dexamethasone is effective and relatively safe in patients with wAIHA.

Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR-874-3P/ATG16L1 axis.

Autophagy is an important mechanism involved in the regulation of acute myeloid leukemia (AML) chemoresistance. The long noncoding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR) exhibits oncogenic activity in several types of human cancers, including AML, but it remains unclear whether it regulates autophagy and chemoresistance in AML. We report here that cytarabine (Ara-C) treatment elevates DANCR expression in human AML cells. In addition, DANCR overexpression confers and its knockdown diminishes Ara-C resistance in human AML cells, suggesting that DANCR positively regulates AML chemoresistance to Ara-C. Moreover, DANCR promotes autophagy in Ara-C-treated human AML cells and acts as a sponge to decrease miR-20a-5p expression, thereby upregulating the expression of ATG16L1, a critical component of the autophagy machinery. Importantly, ATG16L1 silencing abrogates DANCR-promoted autophagy and markedly restores DANCR-conferred Ara-C resistance, suggesting that DANCR promotes MIR-874-3P/ATG16L1 axis-regulated autophagy to confer Ara-C resistance in human AML cells. Together, this study identifies DANCR as a positive regulator of Ara-C resistance in human AML cells, suggesting this lncRNA as a potential target for overcoming Ara-C resistance in AML chemotherapy.

A Rare Case of Adult Aortopulmonary Window Combined with Anomalous Origin of the Right Pulmonary Artery from the Aorta Leading to Eisenmenger Syndrome.

Aortopulmonary window is a rare congenital heart disease that can increase pulmonary vascular resistance, exacerbate left-to-right shunt and lead to heart failure and respiratory tract infections. Most patients die during childhood. We report a 53-year-old male patient with a large aortopulmonary window combined with anomalous origin of the right pulmonary artery from the aorta, with Eisenmenger syndrome and without surgery.

HMGB1: an important regulator of myeloid differentiation and acute myeloid leukemia as well as a promising therapeutic target.

High mobility group box 1 (HMGB1) is a non-histone nuclear protein which has been intensively studied in various physiological and pathological processes including leukemia. Here in this study, we further demonstrated that HMGB1 presents higher expression in the bone marrow mononuclear cells of acute myeloid leukemia (AML) patients compared with the normal controls and contributes to the AML pathogenesis and progression by inhibiting apoptosis, facilitating proliferation, and inducing myeloid differentiation blockade of AML cells. Mechanistic investigation revealed that transforming growth factor beta-induced (TGFBI) acts as a potential downstream target of HMGB1 and lentivirus-mediated knockdown of TGFBI expression impaired phorbol-12-myristate-13-acetate (PMA) and all-trans retinoic acid (ATRA)-induced myeloid differentiation of AML cell lines. On the other hand, chidamide, an orally histone deacetylase inhibitor, decreases HMGB1 expression significantly in AML cells with concomitant upregulation of TGFBI expression, and confers therapeutic effect on AML by inducing cell differentiation, apoptosis and inhibiting cell proliferation. In conclusion, our findings provide additional insights that HMGB1 is a promising therapeutic target of AML, and also present experimental evidence for the clinical application of chidamide as a novel agent in AML therapy by downregulating HMGB1 expression. KEY MESSAGES: HMGB1 induces cell proliferation and myeloid differentiation blockade and inhibits apoptosis of AML cells. TGFBI acts as a potential target of HMGB1. Chidamide, a selective HDAC inhibitor, confers promising therapeutic effect for AML via downregulating HMGB1 expression.

PPAR Gamma-Regulated MicroRNA 199a-5p Underlies Bone Marrow Adiposity in Aplastic Anemia.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation has been implicated in the fatty bone marrow and defective hematopoiesis of aplastic anemia (AA). However, the underlying molecular mechanism remains to be investigated. In this study, we found that microRNA 199a-5p (miR-199a-5p) exhibits significantly higher expression in AA BM-MSCs compared with the normal control and is demonstrated to facilitate adipogenic differentiation of BM-MSCs through lentivirus-mediated miR-199a overexpression. Mechanistic investigation reveals that miR-199a-5p could be regulated by PPAR gamma (PPARγ) in a transcription-independent manner and regulates adipogenic differentiation by targeting the expression of transforming growth factor beta induced (TGFBI), which is subsequently validated as a negative regulator of adipogenesis. Besides, the positive correlation between PPARγ and miR-199a-5p expression as well as the inverse relationship between miR-199a-5p and TGFBI expression in normal and AA BM-MSCs was observed. Altogether, our work demonstrates that PPARγ-regulated miR-199a-5p promotes adipogenesis of BM-MSCs by inhibiting TGFBI expression, which might be a novel mechanism underlying the bone marrow adiposity in AA, and provides promising therapeutic targets for AA treatment.

Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis.

Aplastic anaemia (AA) is a life-threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM-derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM-MSCs through lentivirus-mediated ZFP36L1 knock-down and overexpression assay. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3'-untranslated region bears adenine-uridine-rich elements was verified as a direct downstream target of ZFP36L1, and knock-down of PPARGC1B impaired the adipogenesis of AA BM-MSCs. Collectively, our work demonstrated that ZFP36L1-mediated post-transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM-MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.

Induction of Human Adipose-Derived Mesenchymal Stem Cells into Germ Lineage Using Retinoic Acid.

Accumulating evidence indicates that mesenchymal stem cells (MSCs) have been widely used in tissue engineering and regenerative medicine due to their multilineage differentiation potentials. Recent studies show that germ-like cells can also be derived from stem cells, such as human umbilical cord MSCs and human bone marrow MSCs in vitro. However, whether human adipose-derived MSCs (hAD-MSCs) can be induced into germ-like cells has never been reported. In this study, we isolated hAD-MSCs and confirmed that their characteristics were in accordance with that of MSCs established before. Germ cell lineage differentiation was performed by 10 µM retinoic acid (RA) treatment for 21 days. RA induction led to slender spindles and tadpole-like changes of cell morphology, and the expression of germ cell-specific markers (Oct4, Piwil2, Itgb1, SSEA-1, and Stra8) presented significant upregulation in the RA treatment group according to the polymerase chain reaction and immunofluorescence results. We first demonstrated that hAD-MSCs can differentiate into germ-like cells in vitro, which will provide theoretical and experimental basis for the clinical application of hAD-MSCs in the treatment for infertility.

MnO2/MWCNTs Nanocomposites as Highly Efficient Catalyst for Indoor Formaldehyde Removal.

Formaldehyde (HCHO) is a main indoor pollutant that is capable of harming the health of residents. Here, we fabricated a novel MnO2/MWCNTs nanocomposite film for non-photocatalytic, room temperature removal of indoor HCHO. MnO2/MWCNTs nanocomposites with various amounts of a-MWCNTs, which were fabricated by a co-precipitation method, were assembled into composite films using vacuum filtration and solvent evaporation. Structural analysis confirms that MnO2 nanoparticles are homogeneously distributed on a-MWCNTs. The acetyl acetone method was used to characterize the catalytic activity of MnO2/MWCNTs nanocomposites. The results show that MnO2/MWCNTs composites with 30 wt% a-MWCNTs present the highest catalytic activity due to a highly active surface. The catalytic activity of MnO2/MWCNTs composite film was characterized in a glovebox at room temperature and showed good removal of HCHO. This study suggests that supporting catalysts on MWCNTs and then assembling them into fibers (1D), films (2D) or aerogels (3D) is a worthwhile approach to promote catalytic activity and prevent dust pollution.

Anemia and thrombocytopenia as initial symptoms of occult breast cancer with bone marrow metastasis: A case report.

RATIONALE: Occult breast cancer (OBC) is a rare type of breast cancer without any symptoms in the breast and is often presented with initial symptoms of axillary lymph node metastasis or other metastases. The low incidence rates of OBC make it a great challenge to diagnose and cure. PATIENT CONCERNS: Our case was a 58-year-old female affected by dizziness and fatigue for nearly a month. Blood tests revealed anemia and thrombocytopenia, and pathological results of a bone marrow biopsy confirmed the metastatic carcinoma. DIAGNOSES: It was diagnosed as an OBC based on the positive immunohistochemical staining of cytokeratin (CK) and gross cystic disease fluid protein-15 (GCDFP-15). INTERVENTIONS: Doctor advised her to check whether the bone metastases existed in order to choose an appropriate treatment. It is highly regrettable that the patient gave up all treatments and left the hospital. OUTCOMES: Recently, we conducted a telephone follow-up and received that the patient only took tramadol and other painkilling drugs to alleviate the pain caused by cancer. LESSONS: The current case inferred that symptoms of anemia and thrombocytopenia should not be ignored for the diagnosis of OBC, and bone marrow biopsy is useful in reducing the rates of misdiagnosis and missed diagnosis of OBC.

Immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells.

Bone marrow derived mesenchymal stem cells (MSCs) play a critical role in immune modulation. However, immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells (UC-MSCs) remains unclear. In this study, UC-MSCs were separated from whole umbilical cord using a single enzyme digestion. UC-MSCs (CD73+, CD90+, CD105+, and CD34-, CD45-, HLA-DR-) were differentiated into adipocytes, osteocytes and chondrocytes in vitro under specific stimulatory environments. UC-MSCs suppressed umbilical cord blood lymphocyte proliferation stimulated by mitogen, and ELISA showed that the secretion of INF-γ was downregulated, and the secretion of IL-4 was upregulated, with CD8+ T cells markedly decreased and CD4+ T cells changed lightly. Moreover, the infusion of UC-MSCs in recipient mice transplanted with donor bone marrow cells ameliorated acute graft-versus host disease (aGVHD) and extended survival. In conclusion, UC-MSCs might negatively modulate immunoreactions, and have application potential in the treatment of aGVHD caused by allogeneic stem cells transplantation.

miR-301b~miR-130b-PPARγ axis underlies the adipogenic capacity of mesenchymal stem cells with different tissue origins.

Mesenchymal stem cells (MSCs) have been widely used in regenerative medicine and cellular therapy due to their multi-lineage differentiation potential and immunomodulatory function. The applicability of MSCs also depends on their cellular sources and in vivo functions. Here in this study, we systematically compared the morphologic characteristics, immunophenotypes and the adipogenic differentiation of MSCs derived from umbilical cord (UC), adipose tissue (Ad) and bone marrow (BM). We found that the three tissues-derived MSCs displayed decreased adipogenic capacity in the order: Ad-MSC > BM-MSC > UC-MSC, and no morphologic and immunophenotypic differences were observed. Mechanistic investigation revealed a miR-301b~miR-130b-PPARγ axis, whose expression pattern in UC-MSC, Ad-MSC and BM-MSC significantly correlates with their adipogenic capacity. Our results come up with a potential mechanism to elucidate the differential adipogenesis of Ad-MSC, BM-MSC and UC-MSC, which would provide instructional advice for which source of MSCs to choose according to a certain clinical purpose. Furthermore, the miR-301b~miR-130b-PPARγ axis may also be used as a potential therapeutic target for the disorders associated with MSCs-mediated abnormal adipogenesis.