Co-existence of Langerhans cell histiocytosis and reticulohistiocytosis with initial presentation of skull lesions: A case report.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder resulting from dysregulated clonal proliferation of Langerhans cells. Reticulohistiocytosis (RH) is another rare histiocytosis caused by the proliferation of histiocytes other than Langerhans cells. Co-existence of LCH and RH in different organs and in the same skin area has not been reported. We present the case of a 20-year-old woman who initially had co-existing bone LCH and cutaneous RH. After 1 year of chemotherapy with cytarabine, bone LCH significantly improved but cutaneous LCH developed in the same area where cutaneous RH was, resulting in hybrid LCH and RH of the skin. This unique history provides some evidence to support the theory that LCH and RH originate from the same stem cells and subsequently develop into hybrid LCH and RH of the skin in a cytokine environment influenced by chemotherapy. Repeat skin biopsies may be considered for adjusting treatment regimens in LCH patients whenever pre-existing skin lesions progress.

The role of HGF-MET pathway and CCDC66 cirRNA expression in EGFR resistance and epithelial-to-mesenchymal transition of lung adenocarcinoma cells.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has, in recent years, emerged as an important tumor cell behavior associated with high metastatic potential and drug resistance. Interestingly, protein SUMOylation and hepatocyte growth factor could respectively reduce the effect of small molecule inhibitors on tyrosine kinase activity of mutated epidermal growth factor receptor of lung adenocarcinomas (LADC). The actual mechanism is yet to be resolved. METHODS: Immunohistochemistry was used to stain proteins in LADC specimens. Protein expression was confirmed by Western blotting. In vitro, expression of proteins was determined by Western blotting and immunocytochemistry. Levels of circular RNA were determined by reverse transcription-polymerase chain reaction. RESULTS: SAE2 and cirRNA CCDC66 were highly expressed in LADC. Expression of SAE2 was mainly regulated by EGFR; however, expression of cirRNA CCDC66 was positively regulated by FAK and c-Met but negatively modulated by nAchR7α. EGFR-resistant H1975 also highly expressed cirRNA CCDC66. Immediate response of hypoxia increased phosphorylated c-Met, SAE2, and epithelial-to-mesenchymal transition. Either activation of FAK or silencing of nAchR7α increased cirRNA CCDC66. CONCLUSIONS: HGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase EMT and drug resistance of LADC cells. Multimodality drugs concurrently aiming at these targets would probably provide more benefits for cancer patients.

IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy.

Background: Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods: The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis. Results: CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-ß1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-ß1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-ß1, but increased the viability of cultured podocytes. Conclusions: IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.

Secreted gelsolin desensitizes and induces apoptosis of infiltrated lymphocytes in prostate cancer.

Loss of immunosurveillance is a major cause of cancer progression. Here, we demonstrate that gelsolin, a constituent of ejaculate, induces apoptosis of activated lymphocytes in prostate cancer. Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. In vitro, secreted gelsolin inactivated CD4+ T cells by binding to CD37, and induced apoptosis of activated CD8+ T lymphocytes by binding to Fas ligand during cell contact dependent on major histocompatibility complex I. Moreover, secreted gelsolin bound to sortilin, which in turn bound to Wiskott-Aldrich syndrome protein family member 3, thereby enhancing the endocytosis and intracellular transport of essential lipids needed to facilitate tumor growth and expansion. Under normal conditions, gelsolin is a seemingly harmless protein that prevents immune responses in female recipients. In disease states, however, this protein can inhibit immunosurveillance and promote cancer progression.

Immunohistochemical biomarkers and volumetric parameters for predicting radiotherapy-based outcomes in patients with p16-negative pharyngeal cancer.

BACKGROUND: This study determined the prognostic effects of immunohistochemical biomarkers and volumetric parameters predicting radiotherapy-based treatment in patients with p16-negative squamous cell carcinoma of the oropharynx or hypopharynx. RESULTS: VEGF immunoreactivity > 2 and GLUT1 overexpression were prognostic factors for lower cause-specific survival. Moreover, both factors were associated with lower disease-free survival. The predictors of lower primary relapse-free survival were VEGF immunoreactivity > 2 and CT-based gross tumor volume > 16 mL. MATERIALS AND METHODS: Immunohistochemical biomarkers in pretreatment biopsy specimens from 60 patients with p16-negative cancer were analyzed using tissue microarrays. Computed tomography (CT)-based and biological tumor volumes were retrieved through fluorodeoxyglucose positron emission tomography-CT. Correlations of cause-specific, disease-free, and primary relapse-free survival with volumetric parameters and the immunohistochemical biomarker score were investigated. CONCLUSIONS: For patients with p16-negative pharyngeal cancer receiving radiotherapy, treatment outcomes can be stratified by VEGF and GLUT1 expression and CT-based gross tumor volume.

The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3+IL-17+ T cells.

BACKGROUND: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4+ forkhead box P3 (FOXP3)+ T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3+IL-17+ T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear. METHODS: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days. RESULTS: Juxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4+FOXP3+ T cells increased progressively, along with the number of FOXP3+interleukin (IL)-17+ T cells, after 14 days, and their numbers then progressively decreased with increasing CD4+IL-17+ T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4+FOXP3+IL-17+ T cells in splenic single-cell suspensions. FOXP3+IL-17+ T cells expressed TGF-ß1 both in vitro and in vivo, and TGF-ß1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-ß1-producing cells. CONCLUSIONS: TSA treatment decreased JG hyperplasia, the percentage of FOXP3+IL-17+ cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.

Protective effect of Co-enzyme Q10 On doxorubicin-induced cardiomyopathy of rat hearts.

Q10 is a powerful antioxidant often used in medical nutritional supplements for cancer treatment. This study determined whether Q10 could effectively prevent cardio-toxicity caused by doxorubicin treatment. Four week old SD rats were segregated into groups namely control, doxorubicin group (challenged with doxorubicin), Dox + Q10 group (with doxorubicin challenge and oral Q10 treatment), and Q10 group (with oral Q10 treatment). Doxorubicin groups received IP doxorubicin (2.5 mg/kg) every 3 days and Q10 groups received Q10 (10 mg/kg) every day. Three weeks of doxorubicin challenge caused significant reduction in heart weight, disarray in cardiomyocyte arrangement, elevation of collagen accumulation, enhancement of fibrosis and cell death associated proteins, and inhibition of survival proteins. However, Q10 effectively protected cardiomyocytes and ameliorated fibrosis and cell death induced by doxorubicin. Q10 is, therefore, evidently a potential drug to prevent heart damage caused by doxorubicin. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 679-689, 2017.

p-Cresol mediates autophagic cell death in renal proximal tubular cells.

Higher serum level of p-cresol (PC) in chronic kidney disease (CKD) patients has been linked with CKD progression. The toxic effect of PC on diverse cells has been reported by prior studies, except for renal tubular cells. Both autophagy and apoptosis contribute to renal tubular cell death, yet evidence of its response to PC is limited and their crosstalk is still unclear. Autophagy is an important cellular process involved in toxin-induced cell death. Renal tubular cell death in tubular injury is thought to be one of the key events causing the progression of CKD. Thus, we treated rat (NRK-52E) and human (HRPTEC) renal proximal tubular cells (RPTC) with PC and found the cell proliferation was significantly decreased. Cell apoptosis was significantly increased and accompanied with the activation of autophagy as evidenced by increases in LC3-II, beclin 1 and Atg 4. We also found an increase of p62 by c-Jun activation. p62 accumulation could mediate the activation of caspase 8-dependent cell apoptosis. Conversely, knockdown of p62 by siRNA of p62 had the opposite effect by arresting LC3-II accumulation and promoting increasing cell viability. We conclude that PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. PC can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases.

Ligand-independent androgen receptors promote ovarian teratocarcinoma cell growth by stimulating self-renewal of cancer stem/progenitor cells.

BACKGROUND: Ovarian teratocarcinoma (OVTC) arises from germ cells and contains a high percentage of cancer stem/progenitor cells (CSPCs), which promote cancer development through their ability to self-renew. Androgen and androgen receptor (androgen/AR) signaling has been reported to participate in cancer stemness in some types of cancer; however, this phenomenon has never been studied in OVTC. METHODS: Ovarian teratocarcinoma cell line PA1 was manipulated to overexpress or knockdown AR by lentiviral deliver system. After analyzing of AR expression in PA1 cells, cell growth assay was assessed at every given time point. In order to determine ligand effect on AR actions, luciferase assay was performed to evaluate endogenous and exogenous AR function in PA1 cells. CD133 stem cell marker antibody was used to identify CSPCs in PA1 cells, and AR expression level in enriched CSPCs was determined. To assess AR effects on CD133+ population progression, stem cell functional assays (side population, sphere formation assay, CD133 expression) were used to analyze role of AR in PA1 CSPCs. In tissue specimen, immunohistochemistry staining was used to carry out AR and CD133 staining in normal and tumor tissue. RESULTS: We examined androgen/AR signaling in OVTC PA1 cells, a CSPCs-rich cell line, and found that AR, but not androgen, promoted cell growth. We also examined the effects of AR on CSPCs characteristics and found that AR expression was more abundant in CD133+ cells, a well-defined ovarian cancer stem/progenitor marker, than in CD133- populations. Moreover, results of the sphere formation assay revealed that AR expression was required to maintain CSPCs populations. Interestingly, this AR-governed self-renewal capacity of CSPCs was only observed in CD133+ cells. In addition, we found that AR-mediated CSPCs enrichment was accompanied by down-regulation of p53 and p16. Finally, co-expression of AR and CD133 was more abundant in OVTC lesions than in normal ovarian tissue. CONCLUSION: The results of this study suggest that AR itself might play a ligand-independent role in the development of OVTC.

CD8⁺ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria.

UNLABELLED: We focus on the role of CD8(+) Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4(+)CD25(+)FoxP3(+) and CD8(+)CD25(+)Foxp3(+) Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8(+)FoxP3(+) Treg from PBMCs. IVMP-treated CD8(+)CD25(+) Treg cells directly suppressed CD4(+) T proliferation and induced CD4(+)CD45RO(+) apoptosis. Histologically, CD4(+)FoxP3(+) as well as CD8(+)FoxP3(+) Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8(+)FoxP3(+) Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3(+) Treg cells in PBMNCs (r = -0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4(+)FoxP3(+) Treg cells. CD8(+)Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8(+)CD25(+)Treg-induced CD4(+)CD45RO(+) apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8(+)FoxP3(+) Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN. TRIAL REGISTRATION: DMR97-IRB-259.

Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer.

Our previous study showed that patients with advanced stages of non-small cell lung cancer (NSCLC) were frequently detected with upregulation of hepatocyte growth factor (HGF). In vitro, HGF reduced expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in NSCLC cells. The effect of HGF was via HGF receptor (c-MET) and the downstream effector, focal adhesion kinase (FAK). In this study, we determined the prognostic value of AIF in NSCLC patients. AIF expression was determined by immunohistochemistry and immunoblotting. Our data show that AIF expression was associated with better prognosis. Expression of AIF inversely correlated with that of positive NSCLC markers, e.g., dihydrodiol dehydrogenase (DDH), c-MET, short oncostatin M receptor (OSMRs), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis and poor prognosis. Noteworthy, silence of HER2/neu gene expression increases AIF level and drug sensitivity. Addition of HGF inhibits AIF expression in HER2/neu-silenced cells. These results suggested that both HGF and HER2/neu affect drug resistance by regulating AIF expression in NSCLC.

Non-genomic estrogen/estrogen receptor α promotes cellular malignancy of immature ovarian teratoma in vitro.

Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ERα and ß) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERα- and ß-specific agonists, respectively), as well as ERα- or ERß-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial-mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ERα and ERß, we found that ERα promoted cell migration and invasion. We also found that E2/ERα signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERα activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERα signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERα signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERα, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERα was co-expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors.

Celecoxib plus chemoradiotherapy for locally advanced rectal cancer: a phase II TCOG study.

BACKGROUND: To report the results of a phase II trial combining celecoxib and preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. PATIENTS AND METHODS: Patients with clinical stage II or III rectal cancer were treated with radiotherapy of 44 Gy in 22 fractions. Concurrent chemotherapy consisted of oral tegafur-uracil and folinate on days 1-30 and 38-65. Celecoxib (400 mg/day) given from days 1 to 65. Surgery was done on day 70. The expression of cyclooxygenase 2 (COX-2) in tumor tissues was evaluated microscopically as a prognostic factor. RESULTS: From 2008 to 2011, 53 patients completed CRT+ celecoxib therapy and 47 received radical surgery. Grade 3 diarrhea developed in 5 (9%). Grade 4 anemia was seen in 2 (4%). Pathological complete response (pCR) was seen in 6 (13%). T or N downstaging found in 38 (81%). Sphincter preservation was achieved in 77% of low-positioned tumors. Patients with tumors expressing high-level COX-2 after CRT + celecoxib treatment had inferior pelvic control (P = 0.01), disease-free survival (P = 0.04), and overall survival (P = 0.03) than those with low-level expression. CONCLUSIONS: Celecoxib can be safely combined with preoperative CRT for rectal cancer. More intensified adjuvant therapy may be considered for tumors expressing high-level COX-2 after CRT and surgery.

Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma.

BACKGROUND: ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to investigate the significance of ATAD3A in glioblastoma multiforme (GBM). METHODS: Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair-associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting. RESULTS: Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment. CONCLUSION: Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.

Which FDG/PET parameters of the primary tumors in colon or sigmoid cancer provide the best correlation with the pathological findings?

BACKGROUND: To compare (18)F-fluoro-2-deoxdeoxyglucose (FDG) positron emission tomography (PET) related parameters of primary colon or sigmoid cancer (CSC) with pathological findings. METHODS: Seventy-seven CSC patients who have undergone preoperative PET computed tomograms (PET/CT) are included in this study. Maximum PET-based tumor length (TL) and tumor width (TW) are determined using several auto-segmentation methods, and various thresholds of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are measured. The PET-based TL and TW are compared with maximum pathological length and width on the pathological specimen. RESULTS: Using a 30% threshold level for maximum uptake of TL (TL30%) and TW (TW30%) yield results that provide an optimal match with maximum pathological length (R=0.81, p<0.001) and width (R=0.70, p<0.001). TW30% was an independent factor for predicting pathological T3 or T4 stages (OR=1.26, 95% CI=1.07-1.47, p=0.01). The receiver-operating characteristic curves show MTV at a fixed threshold of 40% maximum uptake (MTV40%), and TW30% achieved better correlation with the advanced pathological T stage. No associations with positive N stage were observed. CONCLUSION: Pretreatment PET/CT is a useful tool for predicting the final pathological findings for CSC patients requiring surgical procedures.

Hyperglycemia: GDNF-EGR1 pathway target renal epithelial cell migration and apoptosis in diabetic renal embryopathy.

Maternal hyperglycemia can inhibit morphogenesis of ureteric bud branching, Glial cell line-derived neurotrophilic factor (GDNF) is a key regulator of the initiation of ureteric branching. Early growth response gene-1 (EGR-1) is an immediate early gene. Preliminary study found EGR-1 persistently expressed with GDNF in hyperglycemic environment. To evaluate the potential relationship of hyperglycemia-GDNF-EGR-1 pathway, in vitro human renal proximal tubular epithelial (HRPTE) cells as target and in vivo streptozotocin-induced mice model were used. Our in vivo microarray, real time-PCR and confocal morphological observation confirmed apoptosis in hyperglycemia-induced fetal nephropathy via activation of the GDNF/MAPK/EGR-1 pathway at E12-E15. Detachment between ureteric branch and metanephrons, coupled with decreasing number and collapse of nephrons on Day 1 newborn mice indicate hyperglycemic environment suppress ureteric bud to invade metanephric rudiment. In vitro evidence proved that high glucose suppressed HRPTE cell migration and enhanced GDNF-EGR-1 pathway, inducing HRPTE cell apoptosis. Knockdown of EGR-1 by siRNA negated hyperglycemic suppressed GDNF-induced HRPTE cells. EGR-1 siRNA also reduced GDNF/EGR-1-induced cRaf/MEK/ERK phosphorylation by 80%. Our findings reveal a novel mechanism of GDNF/MAPK/EGR-1 activation playing a critical role in HRPTE cell migration, apoptosis and fetal hyperglycemic nephropathy.

Wiskott-Aldrich syndrome with IgA nephropathy: a case report and literature review.

The pathogenesis of renal involvement in Wiskott-Aldrich syndrome (WAS) is unclear and renal outcome is generally poor in such situations. Here we present the case of an 8-year-old boy with WAS who developed hematuria, proteinuria, and declining renal function that did not improve with the combined use of immunosuppressive agents and angiotensin-converting-enzyme inhibitor. Renal pathology revealed IgA nephropathy (IgAN). The patient underwent splenectomy for refractory thrombocytopenia. The proteinuria remitted and renal function improved after splenectomy, long-term antibiotic prophylaxis, and tapering of immunosuppressive agents.

Induced apoptosis of Th2 lymphocytes and inhibition of airway hyperresponsiveness and inflammation by combined lactic acid bacteria treatment.

Several lactic acid bacteria (LAB) demonstrably regulate the immune system and inhibit allergic disease. This study examined whether oral feeding of either Lactobacillus paracasei (L. paracasei) BB5 and/or Lactobacillus rhamnosus (L. rhamnosus) BB1 suppresses ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in a murine model. OVA-specific immune responses, cell profile of bronchoalveolar lavage fluid (BALF), and airway AHR were assessed following OVA and methacholine challenge. We investigated whether LAB can enhance CD4(+)FoxP3(+) and CD8(+)FoxP3(+) regulatory T (Treg) cells in splenic cells and apoptosis of CD4(+)IL-4(+) T cells. Results found oral administration of combined LAB better than single L. paracasei or L. rhamnosus strain, improving Penh ratio after challenge with methacholine. High-dose combined LAB starkly decreased synthesis of OVA-specific IgE and IgG2a levels, as well as eosinophils infiltration in BALF. In addition, CD4(+)IL-4(+) T cells decreased while CD4(+)FoxP3(+) and CD8(+)FoxP3(+) Treg cells increased significantly in splenic mononuclear cells of high-dose combined LAB group. Findings indicate allergen-induced AHR and airway allergic inflammation suppressed by enhances CD4(+)FoxP3(+) and CD8(+)FoxP3(+) Treg populations as well as Th1 cell response after treating with combined LAB. This study may provide a basis for developing a novel therapeutic or protective method for airway allergic disease.

HIV-1 Vpr triggers mitochondrial destruction by impairing Mfn2-mediated ER-mitochondria interaction.

Human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) has been shown to induce host cell death by increasing the permeability of mitochondrial outer membrane (MOM). The mechanism underlying the damage to the mitochondria by Vpr, however, is not clearly illustrated. In this study, Vpr that is introduced, via transient transfection or lentivirus infection, into the human embryonic kidney cell line HEK293, human CD4(+) T lymphoblast cell line SupT1, or human primary CD4(+) T cells serves as the model system to study the molecular mechanism of Vpr-mediated HIV-1 pathogenesis. The results show that Vpr injures MOM and causes a loss in membrane potential (MMP) by posttranscriptionally reducing the expression of mitofusin 2 (Mfn2) via VprBP-DDB1-CUL4A ubiquitin ligase complex, gradually weakening MOM, and increasing mitochondrial deformation. Vpr also markedly decreases cytoplasmic levels of dynamin-related protein 1 (DRP1) and increases bulging in mitochondria-associated membranes (MAM), the specific regions of endoplasmic reticulum (ER) which form physical contacts with the mitochondria. Overexpression of Mfn2 and DRP1 significantly decreased the loss of MMP and apoptotic cell death caused by Vpr. Furthermore, by employing time-lapse confocal fluorescence microscopy, we identify the transport of Vpr protein from the ER, via MAM to the mitochondria. Taken together, our results suggest that Vpr-mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1.