Regio- and Enantioselective Ni-Catalyzed Formal Hydroalkylation, Hydrobenzylation, and Hydropropargylation of Acrylamides to α-Tertiary Amides.

The development of enantioselective alkyl-alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio- and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center α-position to the newly formed Csp3 -Csp3 bond for the first time. The use of a newly developed chiral ligand enables the electronically-reversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary α-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.

TLR2 Plays a Critical Role in HMGB1-Induced Glomeruli Cell Proliferation Through the FoxO1 Signaling Pathway in Lupus Nephritis.

The objective of this study was to examine the role and possible mechanisms of toll-like receptor 2 (TLR2) in high-mobility group box chromosomal protein 1 (HMGB1)-induced mouse mesangial cell (MMC) proliferation and glomeruli proliferation of MRL/Fas(lpr) mice. First, the expression of proliferating cell nuclear antigen (PCNA), TLR2 and Forkhead box protein O1 (FoxO1) messenger RNA (mRNA) and protein in the glomeruli of MRL/Fas(lpr) mice was quantified, and the correlation with cell proliferation of glomeruli was analyzed. Then, lipopolysaccharide (LPS), TLR2 neutralization antibody, and small hairpin TLR2 (shTLR2) were used to confirm the role of TLR2 in HMGB1-induced MMC proliferation. Furthermore, wild-type FoxO1 (WT-FoxO1) vector was used to investigate the effect of FoxO1 pathway on HMGB1-induced MMC proliferation. Finally, electroporation was used to knockdown TLR2 in the glomeruli of MRL/Fas(lpr) mice, and renal function, FoxO1, and PCNA expression were detected. The results showed that the TLR2 expression was upregulated and FoxO1 expression was decreased in the glomeruli of MRL/Fas(lpr) mice, and these effects were significantly correlated with cell proliferation of the glomeruli. In vitro, the TLR2 neutralization antibody and the WT-FoxO1 vector, both reduced the MMC proliferation levels induced by HMGB1. The TLR2 neutralization antibody also blocked the HMGB1-dependent activation of the FoxO1 pathway and cell proliferation. In addition, transfection with shTLR2 decreased the proliferation levels and PCNA expression induced by HMGB1. In vivo, treatment with shTLR2 significantly reduced the PCNA expression in the glomeruli of MRL/Fas(lpr) mice and improved renal function. In addition, treatment with shTLR2 or blocking of TLR2 also reduced the translocation of FoxO1. Thus, TLR2 plays a critical role in HMGB1-induced glomeruli cell proliferation through the FoxO1 signaling pathway in lupus nephritis.

[Analysis of malaria endemic situation in Shanxian County from 2002 to 2011].

OBJECTIVE: To analyze the endemic situation of malaria in Shanxian County, Shandong Province, China in the last 10 years, so as to understand the epidemiological characteristics of the disease and provide the evidence for the establishment of control strategy to eliminate malaria. METHODS: The data related to the endemic situation of malaria in Shanxian County from 2002 to 2011 were collected and analyzed. RESULTS: From 2002 to 2011, 125 cases of malaria were reported, and the annual incidences were in the range of 0.18/100,000-2.00/100,000. Totally 60.80% of the cases focused on 3 townships, namely Fugang, Huanggang and Caozhuang. All the 125 cases were new vivax malaria cases, among them, 121 were locally infected, and the other 4 were imported. The epidemic season was from June to October, and the peak time was from July to September. There were more male cases than female cases. The ages of the cases were from 1 to 83 years old, and the incidence in those aged from 46-60 years old was higher. CONCLUSIONS: The malaria incidence in Shanxian County is on the rise, and the 3 townships in the south are the key areas for control. The control measures including the surveillance of floating population and mosquitoes, and malaria control health education should be strengthened.

IFN-γ induces lipogenesis in mouse mesangial cells via the JAK2/STAT1 pathway.

The objective is to investigate the effect of high mobility group box-1 (HMGB1) on lipid deposition in γ-interferon (IFN-γ)-stimulated mouse mesangial cell line (MMC) and to determine whether the Janus kinase 2 and signal transducer and activator of transcription 1 (JAK2/STAT1) signaling pathway plays an important role in this process. We employed a control group, an IFN-γ stimulation group, and an IFN-γ + AG490 (JAK2 inhibitor) group. RNA interference aimed at sterol regulatory element-binding protein-1 (SREBP-1) or HMGB1 was used to investigate the effect of these proteins on IFN-γ-induced lipid deposition. Western blotting was used to detect phospho (p)-JAK2, JAK2, p-STAT1, STAT1, SREBP-1, fatty acid synthase (FAS), and HMGB1 protein expression. RT-PCR was used to detect SREBP-1, FAS, and HMGB1 mRNA. Oil Red O staining and the triglyceride assay were used to detect lipid deposition and triglyceride content. Results were as follows: 1) IFN-γ increased MMC cell lipid deposition, triglyceride content, and p-JAK2, p-STAT1, SREBP-1, and FAS expression; 2) SREBP-1 inhibition prevented FAS upregulation and attenuated IFN-γ-induced MMC cell lipid deposition and triglyceride content; 3) HMGB1 upregulated SREBP-1 and FAS mRNA and protein levels, which increased lipid deposition in MMC cells. Small interfering RNA-mediated inhibition of HMGB1 decreased SREBP-1 and FAS expression and lipid accumulation; 4) AG490 decreased upregulation of HMGB1 and p-JAK2/p-STAT1, as well as IFN-γ-induced lipogenesis. In conclusion, the JAK2/STAT1 pathway mediates IFN-γ-induced lipogenesis in MMC cells through regulation of HMGB1/SREBP-1/FAS.

[Alveolar damage of pneumocystis carinii pneumonia in renal transplantation recipients].

OBJECTIVE: To study the alveolar ultrastructural changes and the interaction between Pneumocystis carinii (PC) and alveoli in Pneumocystis carinii pneumonia (PCP) patients after renal transplantation. METHODS: Twenty-seven patients with suspected PCP after renal transplantation were examinated by bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB). The BAL fluid was centrifuged and the sediments were stained for PC. Cases for which electron microscope showed alveolar tissue in TBLB specimen were included. Then the clinical features, PC, alveolar epithelial damage, exudate in alveolar space, inflammatory cell infiltration, and fibrous tissue in the interstitial space were analyzed and evaluated. RESULTS: Twenty-three cases were studied. The mean time from renal transplantation to onset of illness was 5.6 months, and that from onset of illness to hospitalization was 5.5 days. Clinical features included fever, dyspnea, unproductive cough, and scanty chest signs, to hypoxemic respiratory failure. Chest CT showed diffuse lung interstitial changes in 22 of the 23 cases, 9 with consolidation. After treatment with SMZco, the fever resolved in 1 - 5 days, and the general state of the patients became better, and 19 patients were dischaged within 1 month. PC in BAL fluid was found by special staining in 18 patients, while PC was found by electron microscope in 14 patients. In most cases PC was few in the lung tissue, but in 3 cases abundant PC filled the alveolar space. PC was seen in two forms, the cyst and the trophozoite. Electron and light microscopes showed alveolar exudate, inflammation in interstitium and alveolar space, interstitial fibrosis, and alveolar epithelial damage in all patients. CONCLUSION: In PCP patients after renal transplantation there was marked alveolar damage, which was the major pathological change in the lung.