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SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs. Specifically, stimulating CCK release supports neurogenic proliferation of NSCs through a dominant astrocyte-mediated glutamatergic signaling cascade. In contrast, reducing dentate CCK induces reactive astrocytes, which correlates with decreased neurogenic proliferation of NSCs and upregulation of genes involved in immune processes. Our findings provide novel circuit-based information on how CCK acts on local astrocytes to regulate the key behavior of adult NSCs.Acacia farnesiana pods are rich in secondary metabolites and their biological activities have been recorded as antibacterial, antioxidant and anthelmintic. Previously, an in vitro bioguided study showed the important ovicidal and larvicidal effects of an organic fraction (EtOAc-F) from a hydroalcoholic extract of A. farnesiana pods against Haemonchus contortus. The present study aimed to assess the in vivo anthelmintic effect of EtOAc-F from A. farnesiana pods on the H. contortus faecal egg elimination in female lambs and on the infective larvae (L3) population reduction in coprocultures. The EtOAc-F was obtained from a hydroalcoholic extract from A. farnesiana pods through chromatographic procedures; additionally, some secondary compounds were identified using high-performance liquid chromatography (HPLC). Twenty-one ‘Katahdin’ crossbred female lambs ranging from three to four months of age, with body weights 21.9 ± 0.39 kg were used. Animals were orally infected with H. contortus (L3) by a single dose of 350 L3/kg BW. Three experimental groups (n = 7) were assigned as follows 1) Control (untreated), 2) Albendazole, as a positive control (at 7.5 mg/kg BW, unique dose) and 3) EtOAc-F (at 100 mg/kg BW, once every third day, with three applications in total). Individual faecal samples were collected once a week for 5 weeks (at days 38, 45, 52, 59 and 66) post-treatment, to measure the faecal egg counts (FEC) and to obtain the H. contortus (L3) population from faecal cultures. The highest FEC reduction caused by EtOAc-F was 67.7%; meanwhile, albendazole showed a total FEC reduction after the second week post-treatment (day 45). On the other hand, the fraction caused an important reduction in the larval population in coprocultures (54.3-68.5%). The phytochemical analysis revealed the presence of galloyl derivatives and flavonoids as major compounds. learn more The A. farnesiana pods could serve as a natural anthelmintic for the control of H. contortus, and perhaps for controlling other parasites of veterinary importance.Colorectal cancer (CRC) represents one of the commonest malignancies around the world. PP9, a natural steroidal saponin, was firstly isolated from the rhizomes of Paris polyphylla var. latifolia. However, the therapeutic effects of PP9 on CRC and the underlying molecular mechanism remain undefined. Here, we demonstrated that treatment with PP9 time- and dose-dependently inhibited HT-29 and HCT116 cells without significantly inhibiting normal NCM460 cells. Furthermore, our results indicated that PP9 effectively induced G2/M phase arrest by upregulating p21 and suppressing cdc25C, Cyclin B1 and cdc2. Meanwhile, PP9 upregulated cleaved Caspase 3, cleaved Caspase 9 and cleaved PARP and Bax, while downregulating Bcl-2 to stimulate cell apoptosis. Mechanistically, PP9-suppressed PI3K/Akt/GSK3β signaling, while the PI3K inhibitor LY294002 augmented PP9-mediated apoptosis, G2/M arrest and effects on PI3K/Akt/GSK3β related proteins. Finally, we showed that PP9 (10 mg/kg) significantly reduced tumor growth in nude mouse CRC xenografts, more potently than 5-Fu (20 mg/kg). Jointly, these data firstly demonstrated that PP9 promotes G2/M arrest and apoptotic death in CRC cells through PI3K/Akt/GSK3β signaling suppression, suggesting that PP9 could be considered a new and promising candidate for CRC therapy.

This study aimed at assessing current efficacy and safety of endoscopic combined intrarenal surgery (ECIRS) for the treatment of large and/or complex urolithiasis and identifying relevant tips and tricks able to improve its outcomes, mainly deriving from the adjunct of retrograde flexible ureteroscopy to the traditional antegrade approach of percutaneous nephrolithotomy (PNL).

A systematic review was conducted using relevant databases (Ovid Medline, PubMed, Scopus, and Web of Sciences), employing “ECIRS” as the search term in all cases, and then adding “endoscopic combined intrarenal surgery” and “flexible ureteroscopy AND percutaneous nephrolithotomy” as search terms for PubMed and Scopus. Original articles and systematic reviews were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Additionally, the reference lists of the selected publications were checked manually.

A total of 14 studies were selected for analysis two systematic reviews, one randomized controlled trial, five nonrandomized comparative studies, three prospective case series, and three retrospective case series.