Visible-Light-Promoted α-C(sp3)-H Amination of Ethers with Azoles and Amides.

A visible-light-induced highly efficient C(sp3)-H amination of ethers with amides and azoles has been presented under mild conditions via a nitrogen- and carbon-centered radical coupling process. This protocol successfully utilizes 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tert-butyl nitrite (TBN) as cocatalysts to deliver the aminated products of ethers under aerobic conditions. Notably, the developed reaction features the corresponding products in good yields (up to 93%) with a wide substrate scope. The mechanistic study indicates that C-N bond formation proceeds via a direct radical cross-coupling process. Preliminary biological activity analysis indicates that the resulting products have good and selective inhibitory activity on osteosarcoma (OS) cell lines and are promising for use as hits for drug discovery.

Discovery of potent thiazolidin-4-one sulfone derivatives for inhibition of proliferation of osteosarcoma in vitro and in vivo.

Chemotherapy combining with surgical treatment has been the main strategy for osteosarcoma treatment in clinical. Due to unclear pathogenesis and unidentified drug targets, significant progress has not been made in the development of targeted drugs for osteosarcoma during the past 50 years. Our previous discovery reported compound R-8i with a high potency for the treatment of osteosarcoma by phenotypic screening. However, both the metabolic stability and bioavailability of R-8i are poor (T1/2 = 5.36 min, mouse liver microsome; and bioavailability in vivo F = 52.1 %, intraperitoneal administration) which limits it use for further drug development. Here, we described an extensive structure-activity relationship study of thiazolidine-4-one sulfone inhibitors from R-8i, which led to the discovery of compound 68. Compound 68 had a potent cellular activity with an IC50 value of 0.217 µM, much higher half-life (T1/2 = 73.8 min, mouse liver microsome) and an excellent pharmacokinetic profile (in vivo bioavailability F = 115 %, intraperitoneal administration). Compound 68 also showed good antitumor effects and low toxicity in a xenograft model (44.6 % inhibition osteosarcoma growth in BALB/c mice). These results suggest that compound 68 is a potential drug candidate for the treatment of osteosarcoma.

Primary clostridium difficile infection in patients with ulcerative colitis: Case report and literature review.

RATIONALE: Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disorder characterized by inflammation of the gastrointestinal tract. Patients with IBD are susceptible to various complications, including the coexistence of Clostridioides difficile infection (CDI). The incidence of IBD combined with difficile infection is higher in patients with compromised immune function, which can lead to increased mortality. PATIENT CONCERNS: A 43-year-old male presented with recurrent episodes of mucus and bloody stools persisting for more than a month without any identifiable triggering factors. Initially, the stool consistency was normal, but it progressively shifted to a loose and watery texture, with up to 8 occurrences daily. DIAGNOSES: This case underscores the diagnosis of severe UC through colonoscopy and colonic biopsy, along with the supplementary identification of a positive result for Clostridioides difficile in the fecal sample. INTERVENTIONS: The patient initiated infliximab therapy alongside a full vancomycin course, demonstrating the potential effectiveness of this intervention in managing early-stage ulcerative colitis with concurrent Clostridioides difficile infection. OUTCOMES: Following the completion of a full vancomycin course, the patient initiated infliximab therapy. The patient was free from significant discomfort, exhibited no fever, and had no mucopurulent bloody stools. A follow-up blood test indicated reduced inflammatory markers compared to the preoperative period, and the stools were normal. LESSONS: We illustrate the potential effectiveness of this medication by presenting an in-depth case report of a patient with early-stage UC. The report outlines the patient inclusion of infliximab to better manage UC inflammation alongside an adjunct vancomycin regimen, given the ineffectiveness of mesalazine therapy and the concurrent presence of Clostridium difficile infection. This case prompts consideration of therapeutic approaches for complex UC and contributes to advancing both research and clinical practice. Nonetheless, we should remain attentive to the variations and potential risks unique to each patient in order to formulate personalized treatment strategies.

Ulcerative Colitis Concomitant with Cytomegalovirus Infection, Bullous Sweet's Syndrome, and Acute Myeloid Leukemia: A Case Report and Literature Review.

Background: Ulcerative colitis (UC) is a chronic, relapsing progressive inflammatory immune disease. There is still no cure for it. Even worse, UC may predispose patients to opportunistic infections, and several extra-intestinal manifestations (EIMs) and comorbidities may antedate, occur with, or postdate the onset of UC, which may increase the mortality risk. But case reports of UC patients simultaneously concomitant with opportunistic infection, EIM, and comorbidity are extremely rare. Case Presentation: We report a case of 51-year-old male patient with incipient UC accompanied by cytomegalovirus (CMV) infection and bullous Sweet's syndrome (bSS, a cutaneous EIM of UC) after treatment with oral mesalazine and prednisolone for 3 weeks. After clearance of the CMV infection by using ganciclovir, the patient was administered two cycles of infliximab to cure UC and bSS; however, he developed acute myeloid leukemia (AML) a month later and died after two cycles of chemotherapy. Conclusion: Based on this rare case of UC concomitant with CMV infection, bSS and AML, we recommend that it is important to distinguish between an acute UC flare and opportunistic infections, especially in patients receiving immunosuppressive therapy, and monitor EIMs and comorbidities timely. Particular attention should be paid to cancer surveillance. Clinicians should be mindful of these facts to adopt optimal therapeutic options to address all aspects of UC. Early initiation of biological therapy may be of benefit to patients with newly diagnosed severe UC.

Blockade of Syk modulates neutrophil immune-responses via the mTOR/RUBCNL-dependent autophagy pathway to alleviate intestinal inflammation in ulcerative colitis.

Background: Ulcerative colitis (UC) is a progressive chronic inflammatory disorder. Neutrophils play a critical role in regulating intestinal mucosal homeostasis in UC. Spleen tyrosine kinase (Syk) is involved in several inflammatory diseases. Here, we evaluated the effects and underlying mechanisms of Syk on neutrophil immune-responses in UC. Methods: Syk expression in the colonic tissues of patients with UC was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. Colonic biopsies from patients with UC were obtained for single-cell RNA-sequencing. Neutrophils isolated from peripheral blood were pre-treated with R788 (a Syk inhibitor) and gene differences were determined using RNA sequencing. Neutrophil functions were analyzed using qRT-PCR, flow cytometry, and Transwell assay. R788 was administered daily to mice with dextran sulfate sodium (DSS)-induced colitis to verify the effects of Syk on intestinal inflammation. Results: Syk expression was increased in inflamed mucosa and neutrophils of patients with UC and positively correlated with disease activity. Pharmacological inhibition of Syk in neutrophils decreased the production of pro-inflammatory cytokines, chemokines, neutrophil extracellular traps, reactive oxygen species, and myeloperoxidase. Apoptosis and migration of neutrophils were suppressed by Syk blockade. Syk blockade ameliorated mucosal inflammation in DSS-induced murine colitis by inhibiting neutrophil-associated immune responses. Mechanistically, Syk regulated neutrophil immune-responses via the mammalian target of rapamycin kinase/rubicon-like autophagy enhancer-dependent autophagy pathway. Conclusions: Our findings indicate that Syk facilitates specific neutrophil functional responses to mucosal inflammation in UC, and its inhibition ameliorates mucosal inflammation in DSS-induced murine colitis, suggesting its potential as a novel therapeutic target for UC treatment.

Ex vivo-expanded bone marrow stem cells home to the liver and ameliorate functional recovery in a mouse model of acute hepatic injury.

BACKGROUND: Stem cell transplantation provides a theoretical approach for liver regeneration medicine; it may promote liver regeneration and self-repair. However, the transplantation of bone marrow-mesenchymal stem cells expanded ex vivo as a therapy for liver disease has rarely been investigated. This study aimed to explore whether bone marrow stem cells expanded ex vivo home to the liver and foster hepatic recovery after CCl4 injury. METHODS: Bone marrow cells from BALB/c mice were expanded ex vivo by multiple-passage cultivation, characterized by cytoflow immunofluorescence, and pre-labeled with PKH26 before intravenous infusion into animals treated with CCl4. The integration of bone marrow cells into the liver was examined microscopically, and plasma hepatic enzymes were determined biochemically. RESULTS: Cultured bone marrow cells exhibited antigenic profiles comparable to those of primary medullary stem cells. Double immunofluorescence showed colocalization of these cells with proliferative activity and albumin expression in the liver of CCl4-treated mice. Densitometry showed increased in situ cell proliferation (50+/-14 vs 20+/-3 cells/high-power field, P<0.05) and albumin expression (149+/-25 vs 20+/-5 cells/high-power field, P<0.05) in the liver, as well as reduced serum aminotransferase levels (P<0.05) and better survival rates (P<0.05) in animals receiving cultured bone marrow cells relative to controls. CONCLUSIONS: Ex vivo-expanded bone marrow cells are capable of relocating to and proliferating in the chemically-injured liver. Transplantation of these pluripotent stem cells appears to improve serum indices of liver function and survival rate in mice after CCl4-induced hepatic damage.

A case report about eosinophilic enteritis presenting as abdominal pain.

RATIONALE: Eosinophilic enteritis (EE) is an immune-mediated antigen-driven disease that may lead to clinical symptoms and organ dysfunction and characterized by the presence of extensive eosinophilic infiltrates on histopathological examination of the intestinal mucosa. PATIENT CONCERNS: A 29-year-old man presented with a half-month duration of paroxysmal upper abdominal pain that gradually evolved into continuous pain accompanied by the urge to defecate. DIAGNOSES: Pathological findings of enteroscopy showed acute and chronic inflammation accompanied by eosinophilic infiltration (>20/ high-power field). INTERVENTIONS: The patient was initially treated with IV infusion of dexamethasone 10 mg per day for 3 days, which was reduced to 7.5 mg per day for 2 days once pain relief was achieved. Upon discharged from our hospital, the patient was prescribed with oral prednisolone 30 mg per day, which was reduced by 5 mg per week for 6 weeks until discontinuation. OUTCOMES: The patient was relieved from the pain after receiving dexamethasone for 5 days, and he was maintained on oral prednisolone 30 mg per day upon discharge from the hospital. On the day of discharge, the eosinophil count and derived ratios were normal. LESSONS: In patients with EE, the dynamic changes of the eosinophil count should be monitored. Clinicians must be aware that not all patients with EE have a history of allergies. In the management and treatment of the disease, multisite biopsies should be carried out if EE is suspected, and EE is responsive to steroid therapy.