Profiling of T cell repertoire in peripheral blood of patients from type 2 diabetes with complication.

PURPOSE: More than 90% of patients with diabetes worldwide are type 2 diabetes (T2D), which is caused by insulin resistance or impaired producing insulin by pancreatic ß cells. T2D and its complications, mainly large cardiovascular (LCV) and kidney (Ne) complications, are the major cause of death in diabetes patients. Recently, the dysregulation of peripheral T cell immune homeostasis was found in most T2D patients. However, the characteristics of T-cell receptors (TCR) remain largely unexplored in T2D patients. PATIENTS AND METHODS: Here we investigated the TCR repertoire using high-throughput sequencing in peripheral blood collected from T2D patient with (8 LCV and 7 Ne) or without complications. RESULTS: Our analysis of TCR repertoires in peripheral blood samples showed that TCR profiles in T2D patients with complications tended to be single and specific compared to controls, according to the characteristics of TCR repertoire in V-J combination number, diversity, principal component analysis (PCA) and differential genes. And we identified some differentially expressed V-J gene segments and amino acid clonotypes, which had the potential to contribute to distinguishing T2D patient with or without complications. As the progression of the disease, we found that the profiling of TCR repertoire was also differential between T2D patients with LVD and Ne complications base on this pilot analysis. CONCLUSION: This study demonstrated the protentional unique property of TCR repertoire in peripheral blood of T2D patient with and without complications, or T2D patients with LVD and Ne complications, which provided the possibility for future improvements in immune-related diagnosis and therapy for T2D complications.

Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo-Immunotherapy in Bladder Cancer.

Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD-L1 expression. Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome-wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the "immune cold tumor" is transformed into an "immune hot tumor". In addition, NP2 can upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (αPD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.

JAK/STAT signaling in diabetic kidney disease.

Diabetic kidney disease (DKD) is the most important microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. The Janus kinase/signal transducer and activator of the transcription (JAK/STAT) signaling pathway, which is out of balance in the context of DKD, acts through a range of metabolism-related cytokines and hormones. JAK/STAT is the primary signaling node in the progression of DKD. The latest research on JAK/STAT signaling helps determine the role of this pathway in the factors associated with DKD progression. These factors include the renin-angiotensin system (RAS), fibrosis, immunity, inflammation, aging, autophagy, and EMT. This review epitomizes the progress in understanding the complicated explanation of the etiologies of DKD and the role of the JAK/STAT pathway in the progression of DKD and discusses whether it can be a potential target for treating DKD. It further summarizes the JAK/STAT inhibitors, natural products, and other drugs that are promising for treating DKD and discusses how these inhibitors can alleviate DKD to explore possible potential drugs that will contribute to formulating effective treatment strategies for DKD in the near future.

Polyphotosensitizer-Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy.

Glutathione S-transferase (GST), which is a key enzyme in the conjugation reaction of glutathione (GSH), is overexpressed in cancer cells, leading to cisplatin deactivation and ultimately drug resistance. In addition, many tumors are immune "cold tumors," limiting the application of immune checkpoint inhibitors. Herein, a reactive oxygen species (ROS)-responsive polyphotosensitizer-based nanoparticle (NP2) with Michael addition acceptors inhibiting GST activity and cisplatin deactivation is designed. Under the 808 nm light irradiation, on the one hand, the Michael addition acceptor in NP2 can react with GST and inhibit its activity, thereby decreasing the GSH conjugation and reducing the GSH-mediated deactivation of cisplatin and improving its chemotherapeutic effect. On the other hand, NP2+L induces more ROS production in prostate tumor cells, which can further induce type II immunogenic cell death (ICD) and stimulate a stronger antitumor immune response. It is found that NP2 under the 808 nm light irradiation (NP2+L) can increase PD-L1 expression on the surface of prostate cancer cells. Subsequently, NP2+L combined with PD-L1 treatment is found to simultaneously enhance the efficacies of chemotherapy and photodynamic immunotherapy in prostate tumors, providing a new paradigm for the clinical multimodal treatment of tumors.

Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD-L1 for Enhanced Cancer Immunotherapy.

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half-life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)-sensitive polymer (PHPM) is designed, which is used to co-encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA-Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti-programmed cell death protein ligand-1 antibody (αPD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD-L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

A New Surgical Technique of Combination Retroperitoneal with Transperitoneal Laparoscopic Nephroureterectomy in a Single Position and Comparative Outcomes.

BACKGROUND: The traditional surgical treatment for upper urinary tract urothelial carcinoma (UTUC) is time-consuming owing to changing the surgical position and larger surgical trauma because of open surgery in handling the distal ureter. Therefore, we created a new surgical technique of combination retroperitoneal with transperitoneal (CRT) laparoscopic nephroureterectomy (LNU) in a single position and here report our early outcomes. METHODS: From January 2017 to December 2019, a total of 106 patients underwent LNU by a single surgeon at our department, of whom 50 patients underwent standard technique and 56 patients underwent CRT technique. Relevant clinical data were collected including each patient's characteristics, surgical outcomes, and follow-up results. A comparative analysis between standard LNU cases and CRT LNU cases was performed. RESULTS: LNU was performed successfully on all 106 patients. There was no significant difference in patients' characteristics. Compared to the standard group, patients in the CRT group had shorter operative time (P=0.001), less estimated blood loss (EBL) (P<0.001), lower visual analogue scale (VAS) pain score (P=0.020) and less scarring (P=0.013). The median time of surgical drain stay decreased from 5 to 2 days (P=0.004) and median hospital stay after surgery decreased from 5 to 3 days (P=0.001). The complication rates did not show statistical differences between the two groups within the first 30 days postoperatively (P=0.263). For the long-term complications, the incidence of abdomen bulge or incisional hernia in the CRT group was less than that in the standard group (P<0.001). CONCLUSION: The CRT technique, which combines both the advantages of retroperitoneal and transperitoneal approaches, is a more minimally invasive, simplified and effective way to perform the LNU.

Efficient asymmetric total syntheses of cryptocarya triacetate, cryptocaryolone, and cryptocaryolone diacetate.

Concise and efficient asymmetric total syntheses of three substituted alpha-pyrone-type natural products have been accomplished via 7-9 steps from 5b in high overall yields, which involve linchpin coupling, ring-closing metathesis, and a tandem sequence of deacetylation and intramolecular oxa-Michael addition as the key steps.

Concise asymmetric total synthesis of obolactone.

The first efficient asymmetric synthesis of obolactone 1 has been accomplished in 11 steps and with a 15% overall yield in which Brown's enantioselective allylation reactions and ring-closing metathesis reaction are key steps.

Efficient synthesis of tribenzohexadehydro[12]annulene and its derivatives in the ionic liquid.

A simple and efficient synthesis of tribenzohexadehydro[12]annulene and related derivatives in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate is described. A Sonogashira coupling reaction is the key step. In this system, the amount of CuI normally used can be reduced so that homocoupling is minimized.