Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.

Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.

A review of iron use and recycling in municipal wastewater treatment plants and a novel applicable integrated process.

Chemical methods are expected to play an increasingly important role in carbon-neutral municipal wastewater treatment plants. This paper briefly summarises the enhancement effects of using iron salts in wastewater and sludge treatment processes. The costs and environmental concerns associated with the widespread use of iron salts have also been highlighted. Fortunately, the iron recovery from iron-rich sludge provides an opportunity to solve these problems. Existing iron recovery methods, including direct acidification and thermal treatment, are summarised and show that acidification treatment of FeS digestate from the anaerobic digestion-sulfate reduction process can increase the iron and sulphur recycling efficiency. Therefore, a novel applicable integrated process based on iron use and recycling is proposed, and it reduces the iron salts dosage to 4.2 mg/L and sludge amount by 80%. Current experimental research and economic analysis of iron recycling show that this process has broad application prospects in resource recovery and sludge reduction.

The era of personalized treatments: Updates on immunotherapy within urothelial of bladder cancer.

Bladder cancer is a complex disease of the urinary system with high morbidity and mortality. Recently, the introduction of immunotherapies such as immune checkpoint inhibitors (eg, programmed cell death protein 1/programmed death-ligand 1) has proven to be a reliable means of improving survival outcomes, including patients with limited response to conventional treatment. Nevertheless, difficult questions remain in clinical practice, such as how to select appropriate patients for personalized treatment, how to predict and assess therapeutic efficacy in advance, and how to enhance the therapeutic benefits of immunotherapy treatment. These issues require urgent attention. Herein, we describe recent clinical applications of immune checkpoint inhibitors in bladder cancer therapy, examine underlying mechanisms for treatment failure in a subset of patients, and discuss potential approaches to improve their therapeutic effects.

Current status and future perspectives of immunotherapy in bladder cancer treatment.

The treatment strategy of bladder cancer has evolved not only through the traditional modalities of surgery and chemotherapy but also by immunotherapy over the past several decades. Immunotherapies such as intravesical Bacillus Calmette-Guérin (BCG) vaccines and immune checkpoint blockades (ICBs) are sometimes used for treating patients with bladder cancer, especially those who develop resistance to conventional first-line treatments such as surgery and chemotherapy. Unfortunately, it is a limited number of individuals that see clinical benefits from this approach, and complicating matters more is that many of these patients suffer severe immune-related adverse events (irAEs). If current momentum continues to result in improved response rates and managed irAEs, immunotherapy could be poised to revolutionize the landscape of urothelial carcinoma therapeutics.

Transcription factor YY1 mediates epithelial-mesenchymal transition through the TGFß signaling pathway in bladder cancer.

Bladder cancer is one of the most aggressive urothelial tumors. Previous studies have suggested that epithelial-mesenchymal transition (EMT) contributes to bladder cancer progression. However, the regulatory network of EMT in bladder cancer remains elusive. In this study, we found Yin Yang 1 (YY1) is a critical regulator of EMT in bladder cancer. First, we showed that YY1 was upregulated in bladder cancer tissues than that in adjacent normal tissues. Then, we proved that YY1 promoted EMT of bladder cancer cells. Further experiments indicated that YY1 affected the EMT of bladder cancer through transforming growth factor-ß (TGFß) signaling pathway. Taken together, our study identifies YY1 as a key EMT driver in bladder cancer, suggesting it as a potential therapeutic target.

Communication Of Cancer Cells And Lymphatic Vessels In Cancer: Focus On Bladder Cancer.

Bladder cancer is one of the most commonly diagnosed cancers worldwide and causes the highest lifetime treatment costs per patient. Bladder cancer is most likely to metastasize through lymphatic ducts, and once the lymph nodes are involved, the prognosis is poorly and finitely improved by current modalities. The underlying metastatic mechanism for bladder cancer is thus becoming a research focus to date. To identify relevant published data, an online search of the PubMed/Medline archives was performed to locate original articles and review articles regarding lymphangiogenesis and lymphatic metastasis in urinary bladder cancer (UBC), and was limited to articles in English published between 1998 and 2018. A further search of the clinical trials.gov search engine was conducted to identify both trials with results available and those with results not yet available. Herein, we summarized the unique mechanisms and biomarkers involved in the malignant progression of bladder cancer as well as their emerging roles in therapeutics, and that current data suggests that lymphangiogenesis and lymph node invasion are important prognostic factors for UBC. The growing knowledge about their roles in bladder cancers provides the basis for novel therapeutic strategies. In addition, more basic and clinical research needs to be conducted in order to identify further accurate predictive molecules and relevant mechanisms.

Extracellular vesicles in urologic malignancies-Implementations for future cancer care.

Extracellular vesicles (EVs), a heterogeneous group of vesicles differing in size and shape, cargo content and function, are membrane-bound and nano-sized vesicles that could be released by nearly all variations of cells. EVs have gained considerable attention in the past decades for their functions in modulating intercellular signalling and roles as potential pools for the novel diagnostic and prognostic biomarkers, as well as therapeutic targets in several cancers including urological neoplasms. In general, human and animal cells both can release distinct types of EVs, including exosomes, microvesicles, oncosomes and large oncosomes, and apoptotic bodies, while the content of EVs can be divided into proteins, lipids and nucleic acids. However, the lack of standard methods for isolation and detection platforms rein the widespread usage in clinical applications warranted furthermore investigations in the development of reliable, specific and sensitive isolation techniques. Whether and how the EVs work has become pertinent issues. With the aid of high-throughput proteomics or genomics methods, a fully understanding of contents contained in EVs from urogenital tumours, beyond all doubt, will improve our ability to identify the complex genomic alterations in the process of cancer and, in turn, contribute to detect potential therapeutic target and then provide personalization strategy for patient.