Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBß in Human Osteosarcoma Cell Cultures.

REV-ERBα and its paralog, REV-ERBß, encoded by NR1D1 and NR1D2 genes, are key nuclear receptors that link the circadian timing system and metabolic homeostasis. Since heme is an endogenous ligand, REV-ERBs have been considered key components of the circadian molecular clock and can be pharmacologically targeted to treat various circadian rhythm-related diseases, such as cardiometabolic, inflammatory, and neuropsychiatric diseases, as well as cancer. REV-ERBs are believed to be functionally redundant and compensatory, although they often affect the expression of gene subsets in an isoform-specific manner. Therefore, this study aimed to identify the redundant and distinct roles of each isoform in controlling its target genes by comparing the transcriptome profiles of a panel of mutant U2OS human osteosarcoma cells in which either NR1D1 or NR1D2 was ablated. Indeed, our transcriptomic analyses revealed that most REV-ERB-regulated genes are controlled by redundant or even additive actions. However, the RNA expression profiles of each single mutant cell line also provide strong evidence for isoform-dependent actions. For example, REV-ERBα is more responsible for regulating the NF-κΒ signaling pathway, whereas a group of extracellular matrix components requires REV-ERBß to maintain their expression. We found that REV-ERBs have isoform-selective functions in the regulation of certain circadian output pathways despite their overlapping roles in the circadian molecular clock. Thus, the development of isoform-selective REV-ERB modulators can help treat metabolic disturbances and certain types of cancer.

Association of periodontal disease treatment with mortality in patients with dementia: a population-based retrospective cohort study (2002-2018).

Dementia is one of the leading causes of death worldwide. In this study, we analyzed the association of periodontal treatment with the risk of death in patients with dementia. The analyzed data were obtained by linking the National Health Insurance Corporation claims data between 2002 and 2018 to the Statistics Korea death registry. In total, 1,131,406 patients with dementia aged ≥ 65 years had undergone dental treatment during the study period. Time-dependent Cox proportional hazards model was performed. The mortality rate was approximately 10% among the patients with dementia. The 17-years cumulative survival rates for patients who received periodontal treatment and their untreated counterparts were 83.5% and 71.5%, respectively. The crude hazard ratio of the periodontal group was approximately twice as high as that of the non-periodontal group (1.99; P < 0.001). Furthermore, in the regression model that was adjusted for socio-demographic variables and systematic chronic diseases, the risk of death in the non-periodontal group was approximately 1.83 times higher than that of the periodontal group (P < 0.00). These findings suggest that preventive periodontal treatment may decrease mortality risk in older people with dementia.

Unveiled reactivity of masked diformylmethane with enamines forming resonance-assisted hydrogen bonding leads to di-meta-substituted pyridines.

Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta-substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di-meta-substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications-core remodeling of natural products, drug-natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology.

Selective delivery of imaging probes and therapeutics to the endoplasmic reticulum or Golgi apparatus: Current strategies and beyond.

To maximize therapeutic effects and minimize unwanted effects, the interest in drug targeting to the endoplasmic reticulum (ER) or Golgi apparatus (GA) has been recently growing because two organelles are distributing hubs of cellular building/signaling components (e.g., proteins, lipids, Ca2+) to other organelles and the plasma membrane. Their structural or functional damages induce organelle stress (i.e., ER or GA stress), and their aggravation is strongly related to diseases (e.g., cancers, liver diseases, brain diseases). Many efforts have been developed to image (patho)physiological functions (e.g., oxidative stress, protein/lipid-related processing) and characteristics (e.g., pH, temperature, biothiols, reactive oxygen species) in the target organelles and to deliver drugs for organelle disruption using organelle-targeting moieties. Therefore, this review will overview the structure, (patho)physiological functions/characteristics, and related diseases of the organelles of interest. Future direction on ER or GA targeting will be discussed by understanding current strategies and investigations on targeting, imaging/sensing, and therapeutic systems.

Beyond Nanoparticle-Based Intracellular Drug Delivery: Cytosol/Organelle-Targeted Drug Release and Therapeutic Synergism.

Nanoparticle (NP)-based drug delivery systems are conceived to solve poor water-solubility and chemical/physical instability, and their purpose expanded to target specific sites for maximizing therapeutic effects and minimizing unwanted events of payloads. Targeted sites are also narrowed from organs/tissues and cells to cytosol/organelles. Beyond specific site targeting, the particular release of payloads at the target sites is growing in importance. This review overviews various issues and their general strategies during multiple steps, from the preparation of drug-loaded NPs to their drug release at the target cytosol/organelles. In particular, this review focuses on current strategies for "first" delivery and "later" release of drugs to the cytosol or organelles of interest using specific stimuli in the target sites. Recognizing or distinguishing the presence/absence of stimuli or their differences in concentration/level/activity in one place from those in another is applied to stimuli-triggered release via bond cleavage or nanostructural transition. In addition, future directions on understanding the intracellular balance of stimuli and their counter-stimuli are demonstrated to synergize the therapeutic effects of payloads released from stimuli-sensitive NPs.

Beyond nanoparticle-based oral drug delivery: transporter-mediated absorption and disease targeting.

Various strategies at the microscale/nanoscale have been developed to improve oral absorption of therapeutics. Among them, gastrointestinal (GI)-transporter/receptor-mediated nanosized drug delivery systems (NDDSs) have drawn attention due to their many benefits, such as improved water solubility, improved chemical/physical stability, improved oral absorption, and improved targetability of their payloads. Their therapeutic potential in disease animal models (e.g., solid tumors, virus-infected lungs, metastasis, diabetes, and so on) has been investigated, and could be expanded to disease targeting after systemic/lymphatic circulation, although the detailed paths and mechanisms of endocytosis, endosomal escape, intracellular trafficking, and exocytosis through the epithelial cell lining in the GI tract are still unclear. Thus, this review summarizes and discusses potential GI transporters/receptors, their absorption and distribution, in vivo studies, and potential sequential targeting (e.g., oral absorption and disease targeting in organs/tissues).

Increased GIRK channel activity prevents arrhythmia in mice with heart failure by enhancing ventricular repolarization.

Ventricular arrhythmia causing sudden cardiac death is the leading mode of death in patients with heart failure. Yet, the mechanisms that prevent ventricular arrhythmias in heart failure are not well characterized. Using a mouse model of heart failure created by transverse aorta constriction, we show that GIRK channel, an important regulator of cardiac action potentials, is constitutively active in failing ventricles in contrast to normal cells. Evidence is presented indicating that the tonic activation of M2 muscarinic acetylcholine receptors by endogenously released acetylcholine contributes to the constitutive GIRK activity. This constitutive GIRK activity prevents the action potential prolongation in heart failure ventricles. Consistently, GIRK channel blockade with tertiapin-Q induces QT interval prolongation and increases the incidence of arrhythmia in heart failure, but not in control mice. These results suggest that constitutive GIRK channels comprise a key mechanism to protect against arrhythmia by providing repolarizing currents in heart failure ventricles.