The Solid-state Multi-color Fluorescence Switching from a [2.2]Paracyclophane-based Triarylborane.

The fluorophores, the fluorescence of which can be switched between multi bright colors in the solid state, show promising applications not only in the sophisticated multicolor display but also in the advanced encryption and anti-counterfeiting systems. However, it is very challenging to obtain such fluorophores. Herein, we disclose such an example, g-BPhANMe2-Cp, which contains an electron-donating dimethylamino (NMe2) and an electron-accepting [(2-dimesitylboryl)phenyl]acetyl at the pseudo-gem position of [2.2]paracyclophane skeleton. This molecule can display tricolor mechanochromic luminescence (MCL) due to the different responses of the mechanically ground amorphous state to heating and solvent-fuming. Owing to the absence of intermolecular π-π interactions in the solid state, the fluorescence efficiency is very high irrespective of its morphological state (ΦF = 0.60-0.87). Moreover, this molecule also displays reversible acidochromic luminescence (ACL) by protonation and deprotonation of NMe2 with trifluoroacetic acid (TFA) and triethylamine (TEA), respectively. The protonated sample fluoresces (ΦF = 0.31) at much shorter wavelength due to the interruption of intramolecular charge transfer process. Therefore, with the combination of tricolor MCL and the ACL properties, the solid-state emission of g-BPhANMe2-Cp can be switched among four bright fluorescence colors of yellow, green, cyan and blue via treatment with appropriate stimulus.

Absorption, Metabolism, and Excretion of [14C]-Labeled Anaprazole: A New Proton Pump Inhibitor, After a Single Oral Administration in Healthy Chinese Male Subjects.

Anaprazole is a proton pump inhibitor. This study aims to elucidate absorption, metabolism, and excretion pathways of anaprazole sodium in the human body. A total of 4 healthy Chinese male subjects were administered a single oral dose of 20 mg/100 µCi of [14C]-anaprazole sodium enteric-coated capsules. The whole blood, plasma, and excreta were analyzed for a total radioactivity (TRA) and metabolite profile. The cumulative radioactivity excretion rate was 93.2%, with 53.3% and 39.9% of the radioactive dose excreted in urine and feces, respectively, and 91.6% of dose recovered within 96 hours after dosing. The parent drug, anaprazole, showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism. Overall, 35 metabolites were identified in plasma, urine, and fecal samples. Anaprazole was the most abundant component in plasma followed by the thioether M8-1, accounting for 28.3% and 16.6%, respectively, of the plasma TRA. Thioether carboxylic acid XZP-3409 (26.3% of urine TRA) and XZP-3409 oxidation and dehydrogenation product M417a (15.1% of fecal TRA) were the major metabolites present in urine and feces, respectively. Anaprazole was undetectable in urine, while fecal samples showed traces (0.07% dose). Blood/plasma ratios of the radioactivity (approximately 0.60) remained consistent over time. Anaprazole showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism, and cytochrome P450 3A4 also contributed to its metabolism in healthy individuals.

Microneedle-Mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune-Mediated Alopecia.

Disorders in the regulatory arm of the adaptive immune system result in autoimmune-mediated diseases. While systemic immunosuppression is the prevailing approach to manage them, it fails to achieve long-lasting remission due to concomitant suppression of the regulatory arm and carries the risk of heightened susceptibility to infections and malignancies. Alopecia areata is a condition characterized by localized hair loss due to autoimmunity. The accessibility of the skin allows local rather than systemic intervention to avoid broad immunosuppression. It is hypothesized that the expansion of endogenous regulatory T cells (Tregs) at the site of antigen encounter can restore the immune balance and generate a long-lasting tolerogenic response. A hydrogel microneedle (MN) patch is therefore utilized for delivery of CCL22, a Treg-chemoattractant, and IL-2, a Treg survival factor to amplify them. In an immune-mediated murine model of alopecia, local bolstering of Treg numbers is shown, leading to sustained hair regrowth and attenuation of inflammatory pathways. In a humanized skin transplant mouse model, expansion of Tregs within human skin is confirmed without engendering peripheral immunosuppression. The patch offers high-loading capacity and shelf-life stability for prospective clinical translation. By harmonizing immune responses locally, the aim is to reshape the landscape of autoimmune skin disease management.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia.

Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.

Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression.

Pro-inflammatory cytokine production by the retinal pigment epithelium (RPE) is a key etiology in retinal degenerative diseases, yet the underlying mechanisms are not well understood. TMEM97 is a scarcely studied transmembrane protein recently implicated in retinal degeneration. BAH domain coiled coil 1 (BAHCC1) is a newly discovered histone code reader involved in oncogenesis. A role for TMEM97 and BAHCC1 in RPE inflammation was not known. Here we found that they constitute a novel axis regulating pro-inflammatory cytokine expression in RPE cells. Transcriptomic analysis using a TMEM97-/- ARPE19 human cell line and the validation via TMEM97 loss- and gain-of-function revealed a profound role of TMEM97 in promoting the expression of pro-inflammatory cytokines, notably IL1ß and CCL2, and unexpectedly BAHCC1 as well. Moreover, co-immunoprecipitation indicated an association between the TMEM97 and BAHCC1 proteins. While TMEM97 ablation decreased and its overexpression increased NFκB (p50, p52, p65), the master transcription factor for pro-inflammatory cytokines, silencing BAHCC1 down-regulated NFκB and downstream pro-inflammatory cytokines. Furthermore, in an RPE-damage retinal degeneration mouse model, immunofluorescence illustrated down-regulation of IL1ß and CCL2 total proteins and suppression of glial activation in the retina of Tmem97-/- mice compared to Tmem97+/+ mice. Thus, TMEM97 is a novel determinant of pro-inflammatory cytokine expression acting via a previously unknown TMEM97- > BAHCC1- > NFκB cascade. SYNOPSIS: Retinal pigment epithelium (RPE) inflammation can lead to blindness. We identify here a previously uncharacterized cascade that underlies RPE cell production of pro-inflammatory cytokines. Specifically, transmembrane protein TMEM97 positively regulates the recently discovered histone code reader BAHCC1, which in turn enhances pro-inflammatory cytokine expression via the transcription factor NFκB.

Cucurbit[8]uril-Based Supramolecular Probe for the Detection of 3-Nitrotyrosine in Human Serum and Plasma.

The biomarker 3-nitrotyrosine (3-NT) is widely recognized as an indicator of renal oxidative stress injury, making its detection crucial for the early identification of renal insufficiency. This study presents the design and synthesis of a tetraphenylstyrene imidazole derivative (TIPE-MI), which is utilized to create a supramolecular probe in conjunction with cucurbit[8]uril (Q[8]) through host-guest interactions. The resulting supramolecular self-assembly exhibits excellent optical properties and has been employed for the specific detection of 3-NT through fluorescence quenching. The introduction of 3-NT resulted in a decreased fluorescence intensity of the yellow fluorescent probe, which gradually transitioned from bright yellow to light yellow and then became colorless as the 3-NT concentration was increased. A portable detection platform was devised to augment the efficiency of detection. In order to facilitate biological applications, we have substantiated the probe's exceptional precision in detecting 3-NT in biological samples, encompassing human serum and plasma. The probe also exhibited negligible cytotoxicity. The accumulation of the probe in renal cells elicited a fluorescence signal, thereby indicating the prospective viability of this system for visual detection with renal cytocompatibility.

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B.

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland-Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2-13.3 µM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Long non-coding RNA BRE-AS1 inhibits proliferation, migration and invasion of clear cell renal cell carcinoma by downregulating miR-106b-5p.

OBJECTIVE: The objective of this study was to investigate the involvement of the long non-coding RNA (lncRNA) BRE-AS1 in clear cell renal cell carcinoma (ccRCC) and to explore its potential therapeutic role. METHODS: The expression of BRE-AS1 and miR-106b-5p was determined by qRT-PCR. Overexpression of BRE-AS1 and miR-106b-5p were performed to study their relationship. Transwell assays were used to evaluate cell movement. Methylation-specific PCR (MSP) was performed to explore the role of BRE-AS1 in the methylation of the miR-106b-5p gene. RESULTS: The results showed that the expression levels of BRE-AS1 were decreased, while those of miR-106b-5p were increased in ccRCC tissues. BRE-AS1 was found to be closely associated with the prognosis of patients with ccRCC. The expression of BRE-AS1 was inversely correlated with that of miR-106b-5p in tumor tissues. Overexpression of BRE-AS1 led to decreased expression levels of miR-106b-5p and increased methylation of the miR-106b-5p gene, whereas miR-106b-5p did not affect the expression of BRE-AS1. BRE-AS1 inhibited the movement and proliferation of ccRCC cell lines, while miR-106b-5p suppressed the role of BRE-AS1. CONCLUSION: BRE-AS1 may suppress ccRCC by downregulating the expression of miR-106b-5p.

Neointima abating and endothelium preserving - An adventitia-localized nanoformulation to inhibit the epigenetic writer DOT1L.

Open vascular reconstructions such as bypass are common treatments for cardiovascular disease. Unfortunately, neointimal hyperplasia (IH) follows, leading to treatment failure for which there is no approved therapy. Here we combined the strengths of tailoring nanoplatforms for open vascular reconstructions and targeting new epigenetic mechanisms. We produced adhesive nanoparticles (ahNP) that could be pen-brushed and immobilized on the adventitia to sustainably release pinometostat, an inhibitor drug selective to the epigenetic writer DOT1L that catalyzes histone-3 lysine-79 dimethylation (H3K79me2). This treatment not only reduced IH by 76.8% in injured arteries mimicking open reconstructions in obese Zucker rats with human-like diseases but also avoided the shortcoming of endothelial impairment in IH management. In mechanistic studies, chromatin immunoprecipitation (ChIP) sequencing revealed co-enrichment of the histone mark H3K27ac(acetyl) and its reader BRD4 at the gene of aurora kinase B (AURKB), where H3K79me2 was also enriched as indicated by ChIP-qPCR. Accordingly, DOT1L co-immunoprecipitated with H3K27ac. Furthermore, the known IH driver BRD4 governed the expression of DOT1L which controlled AURKB's protein level, revealing a BRD4- > DOT1L- > AURKB axis. Consistently, AURKB-selective inhibition reduced IH. Thus, this study presents a prototype nanoformulation suited for open vascular reconstructions, and the new insights into chromatin modulators may aid future translational advances.

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl- and HCO3- secretion†.

Aerobic exercises could improve the sperm motility of obese individuals. However, the underlying mechanism has not been fully elucidated, especially the possible involvement of the epididymis in which sperm acquire their fertilizing capacity. This study aims to investigate the benefit effect of aerobic exercises on the epididymal luminal milieu of obese rats. Sprague-Dawley male rats were fed on a normal or high-fat diet (HFD) for 10 weeks and then subjected to aerobic exercises for 12 weeks. We verified that TRPA1 was located in the epididymal epithelium. Notably, aerobic exercises reversed the downregulated TRPA1 in the epididymis of HFD-induced obese rats, thus improving sperm fertilizing capacity and Cl- concentration in epididymal milieu. Ussing chamber experiments showed that cinnamaldehyd (CIN), agonist of TRPA1, stimulated an increase of the short-circuit current (ISC) in rat cauda epididymal epithelium, which was subsequently abolished by removing the ambient Cl- and HCO3-. In vivo data revealed that aerobic exercises increased the CIN-stimulated Cl- secretion rate of epididymal epithelium in obese rats. Pharmacological experiments revealed that blocking cystic fibrosis transmembrane regulator (CFTR) and Ca2+-activated Cl- channel (CaCC) suppressed the CIN-stimulated anion secretion. Moreover, CIN application in rat cauda epididymal epithelial cells elevated intracellular Ca2+ level, and thus activate CACC. Interfering with the PGHS2-PGE2-EP2/EP4-cAMP pathway suppressed CFTR-mediated anion secretion. This study demonstrates that TRPA1 activation can stimulate anion secretion via CFTR and CaCC, which potentially forming an appropriate microenvironment essential for sperm maturation, and aerobic exercises can reverse the downregulation of TRPA1 in the epididymal epithelium of obese rats.

Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

Gene-repressing epigenetic reader EED unexpectedly enhances cyclinD1 gene activation.

Epigenetically switched, proliferative vascular smooth muscle cells (SMCs) form neointima, engendering stenotic diseases. Histone-3 lysine-27 trimethylation (H3K27me3) and acetylation (H3K27ac) marks are associated with gene repression and activation, respectively. The polycomb protein embryonic ectoderm development (EED) reads H3K27me3 and also enhances its deposition, hence is a canonical gene repressor. However, herein we found an unexpected role for EED in activating the bona fide pro-proliferative gene Ccnd1 (cyclinD1). EED overexpression in SMCs increased Ccnd1 mRNA, seemingly contradicting its gene-repressing function. However, consistently, EED co-immunoprecipitated with gene-activating H3K27ac reader BRD4, and they co-occupied at both mitogen-activated Ccnd1 and mitogen-repressed P57 (bona fide anti-proliferative gene), as indicated by chromatin immunoprecipitation qPCR. These results were abolished by an inhibitor of either the EED/H3K27me3 or BRD4/H3K27ac reader function. In accordance, elevating BRD4 increased H3K27me3. In vivo, while EED was upregulated in rat and human neointimal lesions, selective EED inhibition abated angioplasty-induced neointima and reduced cyclinD1 in rat carotid arteries. Thus, results uncover a previously unknown role for EED in Ccnd1 activation, likely via its cooperativity with BRD4 that enhances each other's reader function; i.e., activating pro-proliferative Ccnd1 while repressing anti-proliferative P57. As such, this study confers mechanistic implications for the epigenetic intervention of neointimal pathology.

miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4.

Neointimal hyperplasia (IH) is a common vascular pathology that typically manifests in in-stent restenosis and bypass vein graft failure. Smooth muscle cell (SMC) phenotypic switching is central to IH, both regulated by some microRNAs, yet the role of miR579-3p, a scarcely studied microRNA, is not known. Unbiased bioinformatic analysis suggested that miR579-3p was repressed in human primary SMCs treated with different pro-IH cytokines. Moreover, miR579-3p was software-predicted to target both c-MYB and KLF4 - two master transcription factors known to promote SMC phenotypic switching. Interestingly, treating injured rat carotid arteries via local infusion of miR579-3p-expressing lentivirus reduced IH 14 days after injury. In cultured human SMCs, transfection with miR579-3p inhibited SMC phenotypic switching, as indicated by decreased proliferation/migration and increased SMC contractile proteins. miR579-3p transfection downregulated c-MYB and KLF4, and luciferase assays indicated miR579-3p's targeting of the 3'UTRs of the c-MYB and KLF4 mRNAs. In vivo, immunohistochemistry showed that treatment of injured rat arteries with the miR579-3p lentivirus reduced c-MYB and KLF4 and increased SMC contractile proteins. Thus, this study identifies miR579-3p as a previously unrecognized small-RNA inhibitor of IH and SMC phenotypic switch involving its targeting of c-MYB and KLF4. Further studies on miR579-3p may provide an opportunity for translation to develop IH-mitigating new therapeutics.

Sphingoid Bases Regulate the Sigma-1 Receptor-Sphingosine and N,N'-Dimethylsphingosine Are Endogenous Agonists.

Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N'-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73-8.93 kcal/mol for SPH and 8.56-8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments.

Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation.

The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R. However, the effect of such modulation on AMD pathology remains underexplored. Here, we evaluated S1R- or S2R-selective modulation in an AMD-related model of Abca4-/-Rdh8-/- mice with a disrupted visual cycle that predisposes RPE and photoreceptors to illumination-induced damage. For S1R modulation, we used (+)-pentazocine, which is a high-affinity S1R-selective drug. For S2R modulation, we chose CM398, a high-affinity and highly S2R-selective ligand with drug-like properties. Abca4-/-Rdh8-/- mice received a single i.p. injection of (+)-pentazocine or CM398 or vehicle 30 min before illumination. Pretreatment with (+)-pentazocine improved electroretinogram a- and b-waves compared to that with vehicle. Consistently, in another AMD-related mouse model induced by tail-vein injected NaIO3, S1R genetic ablation aggravated photoreceptor loss. In Abca4-/-Rdh8-/- mice, pretreatment with CM398 appeared to partially avert illumination-induced photoreceptor loss and autofluorescent granule formation that signals RPE damage, as revealed by optical coherence tomography. Thus, this study using AMD-related models provides evidence of photoreceptor protection afforded by selective modulation of S1R or S2R.

Total Syntheses of Daphnezomine L-type and Secodaphniphylline-type Daphniphyllum Alkaloids via Late-Stage C-N Bond Activation.

Here, we report the first total syntheses of daphnezomine L-type alkaloids daphnezomine L methyl ester and calyciphylline K via late-stage C-N bond activation. The first synthesis of secodaphniphylline-type alkaloid caldaphnidine D was also achieved via a similar strategy. Other key transformations employed in our synthesis were a facile vicinal diol olefination and an efficient radical cyclization cascade. Biological studies indicated two synthetic compounds possess promising neuroprotective activity.

Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism.

Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products.

The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, small-molecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges.This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries.We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck-Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.