The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Induction of steatosis in primary human hepatocytes recapitulates key pathophysiological aspects of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Its limited treatment options warrant novel pre-clinical models for target selection and drug validation. We have established and extensively characterized a primary human steatotic hepatocyte in vitro model system that could guide treatment strategies for MASLD. METHODS: Cryopreserved primary human hepatocytes from five donors varying in sex and ethnicity were cultured with free fatty acids (FFA) in 3D collagen sandwich for 7 days and the development of MASLD was followed by assessing classical hepatocellular functions. As proof of concept, the effects of the drug Firsocostat (GS-0976) on in vitro MASLD phenotypes were evaluated. RESULTS: Incubation with FFA induced steatosis, insulin resistance, mitochondrial dysfunction, inflammation, and alterations in prominent human gene signatures similar to patients with MASLD, indicating the recapitulation of human MASLD in this system. As the application of Firsocostat rescued clinically observed fatty liver disease pathologies, it highlights the ability of the in vitro system to test drug efficacy and potentially characterize their mode of action. CONCLUSIONS: Altogether, our human MASLD in vitro model system could guide the development and validation of novel targets and drugs for the treatment of MASLD. IMPACT AND IMPLICATIONS: Due to low drug efficacy and high toxicity, a clinical treatment option for MASLD is limited. To facilitate earlier stop-go decisions in drug development, we have established a primary human steatotic hepatocyte in vitro model. As the model recapitulates clinically relevant MASLD characteristics at high phenotypic resolution, it can serve as a pre-screening platform and guide target identification and validation in MASLD therapy.

Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.

Angularly offset multiline dispersive optical phased array enabling large field of view and plateau envelope.

We propose and demonstrate an angularly offset multiline (AOML) dispersive silicon nitride optical phased array (OPA) that enables efficient line beam scanning with an expanded field of view (FOV) and plateau envelope. The suggested AOML OPA incorporates multiline OPA units, which were seamlessly integrated with a 45° angular offset through a thermo-optic switch based on a multimode interference coupler, resulting in a wide FOV that combines three consecutive scanning ranges. Simultaneously, a periodic diffraction envelope rendered by the multiline OPA units contributes to reduced peak intensity fluctuation of the main lobe across the large FOV. An expedient polishing enabling the angled facet was diligently accomplished through the implementation of oblique polishing techniques applied to the 90° angle of the chip. For each dispersive OPA unit, we engineered an array of delay lines with progressively adjustable delay lengths, enabling a passive wavelength-tunable beam scanning. Experimental validation of the proposed OPA revealed efficient beam scanning, achieved by wavelength tuning from 1530 to 1600 nm and seamless switching between multiline OPAs, yielding an FOV of 152° with a main lobe intensity fluctuation of 2.8 dB. The measured efficiency of dispersive scanning was estimated at 0.97°/nm, as intended.

Hybrid integrated thin-film lithium niobate-silicon nitride electro-optical phased array incorporating silicon nitride grating antenna for two-dimensional beam steering.

This study proposes a solid-state two-dimensional beam-steering device based on an electro-optical phased array (EOPA) in thin-film lithium niobate (TFLN) and silicon nitride (SiN) hybrid platforms, thereby eliminating the requirement for the direct etching of TFLN. Electro-optic (EO) phase modulator array comprises cascaded multimode interference couplers with an SiN strip-loaded TFLN configuration, which is designed and fabricated via i-line photolithography. Each EO modulator element with an interaction region length of 1.56 cm consumed a minimum power of 3.2 pJ/π under a half-wave voltage of 3.64 V and had an estimated modulation speed of 1.2 GHz. Subsequently, an SiN dispersive antenna with a waveguide grating was tethered to the modulator array to form an EOPA, facilitating the out-of-plane radiation of highly defined near-infrared beams. A prepared EOPA utilized EO phase control and wavelength tuning near 1550 nm to achieve a field-of-view of 22° × 5° in the horizontal and vertical directions. The proposed hybrid integrated platform can potentially facilitate low-power and high-speed beam steering.

Retinestatin, a Polyol Polyketide from a Termite Nest-Derived Streptomyces sp.

A new polyol polyketide, named retinestatin (1), was obtained and characterized from the culture of a Streptomyces strain, which was isolated from a subterranean nest of the termite Reticulitermes speratus kyushuensis Morimoto. The planar structure of 1 was elucidated on the basis of the cumulative analysis of ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance spectroscopic data. The absolute configuration of 1 at 12 chiral centers was successfully assigned by employing a J-based configuration analysis in combination with ROESY correlations, a quantum mechanics-based computational approach to calculate NMR chemical shifts, and a 3 min flash esterification by Mosher's reagents followed by NMR analysis. Biological evaluation of retinestatin (1) using an in vitro model of Parkinson's disease revealed that 1 protected SH-SY5Y dopaminergic cells from MPP+-induced cytotoxicity, indicating its neuroprotective effects.

Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures.

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N-hydroxylase (KtzI) and N-N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with 15NH4Cl and applying 1H-15N heteronuclear multiple bond correlation (HMBC) along with 1H-15N heteronuclear single quantum coherence (HSQC) and 1H-15N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid (1), previously reported chloptosin (2) in group I, depsidomycin D (3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B (4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A (4) inhibited STAT3 activation and induced G2/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A (4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

Glycosylated and Succinylated Macrocyclic Lactones with Amyloid-ß-Aggregation-Regulating Activity from a Marine Bacillus sp.

Two new glycosylated and succinylated macrocyclic lactones, succinyl glyco-oxydifficidin (1) and succinyl macrolactin O (2), were isolated from a Bacillus strain collected from an intertidal mudflat on Anmyeon Island in Korea. The planar structures of 1 and 2 were proposed using mass spectrometric analysis and NMR spectroscopic data. The absolute configurations of 1 and 2 were determined by optical rotation, J-based configuration analysis, chemical derivatizations, including the modified Mosher's method, and quantum-mechanics-based calculation. Biological evaluation of 1 and 2 revealed that succinyl glyco-oxydifficidin (1) inhibited/dissociated amyloid ß (Aß) aggregation, whereas succinyl macrolactin O (2) inhibited Aß aggregation, indicating their therapeutic potential for disassembling and removing Aß aggregation.

Tandocyclinones A and B, Ether Bridged C-Glycosyl Benz[a]anthracenes from an Intertidal Zone Streptomyces sp.

Two new proton-deficient metabolites, tandocyclinones A and B (1 and 2), were discovered via the chemical profiling of the Streptomyces sp. strain TDH03, which was isolated from a marine sediment sample collected from the intertidal mudflat in Tando Port, the Republic of Korea. The structures of 1 and 2 were elucidated as new ether-bridged C-glycosyl benz[a]anthracenes by using a combination of spectroscopic analyses of ultraviolet (UV) and mass spectrometry (MS) data, along with nuclear magnetic resonance (NMR) spectra, which were acquired in tetrahydrofuran (THF)-d8 selected after an extensive search for a solvent, resulting in mostly observable exchangeable protons in the 1H NMR spectrum. Their configurations were successfully assigned by applying a J-based configuration analysis, rotating-frame Overhauser enhancement spectroscopy (ROESY) NMR correlations, chemical derivatization methods based on NMR (a modified version of Mosher's method) and circular dichroism (CD) (Snatzke's method using Mo2(OAc)4-induced CD), as well as quantum-mechanics-based computational methods, to calculate the electronic circular dichroism (ECD). Tandocyclinones A and B (1 and 2) were found to have weak antifungal activity against Trichophyton mentagrophytes IFM40996 with an MIC value of 128 µg/mL (244 and 265 µM for 1 and 2, respectively). A further biological evaluation revealed that tandocyclinone A (1) displayed inhibitory activity against Mycobacterium avium (MIC50 = 40.8 µM) and antiproliferative activity against SNU638 and HCT116 cancer cells, with IC50 values of 31.9 µM and 49.4 µM, respectively.

Peripheral serotonin: cultivating companionship with gut microbiota in intestinal homeostasis.

Serotonin, also known as 5-hydroxytryptamine (5-HT), is an evolutionarily ancient and phylogenetically conserved monoamine that regulates multifaceted physiological functions in mammals. 5-HT was, at one time, most extensively studied as a neurotransmitter within the central nervous system but is now known to regulate nonneuronal functions including immune responses in an autocrine-paracrine-endocrine manner. Compelling evidence from intervention studies using germ-free mice or antibiotic-associated microbiota perturbation suggests that novel interactions between 5-HT and the gut microbiota are essential in maintaining intestinal homeostasis. Importantly, recent studies reveal that bidirectional host-microbial interactions mediated by the host serotonergic system can promote distinct changes within the gut microbiota. These changes may potentially lead to a state known as "dysbiosis" that has been strongly associated with various gut pathologies including inflammatory bowel disease (IBD). In this review, we update the current understanding of host-microbiota interaction by focusing on the impact of peripheral 5-HT signaling within this dynamic. We also briefly highlight key environmental risk factors for IBD, such as the Western diet, and draw attention to the interaction of synthetic food colorants with 5-HT signaling that may facilitate future research.

Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects.

Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.

Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

Cinnamoyl-containing nonribosomal peptides (CCNPs) form a unique family of actinobacterial secondary metabolites and display various biological activities. A new CCNP named epoxinnamide (1) was discovered from intertidal mudflat-derived Streptomyces sp. OID44. The structure of 1 was determined by the analysis of one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) data along with a mass spectrum. The absolute configuration of 1 was assigned by the combination of advanced Marfey's method, 3JHH and rotating-frame overhauser effect spectroscopy (ROESY) analysis, DP4 calculation, and genomic analysis. The putative biosynthetic pathway of epoxinnamide (1) was identified through the whole-genome sequencing of Streptomyces sp. OID44. In particular, the thioesterase domain in the nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster was proposed as a bifunctional enzyme, which catalyzes both epimerization and macrocyclization. Epoxinnamide (1) induced quinone reductase (QR) activity in murine Hepa-1c1c7 cells by 1.6-fold at 5 µM. It also exhibited effective antiangiogenesis activity in human umbilical vein endothelial cells (IC50 = 13.4 µM).

TLR2 Plays a Pivotal Role in Mediating Mucosal Serotonin Production in the Gut.

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that mediates various physiological processes in the gut. Enterochromaffin (EC) cells in the mucosal layer of the gut are the main source of 5-HT in the body and are situated in close proximity to the gut microbiota. In this study, we identify a pivotal role of TLR2 in 5-HT production in the gut. Antibiotic treatment reduces EC cell numbers and 5-HT levels in naive C57BL/6 mice, which is associated with downregulation of TLR2 expression but not TLR1 or TLR4. TLR2-deficient (Tlr2 -/-) and Myd88 -/- mice express lower EC cell numbers and 5-HT levels, whereas treatment with TLR2/1 agonist upregulates 5-HT production in irradiated C57BL/6 mice, which are reconstituted with Tlr2 -/- bone marrow cells, and in germ-free mice. Human EC cell line (BON-1 cells) release higher 5-HT upon TLR2/1 agonist via NF-κB pathway. Tlr2 -/- mice and anti-TLR2 Ab-treated mice infected with enteric parasite, Trichuris muris, exhibited attenuated 5-HT production, compared with infected wild-type mice. Moreover, excretory-secretory products from T. muris induce higher 5-HT production in BON-1 cells via TLR2 in a dose-dependent manner, whereby the effect of excretory-secretory products is abrogated by TLR2 antagonist. These findings not only suggest an important role of TLR2 in mucosal 5-HT production in the gut by resident microbiota as well as by a nematode parasite but also provide, to our knowledge, novel information on the potential benefits of targeting TLR2 in various gut disorders that exhibit aberrant 5-HT signaling.

AtCAP2 is crucial for lytic vacuole biogenesis during germination by positively regulating vacuolar protein trafficking.

Protein trafficking is a fundamental mechanism of subcellular organization and contributes to organellar biogenesis. AtCAP2 is an Arabidopsis homolog of the Mesembryanthemum crystallinum calcium-dependent protein kinase 1 adaptor protein 2 (McCAP2), a member of the syntaxin superfamily. Here, we show that AtCAP2 plays an important role in the conversion to the lytic vacuole (LV) during early plant development. The AtCAP2 loss-of-function mutant atcap2-1 displayed delays in protein storage vacuole (PSV) protein degradation, PSV fusion, LV acidification, and biosynthesis of several vacuolar proteins during germination. At the mature stage, atcap2-1 plants accumulated vacuolar proteins in the prevacuolar compartment (PVC) instead of the LV. In wild-type plants, AtCAP2 localizes to the PVC as a peripheral membrane protein and in the PVC compartment recruits glyceraldehyde-3-phosphate dehydrogenase C2 (GAPC2) to the PVC. We propose that AtCAP2 contributes to LV biogenesis during early plant development by supporting the trafficking of specific proteins involved in the PSV-to-LV transition and LV acidification during early stages of plant development.

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.

Jasmonic acid-inducible TSA1 facilitates ER body formation.

Members of the Brassicales contain an organelle, the endoplasmic reticulum (ER) body, which is derived from the ER. Recent studies have shed light on the biogenesis of the ER body and its physiological role in plants. However, formation of the ER body and its physiological role are not fully understood. Here, we investigated the physiological role of TSK-associating protein 1 (TSA1), a close homolog of NAI2 that is involved in ER body formation, and provide evidence that it is involved in ER body biogenesis under wound-related stress conditions. TSA1 is N-glycosylated and localizes to the ER body as a luminal protein. TSA1 was highly induced by the plant hormone, methyl jasmonate (MeJA). Ectopic expression of TSA1:GFP induced ER body formation in root tissues of transgenic Arabidopsis thaliana and in leaf tissues of Nicotiana benthamiana. TSA1 and NAI2 formed a heterocomplex and showed an additive effect on ER body formation in N. benthamiana. MeJA treatment induced ER body formation in leaf tissues of nai2 and tsa1 plants, but not nai2/tsa1 double-mutant plants. However, constitutive ER body formation was altered in young seedlings of nai2 plants but not tsa1 plants. Based on these results, we propose that TSA1 plays a critical role in MeJA-induced ER body formation in plants.

Unusual bridged angucyclinones and potent anticancer compounds from Streptomyces bulli GJA1.

Two new unique angucyclinones (1 and 2) with unprecedented ether bridges connecting carbons 5 and 7 were isolated from the cultures of Streptomyces bulli GJA1, an endophyte of Gardenia jasminoides, together with two known ones (3 and 4). The MS2-based molecular networking system facilitated the isolation of compounds with target functionalities. The stereochemistry of 1 was completely established by ROESY and ECD experiments. Compound 3 showed antivirulence activities by inhibiting the peptide toxin (PSMs) production and the biofilm formation of MRSA. Compounds 3 and 4 showed very potent anti-proliferative effects against OV1 and ES2 ovarian cancer cells.

Donghaecyclinones A-C: New Cytotoxic Rearranged Angucyclinones from a Volcanic Island-Derived Marine Streptomyces sp.

Chemical profiling of the Streptomyces sp. strain SUD119, which was isolated from a marine sediment sample collected from a volcanic island in Korea, led to the discovery of three new metabolites: donghaecyclinones A-C (1-3). The structures of 1-3 were found to be rearranged, multicyclic, angucyclinone-class compounds according to nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses. The configurations of their stereogenic centers were successfully assigned using a combination of quantum mechanics-based computational methods for calculating the NMR shielding tensor (DP4 and CP3) as well as electronic circular dichroism (ECD) along with a modified version of Mosher's method. Donghaecyclinones A-C (1-3) displayed cytotoxicity against diverse human cancer cell lines (IC50: 6.7-9.6 µM for 3).

Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells.

Several reports have described the anti-cancer activity of arctigenin, a lignan extracted from Arctium lappa L. Here, we investigated the effect of arctigenin (ATG) on doxorubicin (DOX)-induced cell death using MDA-MB-231 human breast cancer cells. The results showed that DOX-induced cell death was enhanced by ATG/DOX co-treatment in a concentration-dependent manner and that this was associated with increased DOX uptake and the suppression of multidrug resistance-associated protein 1 (MRP1) gene expression in MDA-MB-231 cells. ATG enhanced DOX-induced DNA damage and decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expressions of RAD51 and survivin. Cell death caused by ATG/DOX co-treatment was mediated by the nuclear translocation of apoptosis inducing factor (AIF), reductions in cellular and mitochondrial Bcl-2 and Bcl-xL, and increases in mitochondrial BAX levels. However, caspase-3 and -7 did not participate in DOX/ATG-induced cell death. We also found that DOX/ATG-induced cell death was linked with activation of the p38 signaling pathway and suppressions of the phosphorylations and expressions of Akt and c-Jun N-terminal kinase. Taken together, these results show that ATG enhances the cytotoxic activity of DOX in MDA-MB-231 human breast cancer cells by inducing prolonged p21 expression and p38-mediated AIF-dependent cell death. In conclusion, our findings suggest that ATG might alleviate the side effects and improve the therapeutic efficacy of DOX.

Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease.

Rhizolutin (1) was discovered as a natural product of ginseng-rhizospheric Streptomyces sp. WON17. Its structure features an unprecedented 7/10/6-tricyclic dilactone carbon skeleton composed of dimethylcyclodecatriene flanked by a 7-membered and a 6-membered lactone ring based on spectroscopic analysis. During an unbiased screening of natural product libraries, this novel compound was found to dissociate amyloid-ß (Aß) plaques and tau tangles, which are key pathological hallmarks of Alzheimer's disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Aß-induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Aß and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials.