RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling.

BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

Effects of Harvest Timing on Phytochemical Composition in Lamiaceae Plants under an Environment-Controlled System.

The Lamiaceae family is widely recognized for its production of essential oils and phenolic compounds that have promising value as pharmaceutical materials. However, the impact of environmental conditions and different harvest stages on the phytochemical composition of Lamiaceae plants remains poorly understood. This study aimed to investigate the effects of harvest time on the phytochemical composition, including rosmarinic acid (RA) and volatile organic compounds (VOCs), of four Lamiaceae plants-Korean mint (AR), lemon balm (MO), opal basil (OBP), and sage (SO)-and was conducted under an environment-controlled system. Although all four plants had RA as the dominant compound, its distribution varied by species. The flowered plants, including AR and OBP, exhibited a rapid increase of RA during the transition from the vegetative stage to the reproductive stage. In contrast, non-flowered groups, including MO and SO, showed a steady increase in the content of total phenolics and RA. The main components of VOCs also differed depending on the plant, with characteristic fragrance compounds identified for each one (AR: estragole; MO: (Z)-neral and geranial; OBP: methyl eugenol, eugenol, and linalool; and SO: (Z)-thujone, camphor, and humulene). The total VOCs content was highest on the 60th day after transplanting regardless of the species, while the trends of total phenolics, RA content, and antioxidant activities were different depending on whether plant species flowered during the cultivation cycle. There was a steady increase in species that had not flowered, and the highest content and activity of the flowering period were confirmed in the flowering plant species.

ELOVL2-AS1 suppresses tamoxifen resistance by sponging miR-1233-3p in breast cancer.

Tamoxifen (Tam) has long been a top treatment option for breast cancer patients, but the challenge of eliminating cancer recurrence remains. Here, we identify a signalling pathway involving ELOVL2, ELOVL2-AS1, and miR-1233-3p, which contributes to drug resistance in Tam-resistant (TamR) breast cancer. ELOVL2-AS1, a long noncoding RNA, was significantly upregulated by its antisense gene, ELOVL2, which is known to be downregulated in TamR cells. Additionally, ELOVL2-AS1 underwent the most hypermethylation in MCF-7/TamR cells. Furthermore, patients with breast cancer who developed TamR during chemotherapy had significantly lower expression of ELOVL2-AS1 compared to those who responded to Tam. Ectopic downregulation of ELOVL2-AS1 by siRNA both stimulated cancer cell growth and deteriorated TamR. We also found that ELOVL2-AS1 sponges miR-1233-3p, which has pro-proliferative activity and elevates TamR, leading to the activation of potential target genes, such as MYEF2, NDST1, and PIK3R1. These findings suggest that ELOVL2-AS1, in association with ELOVL2, may contribute to the suppression of drug resistance by sponging miR-1233-3p in breast cancer.

5-Methylthiopentyl Isothiocyanate, a Sulforaphane Analogue, Inhibits Pro-inflammatory Cytokines by Regulating LPS/ATP-mediated NLRP3 Inflammasome Activation.

BACKGROUND: Pro-inflammatory cytokines secreted from activated macrophages and astrocytes are crucial mediators of inflammation for host defense. Among them, the secretion of IL-1ß, a major pro-inflammatory cytokine, is especially mediated by the activation of NLRP3 inflammasome. Pro-IL-1ß, which is produced in response to the invaded pathogens, such as LPS, is cleaved and matured in the NLRP3 inflammasome by the recognition of ATP. Excessively activated IL-1ß induces other immune cells, resulting in the up-regulation of inflammation. Therefore, regulation of NLRP3 inflammasome can be a good strategy for alleviating inflammation. OBJECTIVE: Our study aimed to examine whether 5-methylthiopentyl isothiocyanate, a sulforaphane analogue (berteroin), has an anti-inflammatory effect on the NLRP3 inflammasome activation induced by LPS and ATP. METHODS: Primary bone marrow-derived macrophages (BMDMs) and astrocytes were stimulated by LPS and ATP with the treatment of 5-methylthiopentyl isothiocyanate, a sulforaphane analogue. The secretion of pro-inflammatory cytokines was measured by ELISA, and the expression level of NLRP3 inflammasome-associated proteins was detected by western blot. The association of NLRP3 inflammasome was assessed by co-immunoprecipitation, and the formation of ASC specks was evaluated by fluorescent microscope. RESULTS: 5-Methylthiopentyl isothiocyanate, a sulforaphane analogue (berteroin), decreased the release of pro-inflammatory cytokines, IL-1ß, and IL-6 in the BMDMs. Berteroin notably prevented the formation of both NLRP3 inflammasome and ASC specks, which reduced the secretion of IL-1ß. Additionally, berteroin reduced the IL-1ß secretion and cleaved IL-1ß expression in the primary astrocytes. DISCUSSION AND CONCLUSION: These results indicated the anti-inflammatory effects of 5-methylthiopentyl isothiocyanate (berteroin) by regulating NLRP3 inflammasome activation, suggesting that berteroin could be the potential natural drug candidate for the regulation of inflammation.

The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease, the Consequence of Neural Cell Death.

Alzheimer's disease (AD) is accompanied by neural cell loss and memory deficit. Neural cell death, occurring via apoptosis and autophagy, is widely observed in the AD brain in addition to neuroinflammation mediated by necroptosis and the NLRP3 inflammasome. Neurotoxicity induced by amyloid-beta (Aß) and tau aggregates leads to excessive neural cell death and neuroinflammation in the AD brain. During AD progression, uncontrolled neural cell death results in the dysregulation of cellular activity and synaptic function. Apoptosis mediated by pro-apoptotic caspases, autophagy regulated by autophagy-related proteins, and necroptosis controlled by the RIPK/MLKL axis are representative of neural cell death occurred during AD. Necroptosis causes the release of cellular components, contributing to the pro-inflammatory environment in the AD brain. Inordinately high levels of neural cell death and pro-inflammatory events lead to the production of pro-inflammatory cytokines and feed-forward hyper neuroinflammation. Thus, neural cell death and neuroinflammation cause synaptic dysfunction and memory deficits in the AD brain. In this review, we briefly introduce the mechanisms of neural cell death and neuroinflammation observed in the AD brain. Combined with a typical strategy for targeting Aß and tau, regulation of neural cell death and neuroinflammation may be effective for the amelioration of AD pathologies.

The Impact of Light Wavelength and Darkness on Metabolite Profiling of Korean Ginseng: Evaluating Its Anti-Cancer Potential against MCF-7 and BV-2 Cell Lines.

Korean ginseng is a source of functional foods and medicines; however, its productivity is hindered by abiotic stress factors, such as light. This study investigated the impacts of darkness and different light wavelengths on the metabolomics and anti-cancer activity of ginseng extracts. Hydroponically-grown Korean ginseng was shifted to a light-emitting diodes (LEDs) chamber for blue-LED and darkness treatments, while white fluorescent (FL) light treatment was the control. MCF-7 breast cancer and lipopolysaccharide (LPS)-induced BV-2 microglial cells were used to determine chemo-preventive and neuroprotective potential. Overall, 53 significant primary metabolites were detected in the treated samples. The levels of ginsenosides Rb1, Rb2, Rc, Rd, and Re, as well as organic and amino acids, were significantly higher in the dark treatment, followed by blue-LED treatment and the FL control. The dark-treated ginseng extract significantly induced apoptotic signaling in MCF-7 cells and dose-dependently inhibited the NF-κB and MAP kinase pathways in LPS-induced BV-2 cells. Short-term dark treatment increased the content of Rd, Rc, Rb1, Rb2, and Re ginsenosides in ginseng extracts, which promoted apoptosis of MCF-7 cells and inhibition of the MAP kinase pathway in BV-2 microglial cells. These results indicate that the dark treatment might be effective in improving the pharmacological potential of ginseng.

Naturally-Occurring Tyrosinase Inhibitors Classified by Enzyme Kinetics and Copper Chelation.

Currently, there are three major assaying methods used to validate in vitro whitening activity from natural products: methods using mushroom tyrosinase, human tyrosinase, and dopachrome tautomerase (or tyrosinase-related protein-2, TRP-2). Whitening agent development consists of two ways, melanin synthesis inhibition in melanocytes and downregulation of melanocyte stimulation. For melanin levels, the melanocyte cell line has been used to examine melanin synthesis with the expression levels of TRP-1 and TRP-2. The proliferation of epidermal surfaced cells and melanocytes is stimulated by cellular signaling receptors, factors, or mediators including endothelin-1, α-melanocyte-stimulating hormone, nitric oxide, histamine, paired box 3, microphthalmia-associated transcription factor, pyrimidine dimer, ceramide, stem cell factors, melanocortin-1 receptor, and cAMP. In addition, the promoter region of melanin synthetic genes including tyrosinase is upregulated by melanocyte-specific transcription factors. Thus, the inhibition of growth and melanin synthesis in gene expression levels represents a whitening research method that serves as an alternative to tyrosinase inhibition. Many researchers have recently presented the bioactivity-guided fractionation, discovery, purification, and identification of whitening agents. Melanogenesis inhibition can be obtained using three different methods: tyrosinase inhibition, copper chelation, and melanin-related protein downregulation. There are currently four different types of inhibitors characterized based on their enzyme inhibition mechanisms: competitive, uncompetitive, competitive/uncompetitive mixed-type, and noncompetitive inhibitors. Reversible inhibitor types act as suicide substrates, where traditional inhibitors are classified as inactivators and reversible inhibitors based on the molecule-recognizing properties of the enzyme. In a minor role, transcription factors can also be downregulated by inhibitors. Currently, the active site copper iron-binding inhibitors such as kojic acid and chalcone exhibit tyrosinase inhibitory activity. Because the tyrosinase catalysis site structure is important for the mechanism determination of tyrosinase inhibitors, understanding the enzyme recognition and inhibitory mechanism of inhibitors is essential for the new development of tyrosinase inhibitors. The present review intends to classify current natural products identified by means of enzyme kinetics and copper chelation to exhibit tyrosinase enzyme inhibition.

The Innovative Approach in Functional Bladder Disorders: The Communication Between Bladder and Brain-Gut Axis.

Functional bladder disorders including overactive bladder and interstitial cystitis may induce problems in many other parts of our body such as brain and gut. In fact, diagnosis is often less accurate owing to their complex symptoms. To have correct diagnosis of these diseases, we need to understand the pathophysiology behind overlapped clinical presentation. First, we focused on reviewing literatures that have reported the link between bladder and brain, as the patients with bladder disorders frequently accompanied mood disorders such as depression and anxiety. Second, we reviewed literatures that have described the relationship between bladder and gut. There exist many evidences of patients who suffered from both bladder and intestinal diseases, such as irritable bowel syndrome and inflammatory bowel disease, at the same time. Furthermore, the interaction between brain and gut, well-known as brain-gut axis, might be a key factor that could change the activity of bladder and vice versa. For example, the affective disorders could alter the activity of efferent nerves or autonomic nervous system that modulate the gut itself and its microbiota, which might cause the destruction of homeostasis in bladder eventually. In this way, the communication between bladder and brain-gut axis might affect permeability, inflammation, as well as infectious etiology and dysbiosis in bladder diseases. In this review, we aimed to find an innovative insight of the pathophysiology in the functional bladder disorders, and we could provide a new understanding of the overlapped clinical presentation by elucidating the pathophysiology of functional bladder disorders.

The Derivatives of Cromolyn Ameliorate the Abnormal Misfolding of Amyloid Proteins and Neuroinflammation in the Neural Cells.

BACKGROUND: The representative symptom of Alzheimer's Disease (AD) has mainly been mentioned to be misfolding of amyloid proteins, such as amyloid-beta (Aß) and tau protein. In addition, the neurological pathology related to neuroinflammatory signaling has recently been raised as an important feature in AD. Currently, numerous drug candidates continue to be investigated to reduce symptoms of AD, including amyloid proteins misfolding and neuroinflammation. OBJECTIVE: Our research aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. METHODS: CNU 010 and CNU 011 derived from cromoglicic acid were synthesized. The inhibitory effects of Aß and tau were identified by thioflavin T assay. Moreover, western blots were conducted with derivates CNU 010 and CNU 011 to confirm the effects on inflammation. RESULTS: CNU 010 and CNU 011 significantly inhibited the aggregation of Aß and tau proteins. Moreover, they reduced the expression levels of mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) signaling proteins, which are representative early inflammatory signaling markers. Also, the inhibitory effects on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression referring to late inflammation were confirmed. CONCLUSION: Our results showing multiple beneficial effects of cromolyn derivatives against abnormal aggregation of amyloid proteins and neuroinflammatory signaling provide evidence that CNU 010 and CNU 011 could be further developed as potential drug candidates for AD treatment.

Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques.

Amyloid-ß (Aß) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aß drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aß peptidomimetics that exploit the self-assembling nature of Aß and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aß, DAB, found to cross the BBB and solubilize Aß oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aß interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Molecular Van Der Waals Heterojunction Photodiodes Enabling Dipole-Induced Polarity Switching.

Solid-state devices capable of controlling light-responsive charge transport at the molecular scale are essential for developing molecular optoelectronic technology. Here, a solid-state molecular photodiode device constructed by forming van der Waals (vdW) heterojunctions between standard molecular self-assembled monolayers and two-dimensional semiconductors such as WSe2 is reported. In particular, two non-functionalized molecular species used herein (i.e., tridecafluoro-1-octanethiol and 1-octanethiol) enable bidirectional modulation of the interface band alignment with WSe2 , depending on their dipole orientations. This dipole-induced band modulation at the vdW heterointerface leads to the opposite change of both photoswitching polarity and rectifying characteristics. Furthermore, compared with other molecular or 2D photodiodes at a similar scale, these heterojunction devices exhibit significantly enhanced photo-responsive performances in terms of photocurrent magnitude, open-circuit potential, and switching speed. This study proposes a novel concept of the solid-state molecular optoelectronic device with controlled functions and enhanced performances.

RNA-based biomarkers for the diagnosis, prognosis, and therapeutic response monitoring of prostate cancer.

Prostate cancer (CaP) is the most common malignant neoplasm of the urinary tract. The current recommendations for CaP diagnosis rely on the prostate-specific antigen levels and a digital rectal examination for anatomical abnormalities. However, these diagnostic tools are not highly sensitive. In particular, prostate-specific antigen has a low positive predictive value (approximately 30%). Thus, there is a need to develop biomarkers to improve the early clinical detection of CaP. Several novel technologies enable the identification of biomarkers from diverse sources, including the urine, serum, and prostate tissues. Furthermore, advances in genomic techniques have enabled the analysis of novel biomarkers, such as deoxyribonucleic acids (DNAs), ribonucleic acids (RNAs), proteins, and circulating tumor cells. Previous studies have demonstrated that RNAs are potential diagnostic biomarkers for various cancers using high-throughput sequencing analysis. The sensitivity and specificity of RNA biomarkers are higher than those of protein biomarkers. Polymerase chain reaction enables the amplification of trace levels of RNAs with high sensitivity and specificity. RNA biomarkers provide dynamic insights into cellular states and regulatory processes when compared with DNA biomarkers. Additionally, multiple copies of various RNAs in a cell provide more information than DNA. The levels of specific RNAs in CaP tissues are upregulated when compared with those in non-cancerous tissues. Additionally, RNAs can be easily isolated from various body fluids. Thus, RNAs are potential non-invasive biomarkers for CaP. Moreover, the analysis of RNA levels adjusted for each stage of CaP enables the determination of prognostic individualized therapy for aggressive or progressive CaP. This review focused on the diagnostic and prognostic values of RNAs for CaP.

Preventive Effect of M. cochinchinensis on Melanogenesis via Tyrosinase Activity Inhibition and p-PKC Signaling in Melan-A Cell.

Whitening research is of particular interest in the cosmetics market. The main focus of whitening research is on melanogenesis inhibition through tyrosinase activity. The mechanism of melanogenesis is involved with tyrosinase activity and p-PKC signaling. In this study, we used Momordica cochinchinensis (Lour.) spreng, a tropical fruit found throughout Southeast Asia, to investigate the inhibitory effect of melanogenesis. M. cochinchinensis contains a high concentration of polyphenols, flavonoids, and unsaturated fatty acids, which might be related to antioxidant activity. This study aimed to determine whether M. cochinchinensis extracts inhibit melanin synthesis in melan-A cells by inhibiting tyrosinase activity and p-PKC signaling. M. cochinchinensis was divided into pulp and aril and extracted under various conditions, and it was confirmed that all pulp and aril extracts have high contents of both phenols and flavonoids. Melan-A cells were treated with PMA for three days to induce melanin synthesis. After PMA treatment, M. cochinchinensis extracts were added to cultured media in a dose-dependent manner. Melanin contents and MTS were used to determine the amount of melanin in live cells. M. cochinchinensis extracts were evaluated for their effects on tyrosinase activity and p-PKC signaling pathways by Western blotting. It was found that M. cochinchinensis extract treatment decreased the amount of melanin and suppressed p-PKC expression. Additionally, tyrosinase activity was reduced after M. cochinchinensis extract treatment in a dose-dependent manner. Therefore, it was concluded that M. cochinchinensis could be used in antimelanogenesis and functional cosmetic materials to improve whitening.

Tailoring the Interfacial Band Offset by the Molecular Dipole Orientation for a Molecular Heterojunction Selector.

Understanding and designing interfacial band alignment in a molecular heterojunction provides a foundation for realizing its desirable electronic functionality. In this study, a tailored molecular heterojunction selector is implemented by controlling its interfacial band offset between the molecular self-assembled monolayer with opposite dipole orientations and the 2D semiconductor (1L -MoS2 or 1L -WSe2 ). The molecular dipole moment direction determines the direction of the band bending of the 2D semiconductors, affecting the dominant transport pathways upon voltage application. Notably, in the molecular heterostructure with 1L -WSe2 , the opposite rectification direction is observed depending on the molecular dipole moment direction, which does not hold for the case with 1L -MoS2 . In addition, the nonlinearity of the molecular heterojunction selector can be significantly affected by the molecular dipole moment direction, type of 2D semiconductor, and metal work function. According to the choice of these heterojunction constituents, the nonlinearity is widely tuned from 1.0 × 101 to 3.6 × 104 for the read voltage scheme and from 0.4 × 101 to 2.0 × 105 for the half-read voltage scheme, which can be scaled up to an ≈482 Gbit crossbar array.

Exposure to Salinity and Light Spectra Regulates Glucosinolates, Phenolics, and Antioxidant Capacity of Brassica carinata L. Microgreens.

The effect of salt treatment on Brassica carinata (BC) microgreens grown under different light wavelengths on glucosinolates (GLs) and phenolic compounds were evaluated. Quantifiable GLs were identified using ultra-high performance-quadrupole time of flight mass spectrometry. Extracts' ability to activate antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)) was evaluated on human colorectal carcinoma cells (HCT116). Furthermore, BC compounds' ability to activate expression of nuclear transcription factor-erythroid 2 related factor (Nrf2) and heme-oxygenase-1 (HO-1) proteins was examined using specific antibodies on HCT116 cells. Sinigrin (SIN) was the abundant GLs of the six compounds identified and its content together with total aliphatic GLs increased in saline conditions. Fluorescent (FL) and blue plus red (B1R1) lights were identified as stable cultivation conditions for microgreens, promoting biomass and glucobrassicin contents, whereas other identified individual and total indole GLs behaved differently in saline and non-saline environments. Blue light-emitting diodes and FL light in saline treatments mostly enhanced SIN, phenolics and antioxidant activities. The increased SOD and CAT activities render the BC microgreens suitable for lowering oxidative stress. Additionally, activation of Nrf2, and HO-1 protein expression by the GLs rich extracts, demonstrate their potential to treat and prevent oxidative stress and inflammatory disorders. Therefore, effective salt treatments and light exposure to BC microgreens present an opportunity for targeted regulation of growth and accumulation of bioactive metabolites.

Postharvest Drying Techniques Regulate Secondary Metabolites and Anti-Neuroinflammatory Activities of Ganoderma lucidum.

Ganoderma lucidum extract is a potent traditional remedy for curing various ailments. Drying is the most important postharvest step during the processing of Ganoderma lucidum. The drying process mainly involves heat (36 h at 60 °C) and freeze-drying (36 h at -80 °C). We investigated the effects of different postharvest drying protocols on the metabolites profiling of Ganoderma lucidum using GC-MS, followed by an investigation of the anti-neuroinflammatory potential in LPS-treated BV2 microglial cells. A total of 109 primary metabolites were detected from heat and freeze-dried samples. Primary metabolite profiling showed higher levels of amino acids (17.4%) and monosaccharides (8.8%) in the heat-dried extracts, whereas high levels of organic acids (64.1%) were present in the freeze-dried samples. The enzymatic activity, such as ATP-citrate synthase, pyruvate kinase, glyceraldehyde-3-phosphatase dehydrogenase, glutamine synthase, fructose-bisphosphate aldolase, and D-3-phosphoglycerate dehydrogenase, related to the reverse tricarboxylic acid cycle were significantly high in the heat-dried samples. We also observed a decreased phosphorylation level of the MAP kinase (Erk1/2, p38, and JNK) and NF-κB subunit p65 in the heat-dried samples of the BV2 microglia cells. The current study suggests that heat drying improves the production of ganoderic acids by the upregulation of TCA-related pathways, which, in turn, gives a significant reduction in the inflammatory response of LPS-induced BV2 cells. This may be attributed to the inhibition of NF-κB and MAP kinase signaling pathways in cells treated with heat-dried extracts.

The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics.

Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases.

Atomic-layer-confined multiple quantum wells enabled by monolithic bandgap engineering of transition metal dichalcogenides.

Quantum wells (QWs), enabling effective exciton confinement and strong light-matter interaction, form an essential building block for quantum optoelectronics. For two-dimensional (2D) semiconductors, however, constructing the QWs is still challenging because suitable materials and fabrication techniques are lacking for bandgap engineering and indirect bandgap transitions occur at the multilayer. Here, we demonstrate an unexplored approach to fabricate atomic-layer-confined multiple QWs (MQWs) via monolithic bandgap engineering of transition metal dichalcogenides and van der Waals stacking. The WOX/WSe2 hetero-bilayer formed by monolithic oxidation of the WSe2 bilayer exhibited the type I band alignment, facilitating as a building block for MQWs. A superlinear enhancement of photoluminescence with increasing the number of QWs was achieved. Furthermore, quantum-confined radiative recombination in MQWs was verified by a large exciton binding energy of 193 meV and a short exciton lifetime of 170 ps. This work paves the way toward monolithic integration of band-engineered heterostructures for 2D quantum optoelectronics.

Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-ß and Tau Fibrils.

BACKGROUND: Alzheimer's disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-ß (Aß) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aß or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aß and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. OBJECTIVE: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aß and tau aggregates through in vitro assessments. METHODS: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aß fibrils. Then, anti-cytotoxic, anti-Aß, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. RESULTS: When HT22 cells were exposed to Aß aggregates, the treatment of borrelidins alleviates the Aß-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aß aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aß aggregates but also directly regulates tau aggregation. CONCLUSION: Borrelidin dissociates insoluble Aß and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aß or anti-tau immunotherapy for clearance of both aggregates.

Natural Products Targeting Amyloid Beta in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aß) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aß peptides and suppress the formation of abnormal Aß aggregates, thus reducing neural cell death, are being conducted. Generation of Aß peptides can be prevented by targeting the secretases involved in Aß-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aß peptides can induce conformational changes in abnormal Aß aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aß peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.