Elevated PINK1/Parkin-Dependent Mitophagy and Boosted Mitochondrial Function Mediate Protection of HepG2 Cells from Excess Palmitic Acid by Hesperetin.

Deregulation of mitochondrial functions in hepatocytes contributes to many liver diseases, such as nonalcoholic fatty liver disease (NAFLD). Lately, it was referred to as MAFLD (metabolism-associated fatty liver disease). Hesperetin (Hst), a bioactive flavonoid constituent of citrus fruit, has been proven to attenuate NAFLD. However, a potential connection between its preventive activities and the modulation of mitochondrial functions remains unclear. Here, our results showed that Hst alleviates palmitic acid (PA)-triggered NLRP3 inflammasome activation and cell death by inhibition of mitochondrial impairment in HepG2 cells. Hst reinstates fatty acid oxidation (FAO) rates measured by seahorse extracellular flux analyzer and intracellular acetyl-CoA levels as well as intracellular tricarboxylic acid cycle metabolites levels including NADH and FADH2 reduced by PA exposure. In addition, Hst protects HepG2 cells against PA-induced abnormal energetic profile, ATP generation reduction, overproduction of mitochondrial reactive oxygen species, and collapsed mitochondrial membrane potential. Furthermore, Hst improves the protein expression involved in PINK1/Parkin-mediated mitophagy. Our results demonstrate that it restores PA-impaired mitochondrial function and sustains cellular homeostasis due to the elevation of PINK1/Parkin-mediated mitophagy and the subsequent disposal of dysfunctional mitochondria. These results provide therapeutic potential for Hst utilization as an effective intervention against fatty liver disease.

Monolithic Two-Terminal Perovskite/Perovskite/Silicon Triple-Junction Solar Cells with Open Circuit Voltage >2.8 V.

The efficiency of perovskite/silicon tandem solar cells has exceeded the previous record for III-V-based dual-junction solar cells. This shows the high potential of perovskite solar cells in multi-junction applications. Perovskite/perovskite/silicon triple-junction solar cells are now the next step to achieve efficient and low-cost multi-junction solar cells with an efficiency potential even higher than that for dual-junction solar cells. Here we present a perovskite/perovskite/silicon triple-junction solar cell with an open circuit voltage of >2.8 V, which is the record value reported for this structure so far. This is achieved through employing a gas quenching method for deposition of the top perovskite layer as well as optimization of interlayers between perovskite subcells. Moreover, for the measurement of our triple-junction solar cells, precise measurement procedures are implemented to ensure the reliability and accuracy of the reported values.

Clinical relevance of potential self-medication drug interactions in antineoplastic and immune-modulating therapy among online pharmacy customers.

Background: Modern oral antineoplastic and immune-modulating drugs offer an array of therapeutic advantages, and yet pose challenges in daily use for patients, physicians and pharmacists. In contrast to intravenous administration, these drugs are not subject to direct medical control. Recently, we have seen a huge rise in sales of non-prescription over-the-counter (OTC) medicines via the internet without any advice from a healthcare professional. Objectives: The aim of this study was to investigate whether the risk of known potential drug-drug interactions between modern oral antineoplastic and immune-modulating drugs and OTC drugs differs between sales in traditional community pharmacies versus online pharmacies. Design: Real-life sales data from community and online pharmacies were used as basis for the analysis. Methods: We determined the most frequently purchased antineoplastic and immune-modulating drug-substances in 14 local community pharmacies within the Munich area, Germany and identified the OTC substance groups that could potentially cause interactions with oncological therapies. Using sales data from 11 local community pharmacies and three online pharmacies, we investigated whether OTC purchases differed between the two sales channels. Results: We identified 10 relevant OTC substance classes and detected significant variations in patients' preferred sales channels between the drug classes. Certain OTC drugs, which seem to be bought more often over the internet, pose risks during antineoplastic and immune-modulating therapy. Conclusion: Patients should therefore be proactively made aware of the corresponding risks in order not to jeopardize the activity of the antineoplastic and immune-modulating drugs and thus the success of their therapy.

Comparing Community and Online Pharmacies: Investigating Potential Interactions Between Cancer and Immune-Modulating Drugs with Over-the-Counter Medications, and the Importance of Patient Awareness and Healthcare Professional Guidance in Minimizing Adverse Effects and Maintaining Treatment Efficacy Modern anticancer and immune-modulating drugs have the advantage of often being taken orally, but they present other challenges in daily use. Unlike intravenously administered drugs, these are usually not administered by a physician but taken by the patient at home. In these cases, patients may be more likely to buy and take self-medicating drugs over-the-counter (OTC) without consulting a healthcare professional. This study aimed to investigate whether there is a different risk of drug interactions between cancer or immune-modulating drugs and OTC drugs when bought in a community pharmacy versus an online pharmacy. Therefore, we looked at the most common cancer and immune-modulating drugs purchased in 14 local community pharmacies in Munich and identified which OTC drugs could cause problems when used simultaneously. Additionally, we analyzed the sales data from 11 local and 3 online pharmacies to determine if people were more likely to buy different OTC drugs from the two types of pharmacies. As a result, this study showed 10 relevant OTC drug types that potentially cause problems and influence effectiveness when used with cancer or immune-modulating drugs. Furthermore, we observed that some of these OTC drugs were purchased more often online than in community pharmacies and thus are more distant from the control of a physician or pharmacist. It is therefore essential for patients to be aware of the risks associated with easily accessible OTC drugs in combination with their cancer or immune-modulating medication, as serious side effects or decreased efficacy may develop. Patients should remember to consult their doctor or pharmacist if there is any uncertainty about potential drug interactions. At the same time, healthcare professionals should proactively draw their patients' attention to these potential risks, especially when purchasing online.

Phyllosphere symbiont promotes plant growth through ACC deaminase production.

Plant growth promoting bacteria can confer resistance to various types of stress and increase agricultural yields. The mechanisms they employ are diverse. One of the most important genes associated with the increase in plant biomass and stress resistance is acdS, which encodes a 1-aminocyclopropane-1-carboxylate- or ACC-deaminase. The non-proteinogenic amino acid ACC is the precursor and means of long-distance transport of ethylene, a plant hormone associated with growth arrest. Expression of acdS reduces stress induced ethylene levels and the enzyme is abundant in rhizosphere colonizers. Whether ACC hydrolysis plays a role in the phyllosphere, both as assembly cue and in growth promotion, remains unclear. Here we show that Paraburkholderia dioscoreae Msb3, a yam phyllosphere symbiont, colonizes the tomato phyllosphere and promotes plant growth by action of its ACC deaminase. We found that acdS is required for improved plant growth but not for efficient leaf colonization. Strain Msb3 readily proliferates on the leaf surface of tomato, only occasionally spreading to the leaf endosphere through stomata. The strain can also colonize the soil or medium around the roots but only spreads into the root if the plant is wounded. Our results indicate that the degradation of ACC is not just an important trait of plant growth promoting rhizobacteria but also one of leaf dwelling phyllosphere bacteria. Manipulation of the leaf microbiota by means of spray inoculation may be more easily achieved than that of the soil. Therefore, the application of ACC deaminase containing bacteria to the phyllosphere may be a promising strategy to increasing plant stress resistance, pathogen control, and harvest yields.

Norbergenin prevents LPS-induced inflammatory responses in macrophages through inhibiting NFκB, MAPK and STAT3 activation and blocking metabolic reprogramming.

Inflammation is thought to be a key cause of many chronic diseases and cancer. However, current therapeutic agents to control inflammation have limited long-term use potential due to various side-effects. This study aimed to examine the preventive effects of norbergenin, a constituent of traditional anti-inflammatory recipes, on LPS-induced proinflammatory signaling in macrophages and elucidate the underlying mechanisms by integrative metabolomics and shotgun label-free quantitative proteomics platforms. Using high-resolution mass spectrometry, we identified and quantified nearly 3000 proteins across all samples in each dataset. To interpret these datasets, we exploited the differentially expressed proteins and conducted statistical analyses. Accordingly, we found that LPS-induced production of NO, IL1ß, TNFα, IL6 and iNOS in macrophages was alleviated by norbergenin via suppressed activation of TLR2 mediated NFκB, MAPKs and STAT3 signaling pathways. In addition, norbergenin was capable of overcoming LPS-triggered metabolic reprogramming in macrophages and restrained the facilitated glycolysis, promoted OXPHOS, and restored the aberrant metabolites within the TCA cycle. This is linked to its modulation of metabolic enzymes to support its anti-inflammatory activity. Thus, our results uncover that norbergenin regulates inflammatory signaling cascades and metabolic reprogramming in LPS stimulated macrophages to exert its anti-inflammatory potential.

Root exudation of contrasting drought-stressed pearl millet genotypes conveys varying biological nitrification inhibition (BNI) activity.

Roots secrete a vast array of low molecular weight compounds into the soil broadly referred to as root exudates. It is a key mechanism by which plants and soil microbes interact in the rhizosphere. The effect of drought stress on the exudation process and composition is rarely studied, especially in cereal crops. This study focuses on comparative metabolic profiling of the exudates from sensitive and tolerant genotypes of pearl millet after a period of drought stress. We employed a combined platform of gas and liquid chromatography coupled to mass spectrometry to cover both primary and secondary metabolites. The results obtained demonstrate that both genotype and drought stress have a significant impact on the concentration and composition of root exudates. The complexity and function of these differential root exudates are discussed. To reveal the potential effect of root exudates on the soil microbial community after a period of drought stress, we also tested for biological nitrification inhibition (BNI) activity. The analysis revealed a genotype-dependent enhancement of BNI activity after a defined period of drought stress. In parallel, we observed a genotype-specific relation of elongated root growth and root exudation under drought stress. These data suggest that the drought stress-dependent change in root exudation can manipulate the microbial soil communities to adapt and survive under harsh conditions. Supplementary Information: The online version contains supplementary material available at 10.1007/s00374-021-01578-w.

Paraburkholderia dioscoreae sp. nov., a novel plant associated growth promotor.

A novel bacterium, designated strain Msb3T, was recently isolated from leaves of the yam family plant Dioscorea bulbifera (Dioscoreaceae). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that this strain belonged to the genus Paraburkholderia with Paraburkholderia xenovorans as nearest validly named neighbour taxon (99.3 % sequence similarity towards the P. xenovorans type strain). Earlier genome sequence analysis revealed a genome of 8.35 Mb in size with a G+C content of 62.5 mol%, which was distributed over two chromosomes and three plasmids. Here, we confirm that strain Msb3T represents a novel Paraburkholderia species. In silico DNA-DNA hybridization and average nucleotide identity (OrthoANIu) analyses towards P. xenovorans LB400T yielded 58.4 % dDDH and 94.5 % orthoANIu. Phenotypic and metabolic characterization revealed growth at 15 °C on tryptic soy agar, growth in the presence of 1 % NaCl and the lack of assimilation of phenylacetic acid as distinctive features. Together, these data demonstrate that strain Msb3T represents a novel species of the genus Paraburkholderia, for which we propose the name Paraburkholderia dioscoreae sp. nov. The type strain is Msb3T (=LMG 31881T, DSM 111632T, CECT 30342T).

Dissecting Metabolism of Leaf Nodules in Ardisia crenata and Psychotria punctata.

Root-microbe interaction and its specialized root nodule structures and functions are well studied. In contrast, leaf nodules harboring microbial endophytes in special glandular leaf structures have only recently gained increased interest as plant-microbe phyllosphere interactions. Here, we applied a comprehensive metabolomics platform in combination with natural product isolation and characterization to dissect leaf and leaf nodule metabolism and functions in Ardisia crenata (Primulaceae) and Psychotria punctata (Rubiaceae). The results indicate that abiotic stress resilience plays an important part within the leaf nodule symbiosis of both species. Both species showed metabolic signatures of enhanced nitrogen assimilation/dissimilation pattern and increased polyamine levels in nodules compared to leaf lamina tissue potentially involved in senescence processes and photosynthesis. Multiple links to cytokinin and REDOX-active pathways were found. Our results further demonstrate that secondary metabolite production by endophytes is a key feature of this symbiotic system. Multiple anhydromuropeptides (AhMP) and their derivatives were identified as highly characteristic biomarkers for nodulation within both species. A novel epicatechin derivative was structurally elucidated with NMR and shown to be enriched within the leaf nodules of A. crenata. This enrichment within nodulated tissues was also observed for catechin and other flavonoids indicating that flavonoid metabolism may play an important role for leaf nodule symbiosis of A. crenata. In contrast, pavettamine was only detected in P. punctata and showed no nodule specific enrichment but a developmental effect. Further natural products were detected, including three putative unknown depsipeptide structures in A. crenata leaf nodules. The analysis presents a first metabolomics reference data set for the intimate interaction of microbes and plants in leaf nodules, reveals novel metabolic processes of plant-microbe interaction as well as the potential of natural product discovery in these systems.

The Potato Yam Phyllosphere Ectosymbiont Paraburkholderia sp. Msb3 Is a Potent Growth Promotor in Tomato.

The genus Paraburkholderia includes a variety of species with promising features for sustainable biotechnological solutions in agriculture through increasing crop productivity. Here, we present a novel Paraburkholderia isolate, a permanent and predominant member of the Dioscoreae bulbifera (yam family, Dioscoreaceae) phyllosphere, making up to 25% of the microbial community on leaf acumens. The 8.5 Mbp genome of isolate Msb3 encodes an unprecedented combination of features mediating a beneficial plant-associated lifestyle, including biological nitrogen fixation (BNF), plant hormone regulation, detoxification of various xenobiotics, degradation of aromatic compounds and multiple protein secretion systems including both T3SS and T6SS. The isolate exhibits significant growth promotion when applied to agriculturally important plants such as tomato, by increasing the total dry biomass by up to 40%. The open question about the "beneficial" nature of this strain led us to investigate ecological and generic boundaries in Burkholderia sensu lato. In a refined phylogeny including 279 Burkholderia sensu lato isolates strain Msb3 clusters within Clade I Paraburkholderia, which also includes few opportunistic strains that can potentially act as pathogens, as revealed by our ecological meta-data analysis. In fact, we demonstrate that all genera originating from the "plant beneficial and environmental" (PBE) Burkholderia species cluster include opportunists. This indicates that further functional examinations are needed before safe application of these strains in sustainable agricultural settings can be assured.

Electrothermal manipulation of individual chromophores in single conjugated polymer chains: controlling intrachain FRET, blinking, and spectral diffusion.

Single molecule spectroscopy of individual chains of a conjugated polymer opens up deep insight into electronic localization phenomena, which govern the underlying optical properties of these complex and disordered materials. We explore the nature of a single chromophore arising in a delocalized pi-electron system by applying periodic electrothermal perturbations at low temperatures. Brief heating of the chromophore leads to a dramatic increase in the transition line width and is generally accompanied by a random jump of the emission energy. This observation demonstrates that chromophores on a polymer chain are not only defined by structural disorder but also by the subtleties of the local dielectric environment. The effect of thermal perturbation becomes more complex when long polymer chains are considered, which can potentially support the formation of multiple chromophores. Here, a momentary increase in temperature can promote intrachain energy transfer to quenching sites, leading to a strong modulation of emission intensity with temperature. Unexpectedly, such energy transfer can serve to either raise or lower the transition line width and quantum yield of the ensemble with increasing temperature, depending on the specific energetics of the chromophores in the system, which in turn vary with time. The controlled perturbation of both the emission spectrum and the intensity by brief heating of the polymer chain offers insight into possible microscopic origins of fluorescence blinking and spectral diffusion, which ultimately impact on the efficiency and spectral purity of devices.

How single conjugated polymer molecules respond to electric fields.

Conjugated polymers find applications in a range of devices such as light-emitting diodes, field-effect transistors and solar cells. The elementary electronic response of these semiconductors to electric fields is understood in terms of nanoscale perturbations of charge density. We demonstrate a general breaking of spatial charge symmetry by considering the linear Stark effect in the emission of single chromophores on individual chains. Spectral shifts of several nanometres occur due to effective dipoles exceeding 10 D. Although the electric field does not ionize the exciton, some molecules exhibit field-induced intensity modulations. This quenching illustrates the equivalence of charge symmetry breaking and polaron-pair or charge-transfer-state formation, and provides a microscopic picture of permanent charging, which leads to doping and exciton dissociation in actual devices. In addition to using this tuneable emission in single-photon electro-optic modulators, hysteresis in the Stark shift suggests a route to designing nanoscale memory elements such as molecular switches.

Single chromophore spectroscopy of MEH-PPV: homing-in on the elementary emissive species in conjugated polymers.

Low-temperature, single-molecule spectroscopy can provide unparalleled access to the primary emissive species of conjugated polymers. We demonstrate this with the example of one of the most commonly studied polymers, poly(2-methoxy-5-(2'-ethylhexoxy)-1,4-phenylenevinylene), MEH-PPV, which is shown to exhibit sharp fluorescence signatures over one hundred times narrower than the ensemble. These unprecedented narrow emission features can be assigned to single chromophores on the polymer chain, which are selectively addressed by the narrow band excitation. As with organic dye systems, the emission from single chromophores is not static with time, but shows a substantial spectral fluctuation. We find that, for single chromophores, this spectral fluctuation always follows a universal Gaussian statistical distribution. High-resolution spectroscopy provides unique insight into low-energy vibrational modes in the polymer emission, which are generally inaccessible with conventional spectroscopic methods such as site-selective fluorescence or Raman spectroscopy. Interchromophoric coupling can also occur owing to the flexible nature of the polymer backbone. This leads to substantial spectral broadening and a loss of resolution in the vibronic progression. We observe reversible switching within one single molecule between narrow and broad emission, which directly correlates with a discrete switching in emission intensity. We conclude that one and the same single molecule can support aggregated and nonaggregated emission, that is, emission from isolated and aggregated chromophores in one single molecule, rather than the tendency for aggregate emission being intrinsic to the molecule.

A universal picture of chromophores in pi-conjugated polymers derived from single-molecule spectroscopy.

Single-molecule spectroscopy can provide insight into the fundamental photophysics of large macromolecules containing tens of thousands of carbon atoms by circumventing disorder broadening. We apply this technique to comparatively ordered ladder-type poly(para-phenylene) and highly disordered poly(phenylenevinylene) (PPV), both of which are materials of substantial technological interest. Identical spectroscopic features are observed on the single-chromophore level, independent of the chemical structure or the chain morphology. Both materials exhibit narrow fluorescence lines down to 0.5 nm wide, which we attribute to the single-chromophore zero-phonon line, accompanied by a discrete vibronic progression providing a signature of the chemical structure. The chromophore units display spectral diffusion, giving rise to dynamic disorder on the scale of the linewidth. Although the energetic range of spectral diffusion is small, it can influence intramolecular excitation energy transfer and thus the overall molecular emission. The spectral diffusion dynamics of single chromophores are identical in both material systems and follow a universal Gaussian distribution. In the case of emission from multiple chromophores situated on the molecule, which we observe for PPV, spectral diffusion follows Lorentzian-like statistics. The fundamental difference between the two materials is the possibility of coherent interchromophoric coupling in PPV, resulting in strong spectral broadening caused by aggregation or superradiance. Such behavior is absent in the ladder-type polymers, where the linewidth of the emissive species is identical for all molecules. Our results demonstrate that structure-property correlations in conjugated polymers derive mainly from chain morphology rather than chromophoric properties and should be considered extrinsic in nature.

Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study.

Based on concepts that endogenous opioids participate in neural transmission of pain, the present study in central poststroke pain (CPSP) patients investigated changes in opioid receptor (OR) binding in neural structures centrally involved in the processing of pain. Five patients with central pain after lesions in the brain stem, thalamus or parietal cortex and twelve healthy volunteers underwent a [11C]diprenorphine positron emission tomography study. Binding potentials were calculated using a reference region model in all subjects. Statistical parametric mapping was applied for t-statistical analysis on voxel-basis. Binding potential values for each individual were extracted from a volume of interest at each identified significant peak. Spectral analysis was applied for quantification of global values. Significant regional reduced 11C-diprenorphine binding (corrected for multiple tests) was detected in contralateral thalamus, parietal, secondary somatosensory, insular and lateral prefrontal cortices, and along the midline in anterior cingulate, posterior cingulate and midbrain gray matter. Individual extracted binding values disclosed a reduced binding in these regions in all patients independent from the particular lesion site. The poststroke pain syndrome is associated with a characteristic pattern of reduced OR binding within the neural circuitry processing pain. It is suggested that an imbalance of excitatory-inhibitory mechanisms in certain brain structures, as evidenced in decreased [11C]diprenorphine binding, is one of the causes or the consequences of poststroke pain.