Abstract
In cellular circumstances where carbohydrates are scarce, plants can use alternative substrates for cellular energetic maintenance. In plants, the main protein reserve is present in the ...chloroplast, which contains most of the total leaf proteins and represents a rich source of nitrogen and amino acids. Autophagy plays a key role in chloroplast breakdown, a well‐recognised symptom of both natural and stress‐induced plant senescence. Remarkably, an autophagic‐independent route of chloroplast degradation associated with chloroplast vesiculation (CV) gene was previously demonstrated. During extended darkness, CV is highly induced in the absence of autophagy, contributing to the early senescence phenotype of
atg
mutants. To further investigate the role of CV under dark‐induced senescence conditions, mutants with low expression of CV (
amircv
) and double mutants
amircv1xatg5
were characterised. Following darkness treatment, no aberrant phenotypes were observed in
amircv
single mutants; however,
amircv1xatg5
double mutants displayed early senescence and altered dismantling of chloroplast and membrane structures under these conditions. Metabolic characterisation revealed that the functional lack of both CV and autophagy leads to higher impairment of amino acid release and differential organic acid accumulation during starvation conditions. The data obtained are discussed in the context of the role of CV and autophagy, both in terms of cellular metabolism and the regulation of chloroplast degradation.
Summary statement
Functional lack of both chloroplast vesiculation (CV) and autophagy leads to higher impairment of amino acid release and differential organic acid accumulation during extended darkness conditions. CV deficiency triggers minor energetic consequences when autophagy is still present and activated.
Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 ...pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone.
The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected.
We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.
Although chemotherapy-induced peripheral neuropathy is one of the main medical complaints of cancer patients, there are currently no specific drugs for the effective treatment. In this respect, ...α-terpineol (TP) seems to be a potential candidate for this purpose, since it has several pharmacological properties that can be improved by nanosytems. Therefore, the objective of this study was to develop and investigate an antinociceptive action of TP in nanocapsules (TP-LNC) on a peripheral neuropathy induced by paclitaxel (PTX) in mice. Nanocapsules were obtained through the interfacial deposition of preformed polymer method and physicochemically characterized. The effect of TP and TP-LNC was assessed using the hyperalgesia test in mice with neuropathy induced by PTX (32 mg/kg, i.p.). Its effect on calcium channels was evaluated by patch-clamp and molecular docking. TP-LNC presented satisfactory stability and encapsulation efficiency of 64.5%; it also prolonged the antihyperalgesic effect when cooperated with free TP. Moreover, it was found that TP presented molecular interactions with different channels for calcium, being able to reduce calcium currents. These findings bring new evidence about the analgesic action of TP and its modulating action of calcium channels and reiterate the benefits of the encapsulation of monoterpenes in nanosystems.
The present study aimed to investigate the antibacterial and modulatory activities of (+)-β-citronellol (βCT), β-cyclodextrin (β-CD), and their complex βCT/β-CD and characterize them using infrared ...spectroscopy. Infrared spectra were recorded in the 750–4000 cm−1 region. The antibacterial effects of these compounds and their modulatory-antibiotic activities were determined using the minimum inhibitory concentration (MIC) test. Signatures of these pure compounds were detected in the infrared spectrum of the βCT/β-CD complex. The MIC of the βCT/β-CD complex against the tested strains was found to be 1024 μg/mL. The antagonistic and synergistic effects of these compounds were also observed using the modulation tests. βCT or β-CD alone did not exhibit any direct antibacterial activity. However, the βCT/β-CD complex in combination with gentamicin showed a synergistic effect against E. coli.
•The β-CD/βCT complex and pure β-CD did not possess direct antibacterial activity.•The β-CD/βCT complex and pure β-CD, WHEN associated with antibiotics displayed synergistic effects.•The β-CD/βCT complex in association with gentamicin showed a synergistic effect against E. coli.
Evaluate the anti-hyperalgesic effect of the complex containing β-caryophyllene (βCP) and β-cyclodextrin (βCD) in a non-inflammatory chronic muscle pain mice model and investigated its action on ...superficial dorsal horn of the lumbar spinal cord.
The βCP-βCD complex were prepared and characterized through the DSC, TG/DTG, FTIR, XRD and SEM. The model of chronic muscle pain was induced by two injections of pH4.0 saline (20μL) into left gastrocnemius 5days apart. After confirming hyperalgesia, male mice were treated with βCP-βCD (10 or 20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 9days. 1h after, the mechanical hyperalgesia, muscle withdrawal thresholds and motor performance were evaluated. To evaluate the βCP-βCD action on spinal cord, animals induced with chronic muscle pain were treated with βCP-βCD (20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) and 90min. after, were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein.
The characterization tests indicated that βCP were efficiently incorporated into βCD. The oral treatment with βCP-βCD, at all doses tested, produced a significant (p<0.05) reduction on mechanical hyperalgesia and a significant (p<0.05) increase in muscle withdrawal thresholds, without produce any alteration in force. In addition, βCP-βCD was able to significantly (p<0.05) decrease Fos expression in the superficial dorsal horn.
Thus, βCP-βCD attenuates the non-inflammatory chronic muscle pain in mice and inhibits the Fos expression in the lumbar spinal cord.
Plants are constantly exposed to environmental changes that affect their performance. Metabolic adjustments are crucial to controlling energy homoeostasis and plant survival, particularly during ...stress. Under carbon starvation, coordinated reprogramming is initiated to adjust metabolic processes, which culminate in premature senescence. Notwithstanding, the regulatory networks that modulate transcriptional control during low energy remain poorly understood. Here, we show that the WRKY45 transcription factor is highly induced during both developmental and dark‐induced senescence. The overexpression of Arabidopsis WRKY45 resulted in an early senescence phenotype characterized by a reduction of maximum photochemical efficiency of photosystem II and chlorophyll levels in the later stages of darkness. The detailed metabolic characterization showed significant changes in amino acids coupled with the accumulation of organic acids in WRKY45 overexpression lines during dark‐induced senescence. Furthermore, the markedly upregulation of alternative oxidase (AOX1a, AOX1d) and electron transfer flavoprotein/ubiquinone oxidoreductase (ETFQO) genes suggested that WRKY45 is associated with a dysregulation of mitochondrial signalling and the activation of alternative respiration rather than amino acids catabolism regulation. Collectively our results provided evidence that WRKY45 is involved in the plant metabolic reprogramming following carbon starvation and highlight the potential role of WRKY45 in the modulation of mitochondrial signalling pathways.
The WRKY45 transcription factor mediates metabolic reprogramming during carbon starvation. The overexpression of WRKY45 triggered a differential accumulation of amino acids, organic acids and respiratory adjustments through the regulation of mitochondrial signalling and alternative respiration.
SUMMARY
The importance of the alternative donation of electrons to the ubiquinol pool via the electron‐transfer flavoprotein/electron‐transfer flavoprotein:ubiquinone oxidoreductase (ETF/ETFQO) ...complex has been demonstrated. However, the functional significance of this pathway during seed development and germination remains to be elucidated. To assess the function of this pathway, we performed a detailed metabolic and transcriptomic analysis of Arabidopsis mutants to test the molecular consequences of a dysfunctional ETF/ETFQO pathway. We demonstrate that the disruption of this pathway compromises seed germination in the absence of an external carbon source and also impacts seed size and yield. Total protein and storage protein content is reduced in dry seeds, whilst sucrose levels remain invariant. Seeds of ETFQO and related mutants were also characterized by an altered fatty acid composition. During seed development, lower levels of fatty acids and proteins accumulated in the etfqo‐1 mutant as well as in mutants in the alternative electron donors isovaleryl‐CoA dehydrogenase (ivdh‐1) and d‐2‐hydroxyglutarate dehydrogenase (d2hgdh1‐2). Furthermore, the content of several amino acids was increased in etfqo‐1 mutants during seed development, indicating that these mutants are not using such amino acids as alternative energy source for respiration. Transcriptome analysis revealed alterations in the expression levels of several genes involved in energy and hormonal metabolism. Our findings demonstrated that the alternative pathway of respiration mediated by the ETF/ETFQO complex affects seed germination and development by directly adjusting carbon storage during seed filling. These results indicate a role for the pathway in the normal plant life cycle to complement its previously defined roles in the response to abiotic stress.
Significance Statement
The importance of the alternative donation of electrons to the ubiquinol pool via the electron‐transfer flavoprotein/electron‐transfer flavoprotein:ubiquinone oxidoreductase (ETF/ETFQO) complex during normal seed development and germination is presented. Our results provide compelling evidence for a pivotal role of the alternative ETF/ETFQO respiration pathway in the normal life cycle of a plant in addition to its previously defined roles in response the to abiotic stress.
Information on how coronavirus disease 2019 (COVID-19) mortality is related to population characteristics in low- and middle-income countries is still limited. We described the deaths from COVID-19 ...in Sergipe state, Northeast Brazil, from April 2 to June 27, 2020. For this purpose, we conducted a study composed of (i) a case series study of all deaths due to COVID-19 and (ii) a population-based study to verify the behavior of the mortality and case-fatality rates (CFR) related to COVID-19. Data from 605 deaths due to COVID-19 were used to describe the characteristics of individuals with the disease, as well as the differences in gender, age, and comorbidities. Additionally, population data were extracted to estimate the mortality and CFR by population stratum. We also performed an adjusted CFR analysis including a time lag of 14 days between the onset of symptoms and reporting deaths. Of the 605 patients included in this study, 321 (53.1%) were males and the median age was 67.0 years. Most patients (
= 447, 73.9%) who died from COVID-19 had at least one pre-existing clinical condition. The mortality rate was 29.3 deaths per 100,000 inhabitants and the crude CRF was 2.6% (95% CI 2.4-2.8). CFR was higher in males (3.1%, 95% CI 2.8-3.4;
< 0.001) and people aged ≥60 years (14.2%, 95% CI 13.0-15.6;
= 0.042). About 25% of patients died during the first 24-h post-hospital admission. The adjusted CFR for a 14-day time lag was ~2-fold higher than the crude CFR over the study period.
Neuropathic pain (NP) is a difficult condition to treat because of the modest efficacy of available drugs. New treatments are required. In the study we aimed to investigate the effects of the ...essential oil from Lippia grata alone or complexed in β-cyclodextrin (LG or LG-βCD) on persistent inflammatory and neuropathic pain in a mouse model. We also investigated Ca2+ currents in rat dorsal root ganglion (DRG) neurons. Male Swiss mice were treated with LG or LG/β-CD (24 mg/kg, i.g.) and their effect was evaluated using an acute inflammatory pleurisy model and nociception triggered by intraplantar injection of an agonist of the TRPs channels. We also tested their effect in chronic pain models: injection of Freund's Complete Adjuvant and partial sciatic nerve ligation (PSNL). In the pleurisy model, LG reduced the number of leukocytes and the levels of TNF-α and IL-1β. It also inhibited cinnamaldehyde and menthol-induced nociceptive behavior. The pain threshold in mechanical and thermal hyperalgesia was increased and paw edema was decreased in models of inflammatory and neuropathic pain. PSNL increased inflammatory protein contents and LG and LG-βCD restored the protein contents of TNF-α, NF-κB, and PKA, but not IL-1β and IL-10. LG inhibited voltage gated Ca2+ channels from DRG neurons. Our results suggested that LG or LG-βCD produce anti-hyperalgesic effect in chronic pain models through reductions in TNF-α levels and PKA, and inhibited voltage-gated calcium channels and may be innovative therapeutic agents for the management of NP.
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