Alzheimer's disease (AD), a heterogeneous neurodegenerative disorder, is the most common cause of dementia accounting for an estimated 60–80% of cases. The pathogenesis of AD remains unclear, and no curative treatment is available so far. Increasing evidence has revealed a vital role of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), in AD. LncRNAs contribute to the pathogenesis of AD via modulating amyloid production, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, synaptic impairment and neuroinflammation. This review describes the biological functions and mechanisms of lncRNAs in AD, indicating that lncRNAs may provide potential therapeutic targets for the diagnosis and treatment of AD.
AbstractThe discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders.
Sugar metabolism not only determines fruit sweetness and quality but also acts as signaling molecules to substantially connect with other primary metabolic processes and, therefore, modulates plant growth and development, fruit ripening, and stress response. The basic region/leucine zipper motif (bZIP) transcription factor family is ubiquitous in eukaryotes and plays a diverse array of biological functions in plants. Among the bZIP family members, the smallest bZIP subgroup, S1-bZIP, is a unique one, due to the conserved upstream open reading frames (uORFs) in the 5′ leader region of their mRNA. The translated small peptides from these uORFs are suggested to mediate Sucrose-Induced Repression of Translation (SIRT), an important mechanism to maintain sucrose homeostasis in plants. Here, we review recent research on the evolution, sequence features, and biological functions of this bZIP subgroup. S1-bZIPs play important roles in fruit quality, abiotic and biotic stress responses, plant growth and development, and other metabolite biosynthesis by acting as signaling hubs through dimerization with the subgroup C-bZIPs and other cofactors like SnRK1 to coordinate the expression of downstream genes. Direction for further research and genetic engineering of S1-bZIPs in plants is suggested for the improvement of quality and safety traits of fruit.
Sniffing out atherosclerosis
Olfactory receptors are best known for their presence in the nose and their role in detecting smells, but they are also present in other tissues and perform additional biological functions. For example, vascular macrophages involved in the pathogenesis of atherosclerosis express multiple subtypes of olfactory receptors. Orecchioni
. focused on olfactory receptor 2, a receptor for the compound octanal, and identified its contribution to atherosclerosis pathogenesis and the formation of atherosclerotic plaques (see the Perspective by Rayner and Rasheed). The authors show that most of the octanal was not directly derived from the diet, but rather was generated as a by-product of lipid peroxidation, suggesting a potential pathway for intervention. —YN
Marine myxobacteria present a virtually unexploited reservoir for the discovery of natural products with diverse biological functions and novel chemical scaffolds. We report here the isolation and structure elucidation of eight new deoxyenhygrolides (1–8) from the marine myxobacterium Plesiocystis pacifica DSM 14875T. The herein described deoxyenhygrolides C–J (1–8) feature a butenolide core with an ethyl residue at C-3 of the γ-lactone in contrast to the previously described derivatives, deoxyenhygrolides A and B, which feature an isobutyl residue at this position. The butenolide core is 2,4-substituted with a benzyl (1, 2 and 7), benzoyl (3 and 4) or benzyl alcohol (5, 6 and 8) moiety in the 2-position and a benzylidene (1–6) or benzylic hemiketal (7 and 8) in the 4-position. The description of these new deoxyenhygrolide derivatives, alongside genomic in silico investigation regarding putative biosynthetic genes, provides some new puzzle pieces on how this natural product class might be formed by marine myxobacteria.
Plants acquire the ability to adapt to the environment using transmembrane receptor-like kinases (RLKs) to sense the challenges from their surroundings and respond appropriately. RLKs perceive a variety of ligands through their variable extracellular domains (ECDs) that activate the highly conserved intracellular kinase domains (KDs) to control distinct biological functions through a well-developed downstream signaling cascade. A new study has emerged that brassinosteroid-insensitive 1 (BRI1) family and excess microsporocytes 1 (EMS1) but not GASSHO1 (GSO1) and other RLKs control distinct biological functions through the same signaling pathway, raising a question how the signaling pathway represented by BRI1 is specified. Here, we confirm that BRI1-KD is not functionally replaceable by GSO1-KD since the chimeric BRI1-GSO1 cannot rescue bri1 mutants. We then identify two subdomains S1 and S2. BRI1 with its S1 and S2 substituted by that of GSO1 cannot rescue bri1 mutants. Conversely, chimeric BRI1-GSO1 with its S1 and S2 substituted by that of BRI1 can rescue bri1 mutants, suggesting that S1 and S2 are the sufficient requirements to specify the signaling function of BRI1. Consequently, all the other subdomains in the KD of BRI1 are functionally replaceable by that of GSO1 although the in vitro kinase activities vary after replacements, suggesting their functional robustness and mutational plasticity with diverse kinase activity. Interestingly, S1 contains αC-β4 loop as an allosteric hotspot and S2 includes kinase activation loop, proposedly regulating kinase activities. Further analysis reveals that this specific function requires β4 and β5 in addition to αC-β4 loop in S1. We, therefore, suggest that BRI1 specifies its kinase function through an allosteric regulation of these two subdomains to control its distinct biological functions, providing a new insight into the kinase evolution.
Long noncoding RNAs (lncRNAs), as a novel regulatory factor, are considered to play a vital role in various biological processes and diseases. However, the overall expression profile and biological functions of lncRNAs in the partially injured anterior cruciate ligament (ACL) and medial collateral ligament (MCL) have not been clearly explored. Partially injured models of ACL and MCL were established in 3-month-old healthy male New Zealand white rabbits. Expression of lncRNAs and mRNAs in the ligament tissue was detected by high-throughput sequencing technology, and biological functions of differentially expressed RNAs were evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Validation of several differentially expressed RNAs was performed using quantitative real-time PCR (qRT-PCR). Protein-protein interaction (PPI) analysis and competitive endogenous RNA (ceRNA) prediction were used to identify interactions among hub genes and the interaction among lncRNAs, miRNAs, and mRNAs. The results showed that compared with the normal group, there were 267 mRNAs and 329 lncRNAs differentially expressed in ACL and 726 mRNAs and 609 lncRNAs in MCL in the injured group. Compared with MCL, 420 mRNAs and 470 lncRNAs were differentially expressed in ACL in the normal group; 162 mRNAs and 205 lncRNAs were differentially expressed in ACL in the injured group. Several important lncRNAs and genes were identified, namely, COL7A1, LIF, FGFR2, EPHA2, CSF1, MMP2, MMP9, SOX5, LOX, MSTRG.1737.1, MSTRG.26038.25, MSTRG.20209.5, MSTRG.22764.1, and MSTRG.18113.1, which are closely related to inflammatory response, tissue damage repair, cell proliferation, differentiation, migration, and apoptosis. Further study of the functions of these genes may help to better understand the specific molecular mechanisms underlying the occurrence of endogenous repair disorders in ACL, which may provide new ideas for further exploration of effective means to promote endogenous repair of ACL injury.
Decades of culture-independent analyses have resulted in proposals of many tentative archaeal phyla with no cultivable representative. Members of DPANN (an acronym of the names of the first included phyla Diapherotrites, Parvarchaeota, Aenigmarchaeota, Nanohaloarchaeota, and Nanoarchaeota), an archaeal superphylum composed of at least 10 of these tentative phyla, are generally considered obligate symbionts dependent on other microorganisms. While many draft/complete genome sequences of DPANN archaea are available and their biological functions have been considerably predicted, only a few examples of their successful laboratory cultivation have been reported, limiting our knowledge of their symbiotic lifestyles. Here, we investigated physiology, morphology, and host specificity of an archaeon of the phylum “Candidatus Micrarchaeota” (ARM-1) belonging to the DPANN superphylum by cultivation. We constructed a stable coculture system composed of ARM-1 and its original host Metallosphaera sp. AS-7 belonging to the order Sulfolobales. Further host-switching experiments confirmed that ARM-1 grew on five different archaeal species from three genera—Metallosphaera, Acidianus, and Saccharolobus—originating from geologically distinct hot, acidic environments. The results suggested the existence of DPANN archaea that can grow by relying on a range of hosts. Genomic analyses showed inferred metabolic capabilities, common/unique genetic contents of ARM-1 among cultivated micrarchaeal representatives, and the possibility of horizontal gene transfer between ARM-1 and members of the order Sulfolobales. Our report sheds light on the symbiotic lifestyles of DPANN archaea and will contribute to the elucidation of their biological/ecological functions.