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Pepper is an economically important vegetable worldwide, containing various specialized metabolites crucial for its development and flavor. Capsaicinoids, especially, are genus-specialized metabolites that confer a spicy flavor to Capsicum fruits. In this work, two pepper cultivars, YB (Capsicum frutescens L.) and JC (Capsicum baccatum L.) pepper, showed distinct differences in the accumulation of capsaicin and flavonoid. However, the molecular mechanism underlying them was still unclear. Metabolome analysis showed that the JC pepper induced a more abundant accumulation of metabolites associated with alkaloids, flavonoids, and capsaicinoids in the red ripening stages, leading to a spicier flavor in the JC pepper. Transcriptome analysis confirmed that the increased expression of transcripts associated with phenylpropanoid and flavonoid metabolic pathways occurred in the JC pepper. Integrative analysis of metabolome and transcriptome suggested that four structural genes, 4CL7, 4CL6, CHS, and COMT, were responsible for the higher accumulation of metabolites relevant to capsaicin and flavonoids. Through weighted gene co-expression network analyses, modules related to flavonoid biosynthesis and potential regulators for candidate genes were identified. The promoter analysis of four candidate genes showed they contained several cis-elements that were bonded to MYB, bZIP, and WRKY transcription factors. Further RT-qPCR examination verified three transcription factors, MYB, bZIP53, and WRKY25, that exhibited increased expression in the red ripening stage of the JC pepper compared to YB, which potentially regulated their expression. Altogether, our findings provide comprehensive understanding and valuable information for pepper breeding programs in the future. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (ApoE4) is involved in the stress‐response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg‐ApoEtm1UncCdh18Tg(GFAP−APOE i4)1Hol/J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4‐induced depression. LPS treatment significantly aggravated depression‐like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin‐1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria‐related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria‐associated protein and mitophagy defects, including PGC‐1α, TFAM, p‐AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 G93A mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 G93A mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation. [ABSTRACT FROM AUTHOR]