Synthesis of Protoberberine Alkaloids by C–H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors

JACS Au, Год журнала: 2025, Номер 5(3), С. 1429 - 1438

Опубликована: Фев. 27, 2025

5′-Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis, and its activation has garnered attention for treating chronic metabolic diseases. Inhibitors of AMPK are underdeveloped but bear implications cancers, controlling autophagy, elderly wasting. Protoberberine alkaloids typically regarded as activators. Herein, we report modular synthesis strategy to access collection oxyberberine alkaloids, including the first stepharotudine. In vitro assays reveal how subtle structural modifications can negate while conferring unprecedented inhibitory properties within same class compounds, which was previously unknown. Key steps include an oxidative Rh(III)-catalyzed C–H functionalization using electron-rich alkenes, NaH-mediated reductive N–O bond cleavage, rare example anionic aza-6π-electrocyclization. Additionally, provide mechanistic support nucleophilic hydride transfer reactivity with NaH DMF.

Язык: Английский

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No energy, no autophagy—Mechanisms and therapeutic implications of autophagic response energy requirements

Journal of Cellular Physiology, Год журнала: 2024, Номер 239(11)

Опубликована: Июль 3, 2024

Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and substrates energy metabolism during nutrient or deficiency, which are the main stimuli autophagy induction. However, like most biological processes, itself requires ATP, there an threshold its initiation execution. We here present first comprehensive review this often-overlooked aspect research. The studies in ATP deficiency suppressed vitro vivo were classified according to pathway involved (oxidative phosphorylation glycolysis). A mechanistic insight was provided by pinpointing critical ATP-consuming autophagic events, including transcription/translation/interaction autophagy-related molecules, autophagosome formation/elongation, fusion with lysosome, lysosome acidification. significance energy-dependent fine-tuning response preserving cell homeostasis, potential implications therapy cancer, autoimmunity, metabolic disorders, neurodegeneration discussed.

Язык: Английский

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TRIM16 mediates secretory autophagy in head and neck cancer-associated fibroblasts

Autophagy, Год журнала: 2025, Номер unknown

Опубликована: Май 18, 2025

Improving treatment options for head and neck squamous cell carcinoma (HNSCC) requires a deeper understanding of the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs). We previously reported that HNSCC-derived FGF2/bFGF (fibroblast growth factor 2) triggers cytokine release from CAFs via secretory autophagy. Here, using transmission electron microscopy, live-cell imaging, immunofluorescence, we show CAF autophagosomes transport cargo, including IL6, to plasma membrane secretion. Autophagy in is constitutive independent STAT3, MAPK1/ERK2-MAPK3/ERK1 phosphoinositide 3-kinase (PI3K) signaling. Despite significant role autophagy CAFs, its molecular machinery has remained elusive. Using both literature based, an unbiased approach, studied involved autophagosome trafficking CAFs. identified TRIM16, protein traffic autophagosomes, upregulated compared normal oral fibroblasts. Immunohistochemistry patient HNSCC stroma revealed co-expression TRIM16 LC3B, linking function. An proteomics profiling immunoprecipitated LC3B+ vesicles primary enrichment proteins, focal adhesion mitochondrial proteins. demonstrate SEC22B, SNAP23, VAMP3, STX4 colocalize with knockdown reduced at decreased IL6 secretion These findings uncover key components autophagy-mediated suggest potential therapeutic targets HNSCC.

Язык: Английский

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Non-hormone replacement therapy to overcome premature ovarian insufficiency: advances in natural products and stem cells targeting autophagy

Frontiers in Endocrinology, Год журнала: 2025, Номер 16

Опубликована: Май 30, 2025

Premature ovarian insufficiency (POI) is the most common cause of female infertility. With increase in people’s bad life habits, causative factors POI have increased, and its incidence has shown a rising trend year by year. At present, commonly used clinical treatment for hormonal replacement therapy (HRT), but it not universally applicable prone to subsequent complications, posing certain health risks patients with POI. Therefore, exploring greener, safer, more efficacious non-hormonal treatments can help address challenges POI-induced infertility better. Studies that autophagy plays key role development degeneration oocytes from their origin follicle any alteration affects reserve follicle. Moreover, natural products human stem cells different sources treat modulating autophagic pathway good efficacy. our study aimed review analyze previous research-based literature on product cell based mechanism POI, provide new insights references related scholars continue explore non-hormone-targeted therapeutic strategies depth.

Язык: Английский

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Phospholipid Supply for Autophagosome Biogenesis

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168691 - 168691

Опубликована: Июнь 27, 2024

Язык: Английский

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Non-apoptotic cell death in osteoarthritis: Recent advances and future

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 179, С. 117344 - 117344

Опубликована: Авг. 27, 2024

Osteoarthritis (OA) is the most common degenerative joint disease. Multiple tissues are altered during development of OA, resulting in pain and permanent damage to osteoarticular joints. Current research has demonstrated that non-apoptotic cell death plays a crucial role OA. With continuous targeted therapies, shown great potential prevention treatment We systematically reviewed progress on pathogenesis, development, outcome including autophagy, pyroptosis, ferroptosis, necroptosis, immunogenic death, parthanatos. This article reviews mechanism OA provides theoretical basis for identification new targets treatment.

Язык: Английский

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Combined Administration of Metformin and Amprolium to Rats Affects Metabolism of Free Amino Acids in the Brain, Altering Behavior, and Heart Rate

Biochemistry (Moscow), Год журнала: 2024, Номер 89(10), С. 1692 - 1710

Опубликована: Окт. 1, 2024

Язык: Английский

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