AMPK x NRF1 x PGC-1α x TFAM

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately half of cases of HF and is frequently clinically underdiagnosed. Although new therapies continue to emerge, determining optimal treatment strategies persists as a key clinical dilemma. Berberine(BBR), an isoquinoline alkaloid, is known to attenuate HF with reduced ejection fraction.

In this study, we explored the cardiovascular benefits of BBR in diastolic dysfunction associated with HFpEF, both in vitro and in vivo.

In vivo, adult male mice were fed with chow or a high-fat diet (60 % calories from lard) with L-NAME (0.5 g/L in drinking water) for 15 weeks. During the last 4 weeks, BBR (100 mg/Kg/d and 200 mg/Kg/d) was administered orally. Rat cardiac myoblast H9C2 cells were pretreated with BBR for 2 h, followed by exposure to palmitic acid (PA, 100 μM) for 24 h.

Exposure to a high-fat stimulation led to p-AMPK and PGC-1α downregulation, apoptotic cascade activation, elevated mt-ROS production, and disruption of mitochondrial homeostasis both in vivo and in vitro. Notably, BBR intervention elevated the expressions of p-AMPK and PGC-1α, inhibited apoptotic reaction, reduced mt-ROS, ameliorated TFAM/NRF1-mediated mitochondrial biogenesis disorder, alleviated mitochondrial impairment, and improved cardiac function. On the other hand, AMPK knockdown abolished the beneficial impact of BBR. Collectively, our findings underscored the cardioprotective role of BBR in maintaining mitochondrial homeostasis and preventing apoptosis, achieved through the modulation of the AMPK/PGC-1α pathway.

In summary, BBR possesses protective activity against cardiac insufficiency in HFpEF by maintaining mitochondrial homeostasis and inhibiting apoptosis.

Zuo Gui Wan (ZGW) is a well-known traditional Chinese medicine decoction used for approximately 400 years to treat age-related degenerative conditions, including cognitive impairment in older adults, osteoporosis, and general aging. However, the mechanism of action for ZGW remains unclear.

This study aims to investigate the efficacy of ZGW in improving cognitive function in Alzheimer's disease (AD) animal models and to explore the underlying mechanisms, presenting a novel perspective in the field.

Six-month-old male APP/PS1 mice were divided into three groups that received either metformin (200 mg/kg daily) or ZGW (6 and 12 g/kg daily). High-performance liquid chromatography was conducted for ZGW's quality control. Cognitive function was assessed using the Morris water maze test. Neuronal loss, synaptic plasticity, and β-amyloid (Aβ) deposition were evaluated through Western blot or immunofluorescence staining. The underlying molecular mechanisms were investigated using ELISA, Western blot, qRT-PCR, co-immunoprecipitation assay, ATP assay, and cytochrome c oxidase assay.

ZGW, administered in both low and high doses, significantly enhanced cognitive performance, notably decreased neuronal loss and Aβ deposition, and reduced levels of Aβ1-40/42. It also inhibited excessive mitochondrial division primarily by suppressing phosphorylated dynamin-related protein 1 (Drp1), especially at high doses of ZGW. Co-immunoprecipitation experiments further confirmed that ZGW inhibited the interaction between Aβ and p-Drp1. Furthermore, similar to the effects of the AMP-activated Protein Kinase (AMPK) activator metformin, ZGW led to a marked increase in the mitochondrial DNA copy number and upregulated the AMPK/PGC-1α/NRF1/TFAM pathway. Improvements in mitochondrial function were evident from the increased ATP production, elevated expression of superoxide dismutase 2, and upregulated cytochrome c oxidase activity. Additionally, the excess byproduct of reactive oxygen species, 4-hydroxy-2-nonenal, decreased in the group treated with ZGW.

This study provides compelling evidence that ZGW improves cognitive impairment in APP/PS1 mice by activating AMPK/PGC-1α-regulated mitochondrial bioenergetics and inhibiting Aβ-induced mitochondrial fragmentation, highlighting its potential as an effective therapeutic strategy for AD.

Zinc deficiency is a global health issue that impairs immune function, growth, and energy metabolism. Although conventional zinc supplements have been developed, their effectiveness is limited by poor bioavailability and susceptibility to dietary inhibitors. In this study, a peptide-zinc complex (IE-Zn) derived from oysters was developed to enhance zinc uptake and address metabolic disruptions caused by deficiency. It was determined that Zn²⁺ binds with high affinity to the IE peptide, promoting structural flexibility that facilitates zinc transport through both zinc ion transporters and oligopeptide transporters. In Caco-2 and IEC-6 cell models, IE-Zn was shown to significantly improve zinc absorption and retention compared to ZnSO₄, driven by the upregulation of ZIP4 and PEPT1 transporters. In vivo studies in a zinc-deficient mouse model confirmed enhanced zinc absorption and distribution across serum, intestine, and liver. Moreover, IE-Zn restored energy homeostasis by activating the AMPK/PGC1-α/NRF-1/TFAM signaling pathway, promoting mitochondrial biogenesis and reducing oxidative stress. These findings suggest that IE-Zn is a superior zinc supplement with higher bioavailability and serves as a potent regulator of cellular energy metabolism, offering therapeutic potential for managing conditions related to zinc deficiency and mitochondrial dysfunction. This study lays the foundation for further exploration of peptide-mineral complexes as advanced nutritional supplements with broad applications. Subsequent studies will further investigate the absorption pathway and targeting of peptide-zinc complex. The hope is to provide potential preventive applications for people in need, including zinc deficiency and a range of diseases caused by zinc deficiency.