Excessive adipose tissue expansion contributes to metabolic dysfunction, highlighting the need to identify compounds that restrain adipocyte differentiation without causing nonspecific cytotoxicity. This study investigated whether 2-O-methylhonokiol suppresses adipogenesis in 3T3-L1 preadipocytes and examined its effects on adipogenic transcription, metabolic signaling, ER stress-related responses, kinase activity, and early cell cycle progression. 3T3-L1 cells were induced to differentiate with an MDI cocktail and treated with 25 or 50 µM 2-O-methylhonokiol during differentiation. Lipid accumulation was evaluated by Oil Red O staining, protein expression and phosphorylation were analyzed by immunoblotting, cell cycle distribution was assessed 24 h after MDI induction, and basal viability was measured using the CCK-8 assay. 2-O-methylhonokiol markedly reduced neutral lipid accumulation and suppressed key adipogenic regulators and maturation markers, including C/EBPβ, PPARγ, C/EBPα, FABP4, and FASN. At the signaling level, 2-O-methylhonokiol increased AMPKα phosphorylation without altering total AMPKα and reduced FASN expression, whereas mTOR phosphorylation was reduced at 50 µM. These findings suggest that 2-O-methylhonokiol is associated with metabolic and lipogenic signaling remodeling during adipocyte differentiation. 2-O-methylhonokiol also modified kinase-associated responses, increasing AKT and JNK phosphorylation while reducing the detectable phosphorylated ERK signal, with total AKT, ERK, and JNK remaining largely unchanged. ER stress-related signaling displayed a selective profile, characterized by increased IRE1α expression, XBP1s induction, elevated p-eIF2α, unchanged total eIF2α, and no compensatory increase in GRP78. During early adipogenesis, 2-O-methylhonokiol attenuated MDI-induced cell cycle redistribution by preserving a larger G0/G1 population and limiting progression toward later cell cycle phases, consistent with impaired mitotic clonal expansion. These effects occurred at concentrations that did not significantly reduce basal cell viability. Overall, 2-O-methylhonokiol suppresses 3T3-L1 adipogenesis by reducing adipogenic and lipogenic execution, accompanied by AMPK-associated metabolic remodeling, kinase signaling changes, selective ER stress-related responses, and restriction of early cell cycle progression. Further pathway-specific studies are required to define the causal contribution of each signaling axis.

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states.

Photoaging of the skin, driven by ultraviolet B (UVB) radiation, is characterized by the upregulation of matrix metalloproteinases (MMPs), accelerated collagen degradation, diminished hyaluronic acid (HA) content, and disruption of extracellular matrix (ECM) integrity, culminating in wrinkle formation, and structural damage. Nutritional and plant-derived compounds have garnered increasing attention as promising therapeutic agents for skin aging. In this study, we explored the anti-photoaging effects of Gynostemma pentaphyllum hydrodistillate (GPHD) and its bioactive constituent, Damulin B, in UVB-irradiated in vivo and in vitro models. In HR-1 hairless mice, GPHD treatment significantly ameliorated UVB-induced wrinkle formation, collagen degradation, epidermal hyperplasia, and transepidermal water loss, while improving hydration and elasticity. It also modulated hyaluronic acid metabolism by upregulating hyaluronic acid synthases (HAS1 and HAS2) and downregulating hyaluronidases (HYAL1 and HYAL2). In UVB-irradiated Hs68 fibroblasts, GPHD and Damulin B attenuated reactive oxygen species (ROS) generation, thereby inhibiting mitogen-activated protein kinase/activator protein-1 (MAPK/AP-1) signaling and restoring transforming growth factor-beta/Smad (TGF-β/Smad) activity, ultimately contributing to ECM stability. Collectively, our findings demonstrate that GPHD and Damulin B exert potent anti-photoaging effects by mitigating oxidative stress and orchestrating downstream signaling pathways essential for ECM remodeling and skin homeostasis.

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders.

In the original publication [...].

Periodontitis and diabetes mellitus are two highly prevalent chronic conditions that share a bidirectional relationship, significantly impacting public health. Periodontitis, a gum inflammation caused by microbial dysbiosis, aggravates glycemic control in diabetics, while uncontrolled diabetes heightens periodontitis severity. These conditions create a vicious cycle, where inflammation and microbial dysbiosis mutually drive disease progression, exacerbating systemic health. The underlying mechanisms involve inflammation, immune dysfunction, and microbial dysbiosis, with both diseases contributing to a chain of chronic inflammation that exacerbates systemic health. This relationship is significant because managing one condition can significantly impact the other. In diabetic individuals, interventions such as periodontal therapy have shown effectiveness in improving glycemic control, underscoring the potential of integrated strategies for managing these conditions simultaneously. In this review, we highlight the importance of a deeper understanding of the molecular and immunological interactions between these diseases is essential for developing integrated therapeutic approaches, with the potential to enhance the quality of life of the patient significantly.

Molecular chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding, stabilization, and function of proteins. Among them, Heat shock protein 90 (Hsp90), represents a highly conserved protein family of molecular chaperones that plays an essential role in diverse biological processes and is fundamental to cellular health and survival. As a highly abundant molecular chaperone, Hsp90 comprises 1–2% of cellular proteins, increasing to 4–6% under stress conditions. It interacts with client proteins, assisting them in proper folding and stability. Unlike classical chaperonins, Hsp90 operates through a highly regulated, ATP-dependent cycle that involves multiple co-chaperones. This process allows Hsp90 to selectively engage with numerous client proteins, including signaling proteins, kinases, hormone receptors, and transcription factors. Recent discoveries have revealed its involvement in processes beyond protein folding, demonstrating its role in diverse cellular functions such as epigenetic regulation, immune signaling, and oncogenic transformation. This current review highlighted the specific characteristics of cytoplasmic and endoplasmic reticulum (ER) as well as mitochondrial paralogs and functions, focusing on its contribution to buffering genetic variation, facilitating oncogene addiction, and modulating disease phenotypes in conditions such as cancer, neurodegeneration, cardiovascular diseases (CVD), and diabetes. We also discuss the therapeutic potential of targeting Hsp90 and its co-chaperones, outlining the challenges and prospects in drug development. These insights not only reshape our understanding of chaperone biology but also present opportunities for precision medicine in various human diseases.

The interplay between oxidative stress and adipogenesis is a critical factor in the development of obesity and its associated metabolic disorders. Excessive reactive oxygen species (ROS) disrupt key transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), impairing lipid metabolism, promoting adipocyte dysfunction, and exacerbating inflammation and insulin resistance. Antioxidants, classified as endogenous (e.g., glutathione, superoxide dismutase, and catalase) and exogenous (e.g., polyphenols, flavonoids, and vitamins C and E), are pivotal in mitigating these effects by restoring redox balance and preserving adipocyte functionality. Endogenous antioxidants neutralize ROS and safeguard cellular structures; however, under heightened oxidative stress, these defenses are often insufficient, necessitating dietary supplementation. Exogenous antioxidants derived from plant-based sources, such as polyphenols and vitamins, act through direct ROS scavenging, upregulation of endogenous antioxidant enzymes, and modulation of key signaling pathways like nuclear factor kappa B (NF-κB) and PPARγ, reducing lipid peroxidation, inflammation, and adipocyte dysfunction. Furthermore, they influence epigenetic regulation and transcriptional networks to restore adipocyte differentiation and limit lipid accumulation. Antioxidant-rich diets, including the Mediterranean diet, are strongly associated with improved metabolic health, reduced obesity rates, and enhanced insulin sensitivity. Advances in personalized antioxidant therapies, guided by biomarkers of oxidative stress and supported by novel delivery systems, present promising avenues for optimizing therapeutic interventions. This review, "Crosstalk Between Antioxidants and Adipogenesis: Mechanistic Pathways and Their Role in Metabolic Health", highlights the mechanistic pathways by which antioxidants regulate oxidative stress and adipogenesis to enhance metabolic health.

In this study, we undertook an extensive investigation to determine how CypB PPIase activity affects preadipocyte differentiation and lipid metabolism. Our findings revealed that inhibition of CypB’s PPIase activity suppressed the expression of crucial proteins involved in adipocyte differentiation and induced changes in proteins regulating the cell cycle. Furthermore, we clarified the impact of CypB’s PPIase activity on lipid metabolism via the AKT/mTOR signaling pathway. Additionally, we demonstrated the involvement of CypB’s PPIase activity in lipid metabolism through the XBP1s pathway. These discoveries offer invaluable insights for devising innovative therapeutic strategies aimed at treating and averting obesity and its related health complications. Targeting CypB’s PPIase activity may emerge as a promising avenue for addressing obesity-related conditions. Furthermore, our research opens up opportunities for creating new therapeutic strategies by enhancing our comprehension of the processes involved in cellular endoplasmic reticulum stress.

Alopecia, a prevalent yet challenging condition with limited FDA-approved treatments which is accompanied by notable side effects, necessitates the exploration of natural alternatives. This study elucidated the hair growth properties of Gynostemma pentaphyllum leaf hydrodistillate (GPHD) both in vitro and in vivo. Furthermore, damulin B, a major component of GPHD, demonstrated hair growth-promoting properties in vitro. Beyond its established anti-diabetic, anti-obesity, and anti-inflammatory attributes, GPHD exhibited hair growth induction in mice parallel to minoxidil. Moreover, it upregulated the expression of autocrine factors associated with hair growth, including VEGF, IGF-1, KGF, and HGF. Biochemical assays revealed that minoxidil, GPHD, and damulin B induced hair growth via the Wnt/β-catenin pathway through AKT signaling, aligning with in vivo experiments demonstrating improved expression of growth factors. These findings suggest that GPHD and damulin B contribute to the hair growth-inducing properties of dermal papilla cells through the AKT/β-catenin signaling pathway.

The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. The heat shock response triggers the expression of a specific set of genes and proteins known as heat shock genes/proteins or molecular chaperones, including HSP100, HSP90, HSP70, HSP60, and small HSPs. Heat shock proteins (HSPs) play a crucial role in thermotolerance and aiding in protecting cells from harmful insults of stressors. HSPs are involved in essential cellular functions such as protein folding, eliminating misfolded proteins, apoptosis, and modulating cell signaling. The stress response to various environmental insults has been extensively studied in organisms from prokaryotes to higher organisms. The responses of organisms to various environmental stressors rely on the intensity and threshold of the stress stimuli, which vary among organisms and cellular contexts. Studies on heat shock proteins have primarily focused on HSP70, HSP90, HSP60, small HSPs, and ubiquitin, along with their applications in human biology. The current review highlighted a comprehensive mechanism of heat shock response and explores the function of heat shock proteins in stress management, as well as their potential as therapeutic agents and diagnostic markers for various diseases.

Cancer is a multifaceted disease influenced by various mechanisms, including the generation of reactive oxygen species (ROS), which have a paradoxical role in both promoting cancer progression and serving as targets for therapeutic interventions. At low concentrations, ROS serve as signaling agents that enhance cancer cell proliferation, migration, and resistance to drugs. However, at elevated levels, ROS induce oxidative stress, causing damage to biomolecules and leading to cell death. Cancer cells have developed mechanisms to manage ROS levels, including activating pathways such as NRF2, NF-κB, and PI3K/Akt. This review explores the relationship between ROS and cancer, focusing on cell death mechanisms like apoptosis, ferroptosis, and autophagy, highlighting the potential therapeutic strategies that exploit ROS to target cancer cells.

Cyclophilin is known to act as a molecular chaperone in the endoplasmic reticulum. Recent studies have reported that the expression of cyclophilin B (CypB) is increased in ob/ob mice and its inhibitor suppresses adipocyte differentiation. However, the mechanism of action of CypB in adipocytes remains to be elucidated. The present study investigated the role of CypB in 3T3-L1 adipocyte differentiation. It showed that the expression level of CypB was increased during 3T3-L1 adipocyte differentiation by reverse transcription-quantitative PCR and western blotting analysis. CypB knockdown using short interfering RNA delayed cell cycle progression from the G(1)/S to G(2)/M phase through the mammalian target of rapamycin (mTOR) signaling pathway and inhibited the expression levels of adipogenic transcription factors including peroxisome proliferator-activated receptor gamma (PPAR gamma) and CCAAT-enhancer binding protein (C/EBP)alpha. Additionally, the accumulation of lipid droplets was inhibited by CypB knockdown. Conversely, overexpression of CypB promoted cell cycle progression from the G(1)/S to G(2)/M phase by the mTOR signaling pathway and enhanced the expression levels of adipogenic transcription factors including PPAR gamma and C/EBP alpha. Finally, the present study showed that CypB downregulated the expression of CHOP, a well-known negative regulator of adipogenesis. Taken together, the data suggested that CypB might serve important physiological regulatory roles in 3T3-L1 adipocyte differentiation.

Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.

The clinical application of cisplatin, one of the most effective chemotherapeutic agents used to treat various cancers, has been limited by the risk of adverse effects, notably nephrotoxicity. Despite intensive research for decades, there are no effective approaches for alleviating cisplatin nephrotoxicity. This study aimed to investigate the protective effects and potential mechanisms of a Gynostemma pentaphyllum leaves hydrodistillate (GPHD) and its major component, damulin B, against cisplatin-induced nephrotoxicity in vitro and in vivo. A hydro-distillation method can extract large amounts of components within a short period of time using non-toxic, environmentally friendly solvent. We found that the levels of AMP-activated protein kinase α1 (AMPKα1), reactive oxygen species (ROS), and apoptosis were tightly associated with each other in HEK293 cells treated with cisplatin. We demonstrated that AMPKα1 acted as an anti-oxidant factor and that ROS generated by cisplatin suppressed the expression of AMPKα1 at the transcriptional level, thereby resulting in induction of apoptosis. Treatment with GPHD or damulin B effectively prevented cisplatin-induced apoptosis of HEK293 cells and cisplatin-induced acute kidney injury in mice by suppressing oxidative stress and maintaining AMPKα1 levels. Therefore, our study suggests that GPHD and damulin B may serve as prospective adjuvant agents against cisplatin-induced nephrotoxicity.

Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients’ overall survival and quality of life.

Doxorubicin is one of the most effective chemotherapeutic agents available for treating various cancers, including lung cancer—the leading cause of cancer death in both men and women. However, its clinical application has been impeded by severe adverse effects, notably cardiotoxicity. Development of cellular resistance to doxorubicin is another major obstacle that must be overcome for broader application of the drug. In the present study, we examined the therapeutic potential of beta-naphthoflavone (BNF), a synthetic derivative of a naturally occurring flavonoid, in combination with doxorubicin for the treatment of lung cancer. Among our novel observations were that BNF enhances the efficacy of doxorubicin by inducing doxorubicin accumulation, mitochondrial ROS generation, and JNK pathway signaling in lung cancer cells. These combined effects were also evident in many other cancer cell types. BNF further exhibited synergistic induction of apoptosis in lung cancer cells when combined with several other cancer drugs, including irinotecan, cisplatin, and 5-fluorouracil. Our results suggest that BNF can be developed as a promising adjuvant agent for enhancing the efficacy of doxorubicin.

The ketone bodies (KBs) β-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, β-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.