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Obesity is an enormous global health problem, and obesity‐induced nonalcoholic steatohepatitis (NASH) is contributing to a rising incidence and mortality for hepatocellular carcinoma (HCC). Increase in de novo lipogenesis and decrease in fatty acid β‐oxidation (FAO) underlie hepatic lipid accumulation in NASH. Astrocyte‐elevated gene‐1/metadherin (AEG‐1) overexpression contributes to both NASH and HCC. AEG‐1 harbors an LXXLL motif through which it blocks activation of peroxisome proliferator activated receptor α (PPARα), a key regulator of FAO. To better understand the role of LXXLL motif in mediating AEG‐1 function, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, we generated a mouse model (AEG‐1‐L24K/L25H) in which the LXXLL motif in AEG‐1 was mutated to LXXKH. We observed increased activation of PPARα in AEG‐1‐L24K/L25H livers providing partial protection from high‐fat diet–induced steatosis. Interestingly, even with equal gene dosage levels, compared with AEG‐1–wild‐type livers, AEG‐1‐L24K/L25H livers exhibited increase in levels of lipogenic enzymes, mitogenic activity and inflammation, which are attributes observed when AEG‐1 is overexpressed. These findings indicate that while LXXLL motif favors steatotic activity of AEG‐1, it keeps in check inflammatory and oncogenic functions, thus maintaining a homeostasis in AEG‐1 function. AEG‐1 is being increasingly appreciated as a viable target for ameliorating NASH and NASH‐HCC, and as such, in‐depth understanding of the functions and molecular attributes of this molecule is essential. Conclusion: The present study unravels the unique role of the LXXLL motif in mediating the balance between the metabolic and oncogenic functions of AEG‐1.

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain’s immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-κB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC.

Alzheimer's disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain's immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD. [ABSTRACT FROM AUTHOR]

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC. [ABSTRACT FROM AUTHOR]

Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-κB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC. [ABSTRACT FROM AUTHOR]