Platinum-based antitumor drugs, such as cisplatin and carboplatin, are well-known for their severe ototoxicity. The ototoxic effects of these drugs are primarily attributed to oxidative stress induced damage within cochlear hair cells (HCs), leading to cell death and subsequent irreversible hearing loss. Over the past decade, studies have demonstrated that upregulating autophagy levels in HCs can greatly alleviate the death of cochlear HCs as part of the oxidative damage induced by ototoxic drugs. However, the molecular mechanisms by which platinum-based drugs affect autophagy and ultimately lead to HCs death remain unclear. In the present study, we investigated the effects of cisplatin on the mTOR signaling pathway, a critical regulator of autophagy, in cochlear explants of mice. Our results indicated that while cisplatin enhances autophagy activity initially, it also activates mTOR Complex1 (mTORC1) within HCs. The persistent activation of mTORC1 inhibits autophagy in HCs, resulting in the accumulation of reactive oxygen species and leading to cell death. Further pharmacological experiments confirmed the protective role of rapamycin, a specific mTORC1 inhibitor, highlighting the importance of autophagy in combating cisplatin-induced ototoxicity. Our findings suggest that modulating the mTOR signaling pathway to regulate autophagy could be an effective strategy for preventing cisplatin-induced ototoxic damage.

This narrative review examines the potential challenges associated with plant-based diets in supporting muscle hypertrophy among resistance-trained athletes. Contrary to common assumptions, current evidence suggests that plant-based diets, when properly planned, can provide protein comparable to omnivorous diets. However, plant-based proteins are generally considered less anabolic due to lower digestibility, essential amino acid (EAA) content, and particularly lower leucine levels. The review discusses challenges and solutions for athletes aiming to maximize hypertrophy through plant-based diets, while highlighting the need for more robust research on advanced resistance-trained athletes.

Lycium barbarum L., also known as Gouqi, a traditional Chinese herbal medicine, is widely utilized in health care products and clinical therapies. Its muscle and bone strengthening efficacy has been recorded in medical classics for a long time. In addition, plant exosome-like nanovesicles (PELNVs) have attracted more and more attention owing to their biological traits. Therefore, we intended to explore the functions, regulatory role, and underlying mechanism of Gouqi-derived Nanovesicles (GqDNVs) on fracture healing.

In this study, we employed the sucrose density gradient differential ultracentrifugation to isolate GqDNVs. The effects of GqDNVs on the proliferation and differentiation of MC3T3-E1 cells were evaluated using the CCK-8 assay, ALP activity measurement, and cell scratch assay. Additionally, leveraging a fracture mouse model, we utilized Micro-CT, immunological staining, and histologic analyses to comprehensively assess the impact of GqDNVs on fracture healing in mice.

GqDNVs stimulated cell viability, increased ALP activity, and promoted cellular osteogenic protein expression (OPN, ALP, and RUNX2). Subsequently, in the mouse fracture model, trabecular thickness, and bone marrow density were increased in the GqDNVs treatment group after 28 days of injection. Meanwhile, the expressions of OPN and BGP were significantly elevated after both 14 and 28 days. Additionally, the expressions of p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, p-4EBP1/4EBP1 and p-p70S6K/ p70S6K were also increased after14 days of treatment.

GqDNVs effectively promoted the proliferation and differentiation of MC3T3-E1 cells. Furthermore, GqDNVs could improve fracture healing, which is associated with PI3K/Akt/mTOR/p70S6K/4EBP1 signaling pathway.

Very little is known about oxidative stress as a modulator of signaling between the host and virus in viral nervous necrosis (VNN) within the aquaculture field. In the present study, we examined whether blocking ROS signaling using mitochondrial Cu/Zn-SOD could affect host cell death and the viral replication of RGNNV during infection in fish cells. Upon the overexpression of Cu/Zn-SOD in fish GF-1 cells, superoxide generation in RGNNV infection was reduced 0.6-fold, which correlated to host cell viability in the middle-late stages. Regarding the regulation of reactive oxygen species (ROS) signaling by superoxide, Cu/Zn-SOD overexpression can enhance superoxide's metabolism to hydrogen peroxide, which suppresses the RIPK3-mediated cell death signals at 48 hpf. On the other hand, ROS-mediated signal suppression can enhance Bcl-2 family Bcl-2/Bcl-xL expression in the early and middle replication stages. Furthermore, the enhancement of superoxide metabolism can reduce the virus' replication ability and expression of the non-structural genes B1 and B2, as well as the genome replication gene Protein A and the major capsid protein protein α, which were correlated with the viral load dropping by two log viral titers at 48 and 72 hpf. Taken together, these data suggest that ROS signals trigger host stress responses related to cell death/necroptosis in RGNNV infection. Then, ROS-mediated stress signals can modulate anti-cell death signals through the Bcl-2/Bcl-xL pathway. In conclusion, an ROS-mediated stress response is required for viral expression and replication cycles, providing new insights into controlling RNA viruses.

Sesamin and episesamin, the major lignans found in refined sesame oil, reportedly exert antioxidant, anti-inflammatory, and hypocholesterolemic effects. Sesamin has also been suggested by previous studies to promote autophagy; however, concerns have been raised regarding the use of non-physiological concentrations, inaccurate methods for evaluating autophagic activity, and incomplete understanding of underlying mechanisms. Additionally, the effects of its metabolic kinetics on autophagy remain unclear. In this study, we demonstrated that sesamin, episesamin, and their metabolites induced autophagy flux at physiological concentrations in human cell cultures expressing monomeric red fluorescent protein-green fluorescent protein tandem fluorescent-tagged microtubule-associated protein 1A/1B-light-chain 3 proteins, a robust method for monitoring autophagy flux. Notably, the monocatechol metabolites of sesamin and episesamin exhibited higher autophagy flux than their unmetabolized forms. Immunoblotting analysis revealed that sesamin and its monocatechol metabolite promoted autophagy by inhibiting mammalian target of rapamycin complex 1 (mTORC1), leading to decreased phosphorylation of unc-51 like autophagy activating kinase 1 and transcription factor EB. This suppression enhanced the isolation membrane formation and transcriptionally stimulated autophagy and lysosomal biogenesis. Importantly, mTORC1 inhibition by sesamin and its metabolites did not affect mTORC2 activity, mirroring the mTORC1-selective inhibition observed with rapamycin. These results suggest that sesamin and episesamin contribute to diverse biological activities via their metabolism in the human body, regulating autophagy and mTORC1 signaling pathways.

The purpose of this review study is to investigate the effect of curcumin on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in various diseases. Curcumin, the main compound found in turmeric, has attracted a lot of attention for its diverse pharmacological properties. These properties have increased the therapeutic potential of curcumin in chronic diseases such as cardiovascular disease, Type 2 diabetes, obesity, non-alcoholic fatty liver disease, kidney disease, and neurodegenerative diseases. One of the main mechanisms of the effect of curcumin on health is its ability to modulate the PI3K/Akt signaling pathway. This pathway plays an important role in regulating vital cellular processes such as growth, cell survival, metabolism, and apoptosis. Disruption of the PI3K/Akt signaling pathway is associated with the incidence of several diseases.

Electronic databases including PubMed, Google Scholar, and Scopus were searched with the keywords "phosphoinositide 3-kinase" AND "protein kinase B "AND "curcumin" in the title/abstract. Also, following keywords "non-alcoholic fatty liver disease" AND "diabetes" AND "obesity" AND "kidney disease" and "neurodegenerative diseases" was searched in the whole text.

Research indicates that curcumin offers potential benefits for several health conditions. Studies have shown it can help regulate blood sugar, reduce inflammation, and protect the heart, kidneys, and brain.

This protective effect is partially achieved by regulating the PI3K-Akt survival pathway, which helps improve metabolic disorders and oxidative stress. By examining how curcumin affects this vital cell pathway, researchers can discover new treatment strategies for a range of diseases.

The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.

In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2 %, 24.0 %, and 5.7 %, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6 %), conversion from serine (45.1 %), and other sources (9.4 %). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7 %) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3 %) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100 %), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.

By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.

The transcriptome analysis following an 8-week feeding trial was employed to investigate the impacts of dietary terrestrial animal fats (TAFs includes lard oil (LO), beef tallow (BT) and poultry oil (PO)) replacing fish oil (FO) on the metabolic mechanism in hepatopancreas of mud crabs (Scylla paramamosain). The fatty acid (FA) transport, biosynthesis and lipid absorption and digestion were reduced through the regulation of PPAR pathway and the mRNA expressions of monoglyceride lipases (mgls), phosphatidate phosphatase-1 (pap1), acyl-sn-glycerol-3-phosphate acyltransferase delta (plcd), cAMP-dependent protein kinase catalytic (pkac), FA-binding protein 1 (fabp-1), FA transport protein 4 (fatp-4), short/branched chain specific acyl-CoA dehydrogenase (acdsb) and enoyl-CoA delta isomerase 2 (eci2), etc., after replacing FO with BT or LO. At the same time, dietary BT and LO regulated glycolysis, gluconeogenesis and insulin signals through increasing the genes of pyruvate dehydrogenase E1 (pdh), phosphoenolpyruvate carboxykinase (pepck) and phosphatidylinositol 3-kinase (pi3k) and regulated immunity status by down regulating the mRNA expressions of heat shock proteins 27 (hsp 27), cytochrome P450 (cyp 450), etc. Replacing FO with PO enhanced phospholipid storage, fat deposition, and inhibited glucose transport by up regulating pap1, mgls, lipin 1, lipinβ and down regulating glycosyl transferase (gt) and glucose transporter type 4 (glut4) expressions. The present study showed the signaling pathways and genes that were significantly regulated by TAFs replacing dietary FO, and revealed molecular mechanisms of TAFs in S. paramamosain. This would be conducive to the application of TAFs in aquatic feed.

The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial nutrient sensor and a major regulator of cell growth and proliferation. While mTORC1 activity is frequently upregulated in cancer, the mechanisms regulating mTORC1 are not fully understood. POLR1D, a shared subunit of RNA polymerases I and III, is often upregulated in colorectal cancer (CRC) and mutated in Treacher-Collins syndrome. POLR1D, together with its binding partner POLR1C, forms a dimer that is believed to initiate the assembly of the multisubunit RNA polymerases I and III. Our data reveal an unexpected link between POLR1D and mTORC1 signalling. We found that the overproduction of POLR1D in human cells stimulates mTORC1 activity. In contrast, the downregulation of POLR1D leads to the repression of the mTORC1 pathway. Additionally, we demonstrate that a pool of POLR1D localises to the cytoplasm and interacts with the mTORC1 regulator RAGA and RAPTOR. Furthermore, POLR1D enhances the interaction between RAPTOR and RAGA and sustains mTORC1 activity under starvation conditions. We have identified a novel role for the RNA polymerase I/III subunit POLR1D in regulating mTORC1 signalling. Our findings suggest the existence of a new node in the already complex mTORC1 signalling network, where POLR1D functions to convey the cell's internal status, namely polymerase assembly, to this kinase.

Pancreatic β-cells play a critical role in glucose homeostasis by secreting insulin. Chronic oxidative stress causes β-cell dysfunction, including β-cell loss; however, the underlying mechanisms remain unclear. Here, we demonstrate the critical role of the regulated in development and DNA damage response 2 (REDD2/DDiT4L/Rtp801L) in β-cell dysfunction. In INS-1 β-cells, Redd2 was induced by high glucose/palmitate or streptozotocin (STZ) exposure. Knockdown of Redd2 attenuated STZ-induced loss of cell viability, while REDD2 overexpression reduced cell viability and p70S6K phosphorylation, suggesting the involvement of suppression of mTORC1 activation. STZ also activated the transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and p53, and overexpression of these transcription factors synergistically induced Redd2 expression. Reporter assays using the Redd2 promoter (-2328/-1) and chromatin immunoprecipitation identified the functional binding sites for Nrf2 (EpRE2, -349/-340) and p53 (p53RE1, -90/-81) on the Redd2 promoter. Purified recombinant p53 and Nrf2 bound directly. There were no noticeable changes in male global Redd2-knockout mice (C57BL/6J background), except for inguinal adipose tissue decrease when the mice were fed a standard diet. In contrast, when the mice were fed a high-fat diet (HFD), Redd2-knockout mice exhibited improved glucose tolerance relative to littermate controls. Redd2-knockout in HFD-fed mice increased β-cell mass due to reduced β-cell apoptosis and elevated plasma insulin concentrations, whereas insulin sensitivity remained unaffected. In both STZ-induced male and female and HFD-fed male models, β-cell specific Redd2-knockout improved glucose tolerance without affecting insulin sensitivity. Our results identify REDD2 as a novel regulator of β-cell dysfunction under oxidative stress.

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality following lung transplantation, with neutrophils playing a central role in its inflammatory pathology. Here, we employ single-cell RNA sequencing and spatial transcriptomics to investigate neutrophil subtypes in the lung ischemia-reperfusion injury (IRI) model. We identify CD177+ neutrophils as an activated subpopulation that significantly contributes to lung injury and serves as an early biomarker for predicting severe PGD in human lung transplant recipients (area under the curve [AUC] = 0.871). CD177+ neutrophils exhibit elevated oxidative phosphorylation and increased mitochondrial complex I activity, driving inflammation and the formation of neutrophil extracellular traps. Targeting mitochondrial function with the complex I inhibitor IACS-010759 reduces CD177+ neutrophil activation and alleviates lung injury in both mouse IRI and rat left lung transplant models. These findings provide a comprehensive landscape of CD177+ neutrophil-driven inflammation in lung IRI and highlight its potential value for future early diagnosis and therapeutic interventions.

T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction.

A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.

In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression.

Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.

Mammalian target of rapamycin (mTOR) signaling constitutes a crucial intracellular signaling pathway indispensable for regulating a variety of pathophysiological processes, including cancers. Intriguingly, the inhibition of mTOR can reverse the adverse effects induced by chemotherapy drugs; however, the fundamental mechanism underlying this phenomenon remains unclear. In this study, we demonstrate that mTOR signaling blockade can mitigate etoposide- or cisplatin-induced intestinal injury in mice. The mTOR inhibitor AZD8055 can inhibit chemotherapy drug-induced normal cell pyroptosis, as manifested by a decreased proportion of PI-positive cells, attenuated intestinal cell swelling, and reduced release of lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1). We further determined that mTOR inhibition suppressed the cleavage of caspase-3 and gasdermin E (GSDME), suggesting the inhibition of the caspase3/GSDME signaling pathway. We also discovered that AZD8055 can impede chemotherapy drug-induced alterations in mitochondrial membrane potential, reactive oxygen species generation, and DNA damage in intestinal cells, which are the key upstream events for activating caspase-3. Correspondingly, data from in vivo mouse models also demonstrated that AZD8055 effectively curtailed intestinal DNA damage and inflammation induced by chemotherapy drugs. Importantly, although AZD8055 counteracts the side effects of chemotherapy drugs, it does not substantially affect their anti-tumor activity. Our study proposes the potential application of mTOR inhibitors as chemoprotective agents, presenting a means to prolong the duration of chemotherapy drug use and optimize the chemotherapeutic regimen.

It is unknown how plasma amino acid (AA) concentrations vary with fortification type, growth and insulin-like growth factor 1 (IGF-1) concentrations in the first weeks of life in very preterm infants (VPIs).

Human milk for VPIs (n = 225) was fortified with bovine colostrum (BC, intact proteins, high bioactivity) or conventional fortifier (CF, hydrolysed bovine whey proteins). Plasma was sampled at fortification start (T0, ~1 week of age) and after one (T1) and two (T2) weeks. Changes in Z-scores for weight, length and head circumference (HC) were calculated from T0 to 35 weeks postmenstrual age.

Compared with CF, BC fortification increased 12 AAs (~10-40%, p < 0.05) and reduced Lys concentrations (10-16%, p < 0.05). Analysed across groups, T0-T2 AA increments associated positively with HC growth (12 AAs) and IGF-1 concentrations (5 AAs), and inversely with gestational age (13 AAs) and weight (8 AAs) at birth. The plasma protein profile (proteome) was unaffected by fortification.

BC fortification increased the plasma concentrations of many AAs. Fortification-induced AA increments associated positively with HC growth and IGF-1 concentrations, and were affected by immaturity and birth weight. Still, plasma AA variability within physiological levels appears to have limited implications for clinical outcomes during the early life of VPIs.

It is unknown how human milk fortification affects plasma amino acid concentrations, in turn influencing growth patterns in very preterm infants. We show that a fortifier based on bovine colostrum induces higher amino acid concentrations than a conventional fortifier. Fortification-induced increments in amino acid concentrations associated with gestational age, birth weight and head growth, but with small effect sizes and limited relation to body weight or length growth. Plasma amino acid concentrations are influenced by fortification of human milk in early life, but have limited practical application as predictors of body growth and health in individual very preterm infants.

Microplastics are ubiquitous in our environment, resulting in animal exposure and consumption via food, water, and air. Animals that consume microplastics may suffer from physiological effects like immunotoxicity or mitochondrial dysfunction, but how specific tissues may differentially respond to plastic consumption is poorly understood, particularly in terrestrial insects. Here, we measured transcriptomic responses of tissues (midgut, hindgut, fat body and ovaries) to microplastic consumption in a generalist ground-dwelling insect, the tropical house cricket, Gryllodes sigillatus. Using this approach, we provide insights on how microplastics may impact specific organ systems. We generated a de novo transcriptome, a useful resource for further studies on this emerging model insect, that we then used to infer differential gene expression due to microplastic consumption in individual organs. Ingestion of microplastics elicited unique changes in gene expression depending on the tissue of focus, with notable differentially-expressed genes related to survival and stress pathways as well as those related to metabolism, immunity, and cancer.

Deoxynivalenol (DON) and octyl gallate (OG) are prevalent compounds in the environment and food. DON is frequently detected in cereals such as corn and wheat, while OG is commonly employed as a food additive. As a result, human exposure to these substances is inevitable. Given this, the objective of this experiment was to investigate the impact of co-exposure to DON (10 μg/kg) and OG (10 μg/kg) on intestinal inflammation. The RAW264.7 macrophage cell line was utilized to analyze cytokine levels as well as proteomic and metabolomic changes. In the quantitative real-time PCR experiments, the DON group showed significant difference compared to the control group (* p < 0.05) and the DON-OG group (# p < 0.05) regarding cytokine levels such as IL-10, TNF-α, Il6, Il1b, Ccl2, Il12α, Nos2, Cxcl1, and Cxcl2. In the animal experiment, C57BL/6 mice were utilized to monitor body weight, the presence of bloody stools, and diarrhea. Additionally, the colonic tissues of the mice underwent pathological analysis. The results indicated that cells treated with both DON and OG displayed lower levels of inflammation compared to those treated with DON alone. Furthermore, proteomic and metabolomic analyses revealed that the regulation of the Lancl2 protein and the mTOR signaling pathway contributed to the milder inflammatory response observed in the DON-OG group. These findings were further corroborated by the pathological analysis of the colonic tissues from the mice. In the combined exposure of DON and OG, OG partially mitigated the intestinal inflammation induced by DON.

Hepatocellular carcinoma is a prevalent malignant tumor with a high mortality rate. Natural plants hold promise for its treatment, however, the mechanism of lysionotin induced apoptosis in liver cancer cells unclearly. This study aims to investigate the microenvironment alterations and the efficacy of lysionotin in liver cancer.

Transmission electron microscopy, and laser confocal microscopy were employed to investigate the effect of lysionotin on autophagy in HCC cells. The molecular mechanism through which lysionotin induces autophagy and autophagy-induced apoptosis was ascertained by transcriptome sequencing, immunoblotting and Hoechst 33258 staining.

RNA sequencing analysis, electron microscopy and laser confocal microscopy revealed that lysionotin initiate autophagy in liver cancer cells. Immunoblotting indicated that lysionotin markedly enhances the activation of LC3-II in HCC cells, resulting in the activation of key effector molecules ATG12, Beclin-1 and the degradation of P62. Combined with autophagy inhibitors CQ and 3-MA significantly inhibited lysionotin-induced cell apoptosis. Immunoblotting and Hoechst staining disclosed that the activation of autophagy by lysionotin might be associated with the suppression of the mTOR-AKT signaling pathway. The treatment of mTOR inhibitor RAPA and activator 1485 demonstrated that inhibiting mTOR activation significantly augments the pro-apoptotic effect of lysionotin on liver cancer cells, while mTOR activator could rescue the effect of lysionotin on cells.

The findings suggest that the activation of autophagy by lysionotin may represent one of the pivotal mechanisms underlying its therapeutic efficacy against HCC and its synergistic enhancement of RAPA's antitumor effects.

Interactions between rumen microorganisms and their metabolites contribute to milk yield and milk fat content in dairy cows. However, whether rumen microbes and host metabolism affect fatty acid synthesis in milk is unknown. In this study, we investigated the potential regulatory mechanisms affecting the unsaturated fatty acid content of Binglangjiang buffalo by using macrogenomics and metabolomics. Macrogenomic analysis showed that Bacteroides was significantly more abundant in the high UFA group (HF), contributing to the improvement of functions related to fatty acid synthesis. Then, we found that the rumen microbiota of the HF group was enriched in 2 important pathways involved in lipid metabolism (i.e., fatty acid biosynthesis and fatty acid metabolism), suggesting that more fatty acids were synthesized in the HF group. Metabolomics analyses showed that most of the UFA were more abundant in the HF group, which was also confirmed by the quantification of related metabolic pathways in milk fatty acids, suggesting that the HF group has a higher capacity to synthesize MUFA and PUFA. Correlation analysis of rumen lipid metabolic pathways and metabolites revealed that metabolic pathways such as fatty acid biosynthesis, fatty acid metabolism, metabolic pathways, and peroxisome proliferator-activated receptor (PPAR) signaling pathway, which were significantly enriched in the HF group compared with the low UFA group, were significantly and positively correlated with multiple UFA . The synthesis of UFA is mainly influenced by Bacteroides, Prevotella, and Bacteroidaceae, and regulated by fatty acid biosynthesis, fatty acid metabolism, and PPAR signaling pathways, which together influence the synthesis of UFA in buffaloes.

Type 2 diabetes mellitus (T2DM) and Major depressive disorder (MDD) act as risk factors for each other, and the comorbidity of both significantly increases the all-cause mortality rate. Therefore, studying the diagnosis and treatment of diabetes with depression (DD) is of great significance. In this study, we progressively identified hub genes associated with T2DM and depression through WGCNA analysis, PPI networks, and machine learning, and constructed ROC and nomogram to assess their diagnostic efficacy. Additionally, we validated these genes using qRT-PCR in the hippocampus of DD model mice. The results indicate that UBTD1, ANKRD9, CNN2, AKT1, and CAPZA2 are shared hub genes associated with diabetes and depression, with ANKRD9, CNN2 and UBTD1 demonstrating favorable diagnostic predictive efficacy. In the DD model, UBTD1 (p > 0.05) and ANKRD9 (p < 0.01) were downregulated, while CNN2 (p < 0.001), AKT1 (p < 0.05), and CAPZA2 (p < 0.01) were upregulated. We have discussed their mechanisms of action in the pathogenesis and therapy of DD, suggesting their therapeutic potential, and propose that these genes may serve as prospective diagnostic candidates for DD. In conclusion, this work offers new insights for future research on DD.

The stability of the sarcolemma is severely impaired in a series of genetic neuromuscular diseases defined as muscular dystrophies. These are characterized by the centralization of skeletal muscle syncytial nuclei, the replacement of muscle fibers with fibrotic tissue, the release of inflammatory cytokines, and the disruption of muscle protein homeostasis, ultimately leading to necrosis and loss of muscle functionality. A specific subgroup of muscular dystrophies is associated with genetic defects in components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role in linking the cytosol to the skeletal muscle basement membrane. In these cases, dystrophin-associated proteins fail to correctly localize to the sarcolemma, resulting in dystrophy characterized by an uncontrolled increase in protein degradation, which can ultimately lead to cell death. In this review, we explore the role of intracellular degradative pathways-primarily the ubiquitin-proteasome and autophagy-lysosome systems-in the progression of DGC-linked muscular dystrophies. The DGC acts as a hub for numerous signaling pathways that regulate various cellular functions, including protein homeostasis. We examine whether the loss of structural stability within the DGC affects key signaling pathways that modulate protein recycling, with a particular emphasis on autophagy.

The most malignant type of tumor in the brain is high-grade gliomas. Glioblastoma (GB), a grade 4 glioma, has the lowest 5-year survival rate and is associated with poor prognosis. An important signaling pathway involved in the pathogenesis of GB is the mammalian target of rapamycin (mTOR). Therefore, our study aimed to investigate how exosomes obtained from GB cells applied with different doses of hesperidin (HSP) affect miR- 9 and change the PDK1/AKT/mTOR pathway. For this purpose, T98G cells were treated with different doses (5, 10, 25, and 50 µg/mL) of HSP in combination with temozolomide (TMZ- 10 µg/mL). At the end of 24 h, cell viability, flow cytometry, and biochemical tests were performed. Additionally, exosomes were isolated from cells belonging to the control, TMZ, and high-concentration TMZ-HSP groups. miR- 9, PDK1, PTEN, AKT- 1, Bax, Bcl- 2, and Caspase 3 genes were expressed in both application groups and exosomes belonging to these groups. HSP was found to reduce the viability of GB cells significantly. The viability was significantly reduced, especially in the TMZ-HSP 50 µg/mL group. Depending on the dose, there was a significant increase in the LDH level and oxidative stress level. The apoptosis level was approximately 26% in the TMZ-HSP 50 µg/mL group. Along with all this, gene expressions changed at the exosomal level, and miR- 9 and miR- 146 levels increased. Similarly, it changed the expression of proteins related to the PDK1/AKT/mTOR signaling pathway at the exosomal level (p < 0.05). In conclusion, the TMZ-HSP combination showed anticancer effects in T98G cells, influenced exosome profiles, and appeared non-toxic and potentially beneficial to healthy cells, highlighting its potential therapeutic value.

Type 2 diabetes mellitus (T2DM) represents a significant risk factor for cardiovascular disease, particularly heart failure with preserved ejection fraction (HFpEF). HFpEF predominantly affects elderly individuals and women, and is characterized by dysfunctions associated with metabolic, inflammatory, and oxidative stress pathways. Despite HFpEF being the most prevalent heart failure phenotype in patients with T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated.

This study aims to investigate the effects of diabetes mellitus on myocardial inflammation, oxidative stress, and protein quality control (PQC) mechanisms in HFpEF, with particular emphasis on insulin signaling, autophagy, and chaperone-mediated stress responses.

We conducted an analysis of left ventricular myocardial tissue from HFpEF patients, both with and without diabetes, employing a range of molecular, biochemical, and functional assays. The passive stiffness of cardiomyocytes (Fpassive) was assessed in demembranated cardiomyocytes before and after implementing treatments aimed at reducing inflammation (IL-6 inhibition), oxidative stress (Mito-TEMPO), and enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), oxidative stress markers (ROS, GSH/GSSG ratio, lipid peroxidation), and components of signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, and PKG) were evaluated using western blotting, immunofluorescence, and ELISA techniques.

Hearts from diabetic HFpEF patients exhibited significantly heightened inflammation, characterized by the upregulation of NF-κB, IL-6, and the NLRP3 inflammasome. This increase in inflammation was accompanied by elevated oxidative stress, diminished nitric oxide (NO) bioavailability, and impaired activation of the NO-sGC-cGMP-PKG signaling pathway. Notably, dysregulation of insulin signaling was observed, as indicated by decreased AKT phosphorylation and impaired autophagy regulation mediated by AMPK and mTOR. Additionally, PQC dysfunction was evidenced by reduced expression levels of HSP27 and HSP70, which correlated with increased cardiomyocyte passive stiffness. Targeted therapeutic interventions effectively reduced Fpassive, with IL-6 inhibition, Mito-TEMPO, and HSP administration leading to improvements in cardiomyocyte mechanical properties.

The findings of this study elucidate a mechanistic relationship among diabetes, inflammation, oxidative stress, and PQC impairment in the context of HFpEF. Therapeutic strategies that target these dysregulated pathways, including IL-6 inhibition, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in HFpEF patients with T2DM. Addressing these molecular dysfunctions could facilitate the development of novel interventions specifically tailored to the diabetic HFpEF population.

Dopamine is involved in many physiological functions including reward phenomenon, motor, learning, and memory functions. Dopamine receptor agonists have been shown to reduce amyloid (Aβ) deposition, enhance memory, and improve cortical plasticity in experimental studies and Alzheimer's disease (AD) patients; however, the molecular mechanisms involved haven't been investigated yet. The target of this investigation was to elucidate the modulatory effects of cabergoline (CAB), a dopamine receptor agonist, against AD. Ovariectomized rats were injected with D-galactose (150 mg/kg/day, i.p) for ten weeks to exacerbate AD. CAB administration (1 mg/kg/day, i.p) for 28 days, beginning from the 7th week of D-galactose administration, attenuated the associated histopathological alterations and enhanced the spatial and recognition memory in Morris water maze and Novel object recognition tests, respectively. CAB decreased the hippocampal concentrations of Aβ42, p-tau, and β-secretase, while upregulating α-secretase. Moreover, CAB diminished nuclear factor-kappa β (NF-κβ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase, while elevating brain-derived neurotrophic factor and phospho-cAMP response element binding protein. Further, CAB reduced the hippocampal phosphorylated forms of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) contrary to elevating Beclin-1, resulting in autophagy induction, which participates in accelerating Aβ42 and p-tau aggregates clearance. Moreover, CAB increased the hippocampal glutamate transporter-1 (GLT-1) protein expression, promoting glutamate uptake that possibly reduced Ca2+ overload and consequently decreased the phosphorylated forms of P38-MAPK and ERK1/2. In conclusion, CAB improved cognitive decline of D-gal/OVX animals, restored hippocampal architecture, exerted neuroprotection, and enhanced autophagic machinery via modulating AKT/mTOR, GLT-1/P38-MAPK, and ERK1/2 pathways.

Podocytes are key components of the glomerular filtration barrier - a specialized structure that is responsible for the filtration of blood by the kidneys. They therefore exist in a unique microenvironment exposed to mechanical force and the myriad molecules that cross the filtration barrier. To survive and thrive, podocytes must continually sense and respond to their ever-changing microenvironment. Sensing is achieved by interactions with the surrounding extracellular matrix and neighbouring cells, through a variety of pathways, to sense changes in environmental factors such as nutrient levels including glucose and lipids, oxygen levels, pH and pressure. The response mechanisms similarly involve a range of processes, including signalling pathways and the actions of specific organelles that initiate and regulate appropriate responses, including alterations in cell metabolism, immune regulation and changes in podocyte structure and cognate functions. These functions ultimately affect glomerular and kidney health. Imbalances in these processes can lead to inflammation, podocyte loss and glomerular disease.

Gene therapy is an approach that employs vectors to deliver genetic material to target cells, aiming to correct genes with pathogenic mutations and modulate one or more genes responsible for disease progression. It holds significant value for clinical applications and offers broad market potential due to the large patient population affected by various conditions. For instance, in 2023, the Food and Drug Administration (FDA) approved 55 new drugs, including five specifically for gene therapy targeting hematologic and rare diseases. Recently, with advancements in understanding the pathogenesis and development of neurodegenerative diseases (NDDs), gene therapy has emerged as a promising avenue for treating Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA), particularly in personalized medicine. Notably, the FDA has approved three clinical applications for combating SMA, utilizing viral vectors delivered via intravenous and intrathecal injections. However, gene therapy for other NDDs remains in clinical trials, necessitating improvements in viral vectors, exploration of new vectors, optimization of delivery routes, and further investigation into pathogenesis to identify novel targets. This review discusses recent advancements in gene therapy for NDDs, offering insights into developing new therapeutic strategies.

Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets.

One of the major consequences of diabetes mellitus that has gained attention due to its rising incidence is cognitive impairment. Recent research suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors can mitigate memory impairment linked to Alzheimer's disease and are now being explored for their cognitive benefits. However, their mechanisms were not thoroughly studied. This research investigates the hypothesis of the neuroprotective effect of empagliflozin administration against scopolamine-heavy metal mixture (SCO + HMM)-treated Alzheimer's rat models in comparison with memantine as a reference drug and the impact of their combination. Yet, the neuroprotective effects of memantine and empagliflozin combination against cognitive impairment have not been previously explored. This study employed adult male albino rats categorized into five groups. The impact of empagliflozin, memantine, and their concomitant administration on cognitive performance was assessed in a scopolamine and heavy metal mixture-treated Alzheimer's disease model in rats. The assessment of rats' cognitive behavior, memory, and spatial learning was conducted, followed by an evaluation of hippocampal brain-derived neurotrophic factor (BDNF), beta-secretase (BACE-1), oxidative stress (OS), and inflammatory marker activity. And, a western blot analysis was conducted to detect phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of rapamycin (p-mTOR), and heme oxygenase-1 (HO-1). Hippocampal and cerebellar histopathology were thoroughly examined, in addition to the expressions of amyloid β (Aβ). The current data demonstrate the involvement of the pAMPK/mTOR/HO-1 signaling pathway in empagliflozin neuroprotection against SCO + HMM-induced AD. In addition, it reduces AD hallmarks (Aβ and BACE1), neuro-inflammation, and oxidative stress sequelae, and enhances neurogenesis and synaptic density via BDNF. This study proposes that EMPA, especially when co-administered with other conventional anti-Alzheimer therapy, may be formulated into an innovative therapeutic strategy for the enhancement of cognitive impairments associated with neurodegenerative disorders.

Fetal growth restriction (FGR) is a common pregnancy complication with significant impact on obstetric and birth outcomes. Increasing evidence shows that the inhibition of placental mechanistic target of rapamycin (mTOR) signaling is closely related to FGR. However, the pathogenesis of FGR is not fully consistent presently, which is subject to the methodological divergence.

Rapamycin was used to construct the FGR mouse model. Hematoxylin & eosin (HE) and periodic acid-schiff (PAS) staining were used to analyze the morphology of mouse placenta. Western blot was used to analyze the expression levels of glucose transporters and key enzymes associated with glycogen metabolism in human/mouse placental tissues in different anatomic layers. HTR-8 cells were treated with dimethyl sulfoxide (DMSO) or rapamycin (2 mM) for 24 h. Cell viability was detected by CCK8 kit. In addition, glycogen concentration in placental tissue or cell samples was detected by Glycogen Assay Kit.

Firstly, we observed a significant reduction of glucose content in different anatomical regions of human small-for-gestational-age (SGA) placenta, also glucose metabolism was undermined to some extent. Then, we found that FGR placentas showed abnormal morphological changes, the glycogen levels in FGR placentas were significantly reduced by quantitative detection. Meanwhile, the expression levels of glucose transporters, Gys1 and p-Gsk3β in FGR placentas were reduced compared to controls. The HTR-8 cells treated with rapamycin revealed decreasing mTOR activity and glycogen levels. In addition, glucose transporter, GYS1, p-GSK3β expressions were all significantly reduced and t-GSK3β level was significantly elevated.

Overall, our data indicate that inhibition of placental mTOR signaling may contribute to the occurrence of FGR by altering glucose metabolism.

With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.

The KIT receptor is a transmembrane protein found on the surface of many different cell types. Mutant forms of KIT are drivers of myeloid neoplasms, including systemic mastocytosis. The KIT D816V mutation is the most common, leading to constitutive activation of the receptor and its downstream targets, and it is highly resistant to c-KIT inhibitors. Metabolic rewiring is a common trait in cancer. We analyzed the metabolic profile induced by the KIT D816 mutation, measuring mitochondrial parameters in two myeloid cell lines. We found that the KIT D816V mutation causes a significant increase in mitochondrial abundance and activity associated with superoxide production, which could promote DNA instability. Functional and morphologic changes in mitochondria were associated with reduced levels of BNIP3 protein expression. We also detected low BNIP3 levels in clinical acute myeloid leukemia samples harboring D816V mutations. In addition, we have found constitutive mTOR activation in mutated cells, a pathway that has been shown to regulate autophagy. Our data suggest that KIT D816V increases mitochondrial activity through downregulation of BNIP3 expression, which increases mitochondrial number through the autophagy pathway. Alterations in the cellular metabolism induced by the KIT D816V mutation could be therapeutically exploited.

In recent years, immunotherapy has become a novel antitumor strategy in addition to traditional surgery, radiotherapy, and chemotherapy and has exhibited promising results in clinical applications. Despite significant breakthroughs in immunotherapy, such as immune checkpoint blockade and CAR-T cell therapy, it remains necessary to develop more efficacious, safer, and cheaper immunotherapeutic drugs due to factors including small reaction populations, acquired resistance, adverse side effects, and high costs. Natural killer (NK) cells are preeminent cytotoxic lymphocytes of the innate immune system that act as the first line of defense against tumors and synergistically enhance the adaptive immune response of T lymphocytes. Therefore, boosting the antitumor function of NK cells is an important direction in the development of immunotherapy. For decades, various immunotherapies such as adoptive cell therapy, antibody drugs, cytokines supplement, and chemical immunomodulators have been developing rapidly to improve the function of NK cells. Compared to biological immunotherapy, immunomodulators derived from natural products have outstanding advantages of low immunogenicity, multi-targeting, and cost-effectiveness. Currently, increasing attention is being focused on discovering NK cell-stimulating agents from natural products, such as polysaccharides, alkaloids, terpenoids, saponins, phenolics, and quinones. This review aims to categorize and summarize the comprehensive research progress on these natural products, discuss their potential molecular mechanisms in regulating NK cells, and explore their clinical applications as standalone treatments or in combination with conventional chemotherapy regimens.

Malignant tumours remain one of the most intractable health problems worldwide. Recently, plant-derived nanovesicles (PDNVs) have emerged as a promising tool in the treatment of malignant tumours, leveraging their high biosafety and potential mechanisms such as cancer-selective apoptosis induction and cell cycle arrest. This paper presents a systematic review of the research progress of nanovesicles in malignant tumours, with a focus on plant-derived vesicles (PDVs) and their potential applications in cancer treatment, based on bibliometric analysis. In this review, the research on PDNVs in malignant tumours was identified and analysed through various countries/institutions, authors, references and research hotspots. Furthermore, we summarized the diverse biological functions and applications of PDNVs sourced from various origins in malignant tumours, both when acting independently and as carriers. Lastly, we provide an outlook on the potential applications of PDNVs in malignant tumours. The purpose of this paper is to summarize the research progress of the role of PDNVs in malignant tumours, and to provide new ideas and clues for overcoming the difficulties of tumour treatment.

The target of the rapamycin (TOR) signaling pathway is crucial for biological function in plant pathogenic fungi, yet its regulatory mechanisms remain limited. In this study, the biological functions of MoPbp1 were identified and characterized, and the findings indicate that MoPbp1 contributes to hyphal growth, conidiation, appressoria formation, metabolism of glycogen and lipid droplets, responses to stress, and pathogenicity in Magnaporthe oryzae. Further investigation revealed that MoPBP1 acts as a negative regulator of TOR activity and influences autophagy. In addition, transcriptome data revealed that MoPBP1 mainly regulates amino acid metabolism pathways, components of membrane, and oxidation-reduction process. Our results suggest that MoPbp1 is required for autophagy and pathogenicity in M. oryzae. Overall, we first revealed the relationship between Pbp1 and TOR activity in plant pathogenic fungi.

Alzheimer's disease (AD) is among the top mortality causing diseases worldwide. The presence of extracellular β-amyloidosis, as well as intraneuronal neurofibrillary aggregates of the abnormally hyperphosphorylated tau protein are two major characteristics of AD. Targeting protein kinases that are involved in the disease pathways has been a common approach in the fight against AD. Unfortunately, most kinase inhibitors currently available target the adenosine triphosphate (ATP)- binding site, which has proven unsuccessful due to issues with selectivity and resistance. As a result, a pressing need to find other alternative sites beyond the ATP- binding site has profoundly evolved. In this review, we will showcase some case studies of inhibitors of tau protein kinases acting beyond ATP binding site which have shown promising results in alleviating AD.

This meta-analysis aims to evaluate the efficacy and safety of rapamycin (mTOR) inhibitors with endocrine therapy versus endocrine therapy alone in treating advanced or metastatic estrogen receptor/progesterone receptor (ER/PR) + breast cancer.

We conducted a comprehensive search in PubMed, Web of Science, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing mTOR inhibitors plus endocrine therapy with endocrine therapy alone up to September 2024.

This analysis included 10 RCTs comprising 3,337 patients. Relative to endocrine therapy alone, the combination of mTOR inhibitors and endocrine therapy significantly improved the clinical benefit rate (RR = 1.41, p < 0.001), overall response rate (RR = 1.40, p = 0.006), progression-free survival (PFS; HR = 0.67, p < 0.001), and overall survival (OS; HR = 0.86, p = 0.056), although the improvement in OS was not statistically significant. Subgroup analyses indicated a more pronounced PFS advantage in patients under 65 years of age (HR = 0.55, p = 0.013) and those who had previously received chemotherapy (HR = 0.51, p = 0.001). However, the incidence of adverse events was higher in the combination therapy group, notably stomatitis (p < 0.001), elevated aspartate aminotransferase/alanine aminotransferase (p = 0.04), and diarrhea (p = 0.01).

The combination of mTOR inhibitors with endocrine therapy offers superior efficacy with manageable toxicities in patients with advanced or metastatic ER/PR+ breast cancer.

Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography (SD-OCT), and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.

Cisplatin (DDP), a frontline chemotherapeutic agent in osteosarcoma (OS) treatment, is frequently paired with other compounds to enhance its therapeutic potency. Cardamom (CAR), a natural flavonoid, exhibits significant inhibitory effects on human OS cells while minimizing toxic side effects. In this study, we combined CAR and DDP to treat OS, revealing that the DDP/CAR combination synergistically inhibits the growth of human OS cells in vitro and in vivo. Network pharmacological analysis indicated that mammalian target of rapamycin (mTOR) may be an important cross-target for DDP/CAR combination. Notably, this combined treatment significantly reduced mTOR phosphorylation and elevated autophagy levels within OS cells. At the mechanistic level, the DDP/CAR regimen enhanced apoptosis and compromised the viability of OS cells by triggering autophagy. This impact was attenuated by the use of the mTOR activator MHY and the autophagy inhibitor hydroxychloroquine (HCQ). Furthermore, in DDP-resistant cell lines, CAR was able to mitigate DDP resistance by bolstering autophagy levels. In general, our results suggest that CAR bolstering autophagy levels DDP against OS cells through the induction of mTOR-mediated autophagy.