Cisplatin (CP) has been used as an effective chemotherapy drug for different types of cancers. Despite its therapeutic benefits, the clinical utility of CP is often hindered by adverse effects, notably acute kidney injury (AKI), which restricts its widespread application. Dihydromyricetin (DHM) is a flavonoid acquired from Ampelopsis grossedentata, exhibiting a range of pharmacological activities. The major objective of this research was to examine the possible molecular mechanism involved in CP-induced AKI and the protective function of DHM.

In this study, the protective function of DHM against CP-induced AKI was assessed in both mice and HK-2 cells. Kidney dysfunction parameters and renal morphology were evaluated to ascertain the extent of protection. Additionally, proteomics techniques were employed to investigate the protective effect of DHM and elucidate the underlying molecular mechanisms involved in mitigating CP-induced AKI. In addition, protein levels of epidermal growth factor receptor (EGFR), p-EGFR, heat shock protein 27 (HSP27), p-HSP27, STAT3, and p-STAT3 in renal tissues were investigated. Furthermore, an EGFR-blocking agent (gefitinib) or si-RNA of HSP27 was used to study the effects of inhibiting EGFR or HSP27 on CP-induced renal injury.

DHM decreased blood urea nitrogen (BUN) and creatinine in serum, alleviated renal morphological injury and downregulated the expression of CP-induced kidney injury molecule-1 and neutrophil gelatinase-related lipocalin. Proteomic data revealed HSP27 as a potential therapeutic target for AKI. DHM treatment resulted in the downregulation of EGFR, HSP27, and STAT3 phosphorylation, ultimately mitigating CP-induced AKI. In addition, the inhibition of EGFR or HSP27 reduced mitochondria-mediated apoptosis and CP-induced cell damage in HK-2 cells.

DHM effectively inhibited CP-induced oxidative stress, inflammation, and mitochondria-mediated apoptosis through the EGFR/HSP27/STAT3 pathway.

Leonurus japonicus Houtt. (L. japonicus), as an important plant resource with both ornamental and medicinal value, has now spread worldwide and is widely studied. Currently, its chromosomal genome and chloroplast genome (cpDNA) have been reported, but the mitochondrial genome (mtDNA) has not yet been explored. In this study, we extracted DNA from fresh leaves of L. japonicus and performed sequencing and assembly of its mtDNA using both second-generation and third-generation sequencing technologies. The complete mtDNA of L. japonicus is 382,905 bp in length, with a GC content of 45.13%. This genome includes 15 tRNA genes, 32 protein-coding genes (PCGs), and 4 rRNA genes. In this mtDNA genome, we predicted a total of 480 RNA editing sites among the 32 PCGs. Subsequently, we conducted analyses on repetitive sequences, organelle genome sequence migration, and Relative Synonymous Codon Usage (RSCU). There are 28 homologous sequence fragments between the mtDNA and cpDNA of L. japonicus, which are related to the migration of 10 mtDNA genes. The RSCU analysis predicted 28 high-frequency codons, most of which prefer to end with A/U. Selection pressure analysis indicated that the Ka/Ks ratio for the majority of PCGs is less than 1, suggesting they are highly conserved during evolutionary processes. Phylogenetic results from 24 species indicate that the genera Leonurus and Scutellaria within the Lamiaceae family have the closest relationships. In summary, we have successfully assembled the complete mtDNA of L. japonicus by integrating second-generation and third-generation sequencing data for the first time. Subsequent multi-faceted analyses have allowed us to gain deeper insights into the numerous features of this genome, providing important reference data for the molecular genetics, dynamic evolution, and species identification of this plant. This work promotes the conservation and development of this important resource of medicinal and edible plants.

We reported the mitogenomes of F. danxiaensis and F. kwangsiensis for the first time. Mitogenome size and structure differ significantly between them. Firmiana danxiaensis and F. kwangsiensis belong to the Firmiana genus and are distributed in the Danxia and Karst regions of southern China. Both species have been designated as endangered. Currently, the chloroplast genomes of F. danxiaensis and F. kwangsiensis have been sequenced, but the mitochondrial genome (mitogenome) of these two species has not been reported. To further understand the mitogenome characteristics, evolution, and phylogeny of F. danxiaensis and F. kwangsiensis, we assembled the mitogenomes of these two species based on a combination of Illumina and Nanopore sequencing methods. The mitogenome of F. danxiaensis exhibits a branching structure consisting of nine circular molecules with a total length of 938,890 bp, while the F. kwangsiensis has a circular structure with a length of 736,334 bp. Compared to F. kwangsiensis, F. danxiaensis has more tRNA genes, SSRs, tandem repeats, and dispersed repeats, while the codon use patterns are similar in these two species. There were 24 and 23 homologous sequences between mitogenome and chloroplast genome of F. danxiaensis and F. kwangsiensis, accounting for 0.37% and 0.49% of the mitogenome, respectively. In addition, the Ka/Ks ratio and the nucleic acid diversity analysis revealed that most of the mitochondria protein-coding genes in F. danxiaensis and F. kwangsiensis are highly conserved and may have undergone purifying selection. Furthermore, the collinear and comparative analysis showed that extensive genomic rearrangement events existed among the Malvaceae species. Lastly, a phylogenetic tree based on shared mitochondrial PCGs of 29 species revealed that F. danxiaensis and F. kwangsiensis form a sister group with high support values. Overall, the current study reports two mitogenomes (F. danxiaensis and F. kwangsiensis) in the Firmiana genus for the first time, which will help enhance comprehension of the mitogenome evolutionary patterns within Firmiana and promote the evolutionary and comparative genomic analyses within Malvaceae species.

As an autophagy receptor, SQSTM1/p62 facilitates the degradation of various cytoplasmic components, including proteins, organelles, and pathogens, by mediating interactions between polyubiquitination cargo and autophagosomes. Our study observed an increase in the expression level of SQSTM1/p62 during autophagy induced by Vibrio alginolyticus (V. alginolyticus) in Penaeus vannamei (P. vannamei), contrary to expectations, which promoted an investigation into the role of SQSTM1/p62 in infectious diseases of aquatic animals. Using silencing techniques, we examined the function and regulatory mechanism of SQSTM1/p62 during V. alginolyticus infection. Silencing the Pvp62 gene in P. vannamei and infecting them with V. alginolyticus led to a significant decrease in the survival rate of P. vannamei, indicating its importance in the infection process. Furthermore, Pvp62 silencing was found to affect the lysosome function of P. vannamei. Immunofluorescence analysis showed that silences of Pvp62 inhibited co-localization of LC3 and lamp1 after infection, while overexpression of Pvp62 promoted this process, suggesting that Pvp62 was a necessary condition for autophagosome-lysosome fusion after infection by V. alginolyticus. Importantly, the overexpression of Pvp62 counteracted the inhibitory effect of the autophagy inhibitor chloroquine on autophagosome-lysosome fusion in primary hemocytes of shrimp after infection, underscoring the protective role of Pvp62-mediated autophagosome-lysosome fusion pathway during V. alginolyticus infection.

Intrinsically theranostic metal nanoclusters are rare unless the stabilizing ligands exhibit therapeutic properties. A promising class of quasi-molecular, near-infrared (NIR) emitting, cytotoxic gold nanoclusters, coined as AXE (Au eXcitable and Eliminable) stabilized through terminal thioester groups on fluorinated, and crosslinked polymers, is presented for simultaneous bioimaging & therapy. Nano Variable Temperature-Electrospray ionization mass spectrometry analysis of these aqueous stable nanoclusters revealed 5 to 7 core gold atoms, with SAXS measurement confirming average size to be under 1 nm, consistent with the theoretical maximum for few atom planar gold clusters. Despite its small size, AXE exhibits a remarkable Stoke shift of ≈470 nm and emission range spanning 700 to 1100 nm. Fluorination notably enhanced the quantum yield by up to twofold, attributed to charge transfer from the fluorinated monomer to the gold core, as indicated by Löwdin charge distribution analysis. The AXE nanocluster demonstrated dose-dependent pro-apoptotic effects on cancer cells while sparing normal cells at lower concentrations. Preclinical evaluation in a breast tumor model confirmed its anticancer efficacy, with intravenous and intraperitoneal administrations significantly inhibiting tumor growth and controlling lung metastasis, surpassing the clinical standard, doxorubicin.

Germacranes are a type of sesquiterpene lactones with anti-inflammatory and cytotoxic properties against cancer cell lines. In this in vitro study, erioflorin and erioflorin acetate were isolated and purified from the leaves of Podanthus mitiqui Lindl (Mitique or Mitriu), a shrub endemic to Chile and traditionally used in Mapuche medicine to treat urinary and digestive disorders. Their effects on advanced prostate cancer cell lines (DU-145 and 22Rv1) were evaluated. Cytotoxicity was assessed using real-time cell death and clonogenic assays. Apoptosis was determined by measuring reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptotic cell percentage through flow cytometry. Gene expression of BAX and BCL-2 was analyzed via RT-qPCR, while NF-κB activation was studied in DU-145 cells and human monocytic NF-κB reporter assays using LPS stimulation and alkaline phosphatase activity quantification. Erioflorin acetate exhibited the highest cytotoxicity, with IC50 values of 35.1 µM (22Rv1) and 27.3 µM (DU-145), compared to erioflorin, which had IC50 values of 50.3 µM and 56.5 µM, respectively. Both compounds increased ROS levels, reduced ΔΨm, and induced apoptosis. RT-qPCR analysis revealed that erioflorin elevated the BAX/BCL-2 ratio, and both compounds inhibited NF-κB activation by preventing IκBα phosphorylation. In conclusion, the findings demonstrate that erioflorin and erioflorin acetate exert significant in vitro cytotoxic and cytostatic effects on prostate cancer cells, supporting their potential as natural candidates for prostate cancer therapy.

Capsaicin (CAP), the active component of chili peppers, exerts a range of health benefits, including anti-inflammatory, antitumor, obesity-prevention, metabolic control, and biological rhythm-modulating effects, primarily through the activation of the transient receptor potential vanilloid 1 (TRPV1) receptor. The research explores the role of TRPV1 and its interaction with hepatic circadian clock regulation in modulating lipid metabolism and liver health. The effect of CAP on lipid metabolism and the potential mechanism was examined in HepG2 cells and high-fat, high-sugar diet (HFFD)-induced obese mice. In vitro, CAP (50 μM) decreased lipid droplet overaccumulation (from 152.8 ± 2.30 to 110.13 ± 3.91%), enhanced mitochondrial function (from 57.94 ± 1.93 to 86.74 ± 1.83%), and alleviated circadian desynchrony through a Trpv1-dependent mechanism in HepG2 cells. In vivo, CAP (5 mg/kg) reduced the body weight gain (from 50.61 ± 3.77 to 38.36 ± 2.04%), restored the hepatic circadian rhythm, and modulated the expression of lipid-related genes through the involvement of TRPV1 in mice. This study highlighted the potential of CAP to attenuate Reverbα-mediated lipid metabolic dysfunction through a Trpv1-dependent mechanism, revealing a complex interplay between circadian regulation and lipid metabolism.

Chemobrain can be defined as the development of cognitive side effects following chemotherapy, which is increasingly reported in cancer survivor patients. Chemobrain leads to reduced patients' quality of life by causing different symptoms ranging from strokes and seizures to memory loss and mood disorders. Metformin, an antidiabetic drug, has been proposed as a potential treatment to improve the symptoms of chemotherapy-induced cognitive dysfunction. Several benefits of metformin on chemobrain have been suggested, including anti-inflammation, anti-oxidative stress, restoring impaired mitochondrial function, stabilizing apoptosis, ameliorating impairments to dendritic spine density, normalizing brain senescence protein levels, and attenuating reductions in cell viability, along with reversing learning and memory deficits. These benefits occur through various pathways of metformin, including adenosine monophosphate-activated protein kinase (AMPK), TAp73, and phosphatidylinositol 3-kinase/protein kinase B (Akt) pathways. In addition, metformin can exert neuroprotective effects and restore deficits in brain homeostasis caused by chemotherapy. Furthermore, activation of AMPK following metformin therapy promotes autophagy, stimulates energy production, and improves cell survival. Metformin's interaction with Tap73 and Akt pathways allows for regulated cell proliferation in adult neural precursor cells and cell growth, respectively. Although the negative effects on cerebral function induced by chemotherapeutics have been alleviated by metformin in several instances, further studies are required to confirm its beneficial effects. This research is essential as it addresses the pressing issue of chemobrain, which is on the rise alongside global increases in cancer. Exploring metformin's potential as a neuroprotective agent offers a promising avenue for mitigating these cognitive impairments and highlights the need for further studies to validate its therapeutic mechanisms. This review comprehensively summarises evidence from both in vitro and in vivo studies to demonstrate metformin's effects on cognitive function when co-administered with chemotherapy and identifies gaps in knowledge for further investigation.

The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.

Recently, the curcumin derivative CU17 possessing HDAC inhibitory activity has been shown to synergistically enhance the anti-proliferative activity of Gem against lung cancer cells. Nevertheless, the mechanism(s) underlying the synergistic anti-cancer effect remains to be investigated. This study aimed to investigate the mechanisms that underpin the anti-cancer activity of the combined Gem and CU17 against NSCLC A549 cells both in vitro and in mouse xenograft models. CU17 was successfully synthesized and subsequently investigated for its combination effects with Gem on inductions of cell cycle arrest and apoptosis in A549 cells. The combination treatment substantially decreased cell survival through S phase prolongation and G2/M phase cell cycle arrest via up-regulating the expressions of p21 and p53 proteins. Additionally, CU17 potentiated the apoptotic effect of Gem in A549 cells by increasing the Bax/Bcl-2 ratio. The co-treatment resulted in an up-regulation of pERK1/2 and Ac-H3 expression. An in vivo study demonstrated that CU17 significantly improved the anti-cancer effect of Gem in nude mice utilizing A549 cell xenografts. The hematoxylin and eosin (H&E) staining results indicated that CU17 decreased the toxicity of Gem to the liver, kidneys, and spleen. Overall, CU17 enhanced the effectiveness of Gem while decreasing its toxicity. This compound shows promise as a chemosensitizer for NSCLC treatment with Gem.

This study pursued to evaluate the tropisetron effects in attenuating D-galactose induced heart aging in mice. The study aimed to ascertain whether tropisetron affects apoptotic processes, mitochondrial oxidative stress, or inflammatory variables in cardiac tissue, presumably through the modulation of the SIRT1 signaling pathway or sirtuin 1. Aging was induced via administration of D-galactose (200 mg/kg, s.c.). Then, mice were treated with tropisetron (1, 3, and 5 mg/kg/day, i.p.). After 8 weeks, the key indicators of oxidative mitochondrial dysfunction, oxidative stress, pro-inflammatory cytokines, interleukin-6, tumor necrosis factor-α, and nitric oxide concentrations were evaluated. Additionally, the gene expressions of apoptotic regulators Bax and Bcl2, as well as SIRT1, were assessed using real-time PCR. Histological alterations and serum lactate dehydrogenase levels were also assessed. Tropisetron alleviated mitochondrial oxidative stress and inflammatory mediators while decreasing immune cell infiltration into cardiac tissue generated by D-galactose. The simultaneous injection of tropisetron effectively inhibited D-galactose-induced apoptosis by modulating the Bax/Bcl2 ratio and activating the SIRT1 pathway. The administration of tropisetron resulted in reduced serum lactate dehydrogenase levels compared to the group treated just with D-galactose. Moreover, tropisetron successfully reinstated mitochondrial activity and diminished D-galactose-induced aberrant nitric oxide generation. The research concludes that tropisetron may provide protection against cardiac aging by activating multiple mechanisms associated with the SIRT1 pathway.

Aminocyanines incorporating Cy7 and Cy7.5 moieties function as molecular jackhammers (MJH) through vibronic-driven action (VDA). This mechanism, which couples molecular vibrational and electronic modes, results in picosecond-scale concerted stretching of the entire molecule. When cell-associated and activated by near-infrared light, MJH mechanically disrupts cell membranes, causing rapid necrotic cell death. Unlike photodynamic and photothermal therapies, the ultrafast vibrational action of MJH is unhindered by high concentrations of reactive oxygen species scavengers and induces only a minimal temperature increase. Here, the efficient synthesis of a library of MJH is described using a practical approach to access a key intermediate and facilitating the preparation of various Cy7 and Cy7.5 MJH with diverse side chains in moderate to high yields. Photophysical characterization reveals that structural modifications significantly affect molar extinction coefficients and quantum yields while maintaining desirable absorption and emission wavelengths. The most promising compounds, featuring dimethylaminoethyl and dimethylcarbamoyl substitutions, demonstrate up to sevenfold improvement in phototherapeutic index compared to Cy7.5 amine across multiple cancer cell lines. This synthetic strategy provides a valuable platform for developing potent, light-activated therapeutic agents for cancer treatment, with potentially broad applicability across various cancer types.

Cellular death evasion is a defining characteristic of human malignancies and a significant contributor to therapeutic inefficacy. As a result of oncogenic inhibition of cell death mechanisms, established therapeutic regimens seems to be ineffective. Mitochondria serve as the cellular powerhouses, but they also function as repositories of self-destructive weaponry. Changes in the structure and activities of mitochondria have been consistently documented in cancer cells. In recent years, there has been an increasing focus on using mitochondria as a targeted approach for treating cancer. Considerable attention has been devoted to the development of delivery systems that selectively aim to deliver small molecules called "mitocans" to mitochondria, with the ultimate goal of modulating the physiology of cancer cells. This review summarizes the rationale and mechanism of mitochondrial targeting with small molecules in the treatment of cancer, and their impact on the mitochondria. This paper provides a concise overview of the reasoning and mechanism behind directing treatment towards mitochondria in cancer therapy, with a particular focus on targeting using small molecules. This review also examines diverse small molecule types within each category as potential therapeutic agents for cancer.

Oxidative stress and neuroapoptosis are significant pathological processes that occur in response to intracerebral hemorrhage (ICH), however, the optimal therapeutic strategy to treat these responses remains unknown. Pterostilbene (PTE) influences neural cell survival in in the pathology of a number of neurological diseases, but the mechanisms underlying this influence at present are not clear. The objective of the present study was to examine the potential impact of PTE on mitigating oxidative stress and neuronal apoptosis following ICH, while also elucidating the potential underlying pathways.

For in vivo experimentation, male C57BL/6 mice were used to establish ICH models. Wet-to-dry weight ratios were utilized to assess the degree of cerebral edema in the context of PTE intervention. Behavioral experiments were conducted to evaluate neurological dysfunction and cognitive impairment, and hematoxylin and eosin staining was employed to observe histopathological changes in the brain. Furthermore, oxidative stress levels in hippocampal tissues were measured, and cell apoptosis was examined using TUNEL staining and western blotting techniques. In vitro experiments were conducted to evaluate the extent of oxidative stress and neural apoptosis after sirtuin 1 (SIRT1) siRNA treatment. Immunofluorescence cytochemistry was used to analyze the immunofluorescence colocalization of SIRT1 and NeuN.

Mice that experienced ICH exhibited worsening neurological deterioration, increased oxidative stress and neuronal cell apoptosis. However, the addition of PTE was found to lessen these effects. Furthermore, PTE was found to activate the SIRT1-mediated Nrf2 pathway in mice with ICH. When SIRT1 was inhibited, levels of oxidative stress and neuronal apoptosis increased, even in the presence of PTE.

The present study provided evidence to indicate that PTE can suppress oxidative damage and neuronal apoptosis following ICH by activating the SIRT1/Nrf2 pathway.

Satureja nabateorum, known as Nabatean savory is a Lamiaceae plant native to the Arabian Peninsula, specifically in the mountainous regions of Saudi Arabia. The study aims to investigate the phytochemical components of the S. nabateorum leaves (SNL) and stems (SNS) extract and to assess their antioxidant, antimicrobial, and antiproliferative properties. Methanol extracts from leaves and stems were analyzed for chemical constituents using the GC-MS technique. Antioxidant capacities were measured using hydrogen peroxide and ABTS radical-scavenging methods, and antimicrobial activity was tested against various microorganisms. Cytotoxic activity on four human malignant cell lines was assessed using MTT and flow cytometry. Molecular docking and molecular dynamics studies were conducted to understand the interactions and binding modes of the extracted compounds at a molecular level. GC-MS analysis of SNL extract revealed thymol, carvacrol, and p-cymen-8-ol as major constituents. SNS extract contained β-sitosterol, stigmasterol, lupeol, and lup-20(29)-ene-3β,28-diol. SNS extract exhibited more potent antioxidant, antimicrobial, and anticancer effects than SNL extract. The extract, SNS, exhibited potential toxicity in A549 cells with an IC50 value of 3.62 µg/mL and induced marked apoptotic effects with S phase-cell cycle arrest. SNS extract also showed higher levels of Caspase 3, Bax, p53, and the Bax/Bcl2 ratio and lower levels of Bcl-2. Molecular docking and dynamic simulation supported these findings, targeting the EGFR TK domain. The study suggests that the S. nabateorum stem extract holds promise as a potent antimicrobial, antioxidant, and anticancer agent. It provides valuable insights for considering the extract as a substitute for chemotherapy and/or protective agents.

Dual targeting of EGFR and HER2 is a valid anti-cancer approach for treating solid tumors. We designed and synthesized a new series of EGFR/HER-2 dual-target inhibitors based on quinoline derivatives. The structure of the newly synthesized compounds was verified using 1H NMR, 13C NMR, and elemental analysis. The targeted compounds were tested for antiproliferative efficacy against four cancer cell lines. All the compounds had GI50s ranging from 25 to 82 nM, with breast (MCF-7) and lung (A-549) cancer cell lines being the most sensitive. Compound 5a demonstrated the most significant antiproliferative action. With inhibitory (IC50) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the anti-apoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends.

Male infertility affects nearly 50% of infertile couples, with various underlying causes, including endocrine disorders, testicular defects, and environmental factors. Spermatozoa rely on mitochondrial oxidative metabolism for motility and fertilization, with mitochondria playing a crucial role in sperm energy production, calcium regulation, and redox balance. Voltage-dependent anion channels (VDACs), located on the outer mitochondrial membrane, regulate energy and metabolite exchange, which are essential for sperm function. This review offers an updated analysis of VDACs in the male reproductive system, summarizing recent advances in understanding their expression patterns, molecular functions, and regulatory mechanisms. Although VDACs have been widely studied in other tissues, their specific roles in male reproductive physiology still remain underexplored. Special attention is given to the involvement of VDAC2/3 isoforms, which may influence mitochondrial function in sperm cells and could be implicated in male fertility disorders. This update provides a comprehensive framework for future research in reproductive biology, underscoring the significance of VDACs as a molecular link between mitochondrial function and male fertility.

Sonic hedgehog (SHH) medulloblastoma etiology is associated with the SHH molecular pathway activation at different levels. We investigated the effect of arsenic trioxide as a downstream-level inhibitor of the SHH signaling pathway on morphology, cytotoxicity, migration, and SHH-related and apoptotic gene expression of DAOY cells. Cells were treated at various arsenic trioxide (ATO)concentrations (1, 2, 3, 5, and 10 μM) for different times (24 and 48 hr). Following treatments, the morphology of the cells was investigated at ×20 and ×40 magnification by an inverted microscope. Then, cytotoxicity was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue assays. Cell migration was analyzed through the wound-healing assay. Furthermore, the expression of SHH-related (GLI1, GLI2, SMO, and MYCN) and apoptotic genes (BAX, BCL2, and TP53) was assessed by real-time quantitative polymerase chain reaction (qPCR). Finally, GLI1, SMO, and MYCN markers were analyzed through immunocytochemistry. Data were analyzed by SPSS (version 16) and P≤0.05 was considered significant. Morphological changes were seen at 3 and 2 μM in 24 and 48 hr of treatment, respectively. The MTT assay showed a dose-dependent cytotoxicity indicating an IC50 value of 3.39±0.35 and 2.05±0.64 μM in 24 and 48hr treatment, respectively. In addition, the trypan blue assay showed higher IC50 values of 4.29±0.25 and 3.92±0.22 μM in 24 and 48 hr treatment, respectively. The wound-healing assay indicated a dose-dependent reduction of cell migration speed showing a 50% reduction at 2.89±0.26 μM. Significant downregulation of GLI1 and GLI2, as well as the upregulation of BAX, BAX/BCL2 ratio, and TP53 were evident. Significant increases in GLI1 and MYCN markers were also evident in immunocytochemistry. ATO, as a downstream effective inhibitor of the SHH pathway, substantially leads to cell death, cell migration inhibition, apoptosis upregulation, and downregulation of SHH target genes in DAOY medulloblastoma. Since ATO is a toxic chemotherapeutic agent, it must be used at low concentrations (2 μM) in order not to damage healthy cells.

Fetal hypoxia has long-term effects on postnatal reproductive functions and the mitochondrial impairments of ovarian granulosa cells may be one of the causes. Melatonin applied to mitigate mitochondrial dysfunction and autophagy in mammalian cells has been reported. However, the potential mechanisms by which fetal hypoxia damages reproductive function in neonatal female mice and the melatonin effects on this problem remain unclear.

This research aimed to explore the mechanism that fetal hypoxia damages reproductive function in neonatal female mice and attempt to improve the reproductive function by treating with melatonin in vivo and in vitro.

We established a fetal hypoxia model and confirmed that fetal hypoxia affects ovarian function by inducing GC excessive autophagy. Transcriptomic analysis, gene interference, cell immunofluorescence, immunohistochemistry and western blot were conducted to explore and verify the underlying mechanisms in mice GCs and KGN cells. Finally, melatonin treatment was executed on hypoxia-treated mice GCs and KGN cells and melatonin injection to fetal-hypoxia-treated mice to determine its effect.

The results of in vitro experiments found that fetal hypoxia led to mitochondrial dysfunction in ovarian GCs causing autophagic cell death. And the PI3K/Akt/FoxO pathway mediated the occurrence of this process by transcriptome analysis of ovarian GCs from normal and fetal hypoxia mice, which was further verified in mice GCs and KGN cells. Additionally, melatonin administration prevented autophagic injuries and mitochondrial impairments in hypoxia-treated mice GCs and KGN cells. Meanwhile, in vivo experiments by melatonin injection ameliorated oxidative stress of ovary in fetal-hypoxia-treated mice and improved their low fertility.

Our data found that fetal hypoxia causes ovarian GCs excessive autophagy leading to low fertility in neonatal female mice and mitigated by melatonin. These results provide a potential therapy for hypoxic stress-related reproductive disorders.

Mitochondria are metabolic hub, and act as primary sites for reactive oxygen species (ROS) and metabolites generation. Mitochondrial Ca2+ uptake contributes to Ca2+ storage. Mitochondria-organelle interactions are important for cellular metabolic adaptation, biosynthesis, redox balance, cell fate. Organelle communications are mediated by Ca2+/ROS signals, vesicle transport and membrane contact sites. The permeability transition pore (PTP) is an unselective channel that provides a release pathway for Ca2+/ROS, mtDNA and metabolites. F-ATP synthase inhibitory factor 1 (IF1) participates in regulation of PTP opening and is required for the translocation of transcriptional factors c-Myc/PGC1α to mitochondria to stimulate metabolic switch. IF1, a mitochondrial specific protein, has been suggested to regulate other organelles including nucleus, endoplasmic reticulum and lysosomes. IF1 may be able to mediate mitochondria-organelle interactions and cellular physiology through regulation of PTP activity.

The present study details the design, synthesis, and bio-evaluation of indoles 3-16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3-16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids' 12- and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8-16, highlighting their potential as therapeutic agents with reduced toxicity.

Adenosine nucleotide translocases (ANTs) are a family of proteins abundant in the inner mitochondrial membrane, primarily responsible for shuttling ADP and ATP across the mitochondrial membrane. Additionally, ANTs are key players in balancing mitochondrial energy metabolism and regulating cell death. ANT2 isoform, highly expressed in undifferentiated and proliferating cells, is implicated in the development and drug resistance of various tumors. We conduct a detailed analysis of the potential mechanisms by which ANT2 may influence tumorigenesis and drug resistance. Notably, the significance of ANT2 extends beyond oncology, with roles in non-tumor cell processes including blood cell development, gastrointestinal motility, airway hydration, nonalcoholic fatty liver disease, obesity, chronic kidney disease, and myocardial development, making it a promising therapeutic target for multiple pathologies. To better understand the molecular mechanisms of ANT2, this review summarizes the structural properties, expression patterns, and basic functions of the ANT2 protein. In particular, we review and analyze the controversy surrounding ANT2, focusing on its role in transporting ADP/ATP across the inner mitochondrial membrane, its involvement in the composition of the mitochondrial permeability transition pore, and its participation in apoptosis.

Altersolanol A, a fungus-derived tetrahydroanthraquinone, has shown cytotoxic effects on multiple cancer cells. However, its reproductive toxicity in humans has not been well-addressed. The present study was aimed at investigating the cytotoxicity of altersolanol A on human placental trophoblasts including choriocarcinoma cell line JEG-3 and normal trophoblast cell line HTR-8/SVneo in vitro. The results showed that altersolanol A inhibited proliferation and colony formation of human trophoblasts, and the choriocarcinoma cells were more sensitive to the compound than the normal trophoblasts. Altersolanol A induced cell cycle arrest at G2/M phase in JEG-3 cells and S phase in HTR-8/SVneo cells, downregulated the expression of cell cycle-related checkpoint proteins, and upregulated the p21 level. Altersolanol A also promoted apoptosis in human trophoblasts via elevating the Bax/Bcl-2 ratio and decreasing both caspase-3 and caspase-9 levels. Meanwhile, altersolanol A suppressed the mitochondrial membrane potential and induced ROS production and cytochrome c release, which activated the mitochondria-mediated intrinsic apoptosis. Moreover, migration and invasion were inhibited upon altersolanol A exposure with downregulation of matrix metalloproteinase (MMP)-2 in JEG-3 cells and MMP-9 in HTR-8/SVneo cells. Mechanically, altersolanol A supplement decreased the phosphorylation of JNK, ERK, and p38, manifesting the inactivation of MAPK signaling pathway in the human trophoblasts. In conclusion, altersolanol A exhibited potential reproductive cytotoxicity against human trophoblasts via promoting mitochondrial-mediated apoptosis and inhibiting the MAPK signaling pathway.

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.

Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy. Especially, DOX-induced cardiotoxicity remains a big challenge. In contrast, the natural chalcone cardamonin (CD) has been shown to selectively kill tumor cells. Besides its anti-tumor activity, CD exhibits anti-oxidative, anti-inflammatory and anti-bacterial properties. In this study, we investigated the effect of the combinational treatment of DOX with CD on A375 melanoma cells compared to normal human dermal fibroblasts (NHDF) and rat cardiac myoblasts (H9C2 cells). DOX-induced cytotoxicity was unselective and affected all cell types, especially H9C2 cardiac myoblasts, demonstrating its cardiotoxic effect. In contrast, CD only decreased the cell viability of A375 melanoma cells, without harming normal (healthy) cells. The addition of CD selectively protected human dermal fibroblasts and rat cardiac myoblasts from DOX-induced cytotoxicity. While no apoptosis was induced by the combinational treatment in normal (healthy) cells, an apoptosis-mediated cytotoxicity was demonstrated in A375 melanoma cells. CD exhibited thiol reactivity as it was able to directly interact with N-acetylcysteine (NAC) in a cell-free assay and to induce heme oxygenase-1 (HO-1) in all cell types. And that took place in a reactive oxygen species (ROS)-independent manner. DOX decreased the mitochondrial membrane potential (Δψm) in all cell types, whereas CD selectively decreased mitochondrial respiration, affecting basal respiration, maximal respiration, spare respiratory capacity and ATP production in A375 melanoma cells, but not in healthy cardiac myoblasts. The DOX-induced cytotoxicity seen in melanoma cells was ROS-independent, whereas the cytotoxic effect of CD was associated with CD-induced ROS-formation and/or its thiol reactivity. This study highlights the beneficial properties of the addition of CD to DOX treatment, which might protect patients from DOX-induced cardiotoxicity. Future experiments with other tumor cell lines or a mouse model should substantiate this hypothesis.

Water hyacinth (Pontederia crassipes Mart.) is a monocotyledonous aquatic plant renowned for its rapid growth, extensive proliferation, biological invasiveness, and ecological resilience to variations in pH, nutrients, and temperature. The International Union for Conservation of Nature (IUCN) has listed P. crassipes among the top 100 invasive species. However, comprehensive genomic information, particularly concerning its mitochondrial genome (mitogenome), remains surprisingly limited. In this study, the complete mitogenome of P. crassipes was analyzed using bioinformatics approaches. The mitogenome is 399,263 bp long and contains 38 protein-coding genes (PCGs), 24 tRNA genes, and 3 rRNA genes. Sequence analysis revealed that the complete mitogenome of the species contains 3,289 dispersed repeats, and 765 RNA editing sites in protein-coding genes. The P. crassipes mitogenome possessed un-conserved structures, including extensive sequence transfer between its chloroplasts and mitochondria. Our study on the mitogenome of P. crassipes offers critical insights into its evolutionary patterns and phylogenetic relationships with related taxa. This research enhances our understanding of this invasive species, known for its significant biomass and rapid overgrowth in aquatic environments.

Oxidative stress (OS) and disrupted antioxidant defense mechanisms play a pivotal role in the etiology of male infertility. The alterations in reactive oxygen species (ROS) production and calcium (Ca2+) homeostasis are the main activators for the mitochondrial permeability transition pore (mPTP) opening. The mPTP opening is one of the main mechanisms involved in mitochondrial dysfunction in spermatozoa. This alteration in mitochondrial function adversely affects energy supply, sperm motility, and fertilizing capacity and contributes to the development of male infertility. In human spermatozoa, the mPTP opening has been associated with ionomycin-induced endogenous oxidative stress and peroxynitrite-induced nitrosative stress; however, the effect of exogenous oxidative stress on mPTP opening in sperm has not been evaluated. The aim of this study was to determine the effect of exogenous oxidative stress induced by hydrogen peroxide (H2O2) on mPTP opening, mitochondrial function, motility, and cell death markers in human spermatozoa. Human spermatozoa were incubated with 3 mmol/L of H2O2 for 60 min, and intracellular Ca2+ concentration, mPTP opening, mitochondrial membrane potential (ΔΨm), ATP levels, mitochondrial reactive oxygen species (mROS) production, phosphatidylserine (PS) externalization, DNA fragmentation, viability, and sperm motility were evaluated. H2O2-induced exogenous oxidative stress caused increased intracellular Ca2+, leading to subsequent mPTP opening and alteration of mitochondrial function, characterized by ΔΨm dissipation, decreased ATP levels, increased mROS production, and the subsequent alteration of sperm motility. Furthermore, H2O2-induced opening of mPTP was associated with the expression of apoptotic cell death markers including PS externalization and DNA fragmentation. These results highlight the role of exogenous oxidative stress in causing mitochondrial dysfunction, deterioration of sperm motility, and an increase in apoptotic cell death markers, including PS externalization and DNA fragmentation, through the mPTP opening. This study yielded new knowledge regarding the effects of this type of stress on mitochondrial function and specifically on mPTP opening, factors that can contribute to the development of male infertility, considering that the role of mPTP in mitochondrial dysfunction in human sperm is not completely elucidated. Therefore, these findings are relevant to understanding male infertility and may provide an in vitro model for further research aimed at improving human sperm quality.

At present, liquid storage is the most efficient method for pig semen preservation. This approach relies upon reducing sperm metabolism, allowing for the maintenance of cell lifespan. In this context, the study of proteins that could protect sperm during liquid storage is of high relevance. The 70 kDa Heat Shock Protein (HSP70) is an anti-apoptotic protein that has been reported to be relevant to sperm survival. Thus, we explored the role of HSP70 during prolonged storage of pig semen at 17 °C. Six semen pools were incubated with YM-1 (0, 0.05, 0.1 and 0.2 μM), an HSP70 inhibitor, and stored at 17 °C for 21 days. On days 0, 4, 10, 14 and 21, sperm quality and function were evaluated through flow cytometry and Computer-Assisted Sperm Analysis (CASA), and HSP70 activity and chromatin condensation were also determined. While inhibition of HSP70 increased progressive motility, Ca2+ and Reactive Oxygen Species (ROS) levels, and mitochondrial activity during the first 10 days of storage, it had a detrimental effect on sperm motility after 14 and 21 days. In spite of this, sperm viability was not altered. We can conclude that HSP70 contributes to the liquid storage of pig semen because it keeps mitochondrial activity low, which is needed for the maintenance of sperm function.

Ferroptosis is an emerging non-apoptotic death process, mainly involving lipid peroxidation (LPO) caused by iron accumulation, which is potentially lethal to the intrinsically apoptotic-resistant malignant tumor. However, it is still restricted by the inherent antioxidant systems of tumor cells and the poor efficacy of traditional iron-based ferroptosis initiators. Herein, the study develops a novel ferroptosis-inducing agent based on PEGylated Cu+/Cu2+-doped black phosphorus@polypyrrole heterojunction (BP@CPP), which is constructed by utilizing the phosphate on the surface of BP to chelate Cu ions and initiating subsequent in situ polymerization of pyrrole. As a novel Z-scheme heterojunction, BP@CPP possesses an excellent photocatalytic activity in which the separated electron-hole pairs under laser irradiation endow it with powerful oxidizing and reducing capacities, which synergy with Cu+/Cu2+ self-cycling catalyzing Fenton-like reaction to further strengthen reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, ultimately leading to efficient ferroptosis. Systematic in vitro and in vivo evaluations demonstrate that BP@CPP effectively inhibit tumor growth by inducing desired ferroptosis while maintaining a favorable biosafety in the body. Therefore, the developed BP@CPP-based ferroptosis initiator provides a promising strategy for ferroptosis-like cancer therapy.

Lung cancer, a chronic and heterogeneous disease, is the leading cause of cancer-related death on a global scale. Presently, despite a variety of available treatments, their effectiveness is limited, often resulting in considerable toxicity and adverse effects. Additionally, the development of chemoresistance in cancer cells poses a challenge. Trilobolide-6-O-isobutyrate (TBB), a natural sesquiterpene lactone extracted from Sphagneticola trilobata, has exhibited antitumor effects. Its pharmacological properties in NSCLC lung cancer, however, have not been explored.

This study evaluated the impact of TBB on the A549 and NCI-H460 tumor cell lines in vitro, examining its antiproliferative properties and initial mechanisms of cell death.

TBB, obtained at 98 % purity from S. trilobata leaves, was characterized using chromatographic techniques. Subsequently, its impact on inhibiting tumor cell proliferation in vitro, TBB-induced cytotoxicity in LLC-MK2, THP-1, AMJ2-C11 cells, as well as its effects on sheep erythrocytes, and the underlying mechanisms of cell death, were assessed.

In silico predictions have shown promising drug-likeness potential for TBB, indicating high oral bioavailability and intestinal absorption. Treatment of A549 and NCI-H460 human tumor cells with TBB demonstrated a direct impact, inducing significant morphological and structural alterations. TBB also reduced migratory capacity without causing toxicity at lower concentrations to LLC-MK2, THP-1 and AMJ2-C11 cell lines. This antiproliferative effect correlated with elevated oxidative stress, characterized by increased levels of ROS, superoxide anion radicals and NO, accompanied by a decrease in antioxidant markers: SOD and GSH. TBB-stress-induced led to changes in cell metabolism, fostering the accumulation of lipid droplets and autophagic vacuoles. Stress also resulted in compromised mitochondrial integrity, a crucial aspect of cellular function. Additionally, TBB prompted apoptosis-like cell death through activation of caspase 3/7 stressors.

These findings underscore the potential of TBB as a promising candidate for future studies and suggest its viability as an additional component in the development of novel anticancer drugs prototypes.

Sleep is a highly intricate biological phenomenon, and its disorders play a pivotal role in numerous diseases. However, the specific regulatory mechanisms remain elusive. In recent years, the role of mitochondria in sleep disorders has gained considerable attention. Sleep deprivation not only impairs mitochondrial morphology but also decreases the number of mitochondria and triggers mitochondrial dysfunction. Furthermore, mitochondrial dysfunction has been implicated in the onset and progression of various sleep disorder-related neurological diseases, especially neurodegenerative conditions. Therefore, a greater understanding of the impact of sleep disorders on mitochondrial dysfunction may reveal new therapeutic targets for neurodegenerative diseases. In this review, we comprehensively summarize the recent key findings on the mechanisms underlying mitochondrial dysfunction caused by sleep disorders and their role in initiating or exacerbating common neurodegenerative diseases. In addition, we provide fresh insights into the diagnosis and treatment of sleep disorder-related diseases.

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.

Copper is a necessary micronutrient for maintaining the well-being of the human body. The biological activity of organic ligands, especially their anticancer activity, is often enhanced when they coordinate with copper(I) and (II) ions. Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and paraptosis. Some of the copper complexes are currently being evaluated in clinical trials for their ability to map tumor hypoxia in various cancers, including locally advanced rectal cancer and bulky tumors. Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy. Despite the promising anticancer activity of copper-based compounds, their use in clinical trials is subject to certain limitations. Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes.

Dasatinib-related resistance frequently occurs and may lead to the failure of chemotherapy; thus, dose interruptions are necessary. Cannabidiol (CBD) has potential for integration with orthodox cancer care. In this study, we explored the combination effect of CBD and dasatinib on A549 cells. CBD in combination with dasatinib could induce significant synergistic apoptosis in vitro (ZIP > 10) and in vivo. The combination of CBD and low-dose dasatinib exhibited antiproliferative and proapoptotic effects through up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2 in A549 cells. The xenograft mouse model suggested that the combination was more efficient and safer. In short, CBD and low-dose dasatinib exhibited a synergistic effect on anticancer by targeting the SRC/PI3K/AKT signaling pathway, suggesting a potential therapeutic option for the treatment of lung cancer.

The perfluoalkyl substance (PFASs) perfluorooctane sulfonate (PFOS) has been widely used in industry. However, PFOS is a persistent organic pollutant and has been gradually replaced by its short-chain analogs, perfluorohexane sulfonate (PFHxS) and perfluorobutane sulfonate (PFBS). PFASs are extremely persistent and are very frequently detected among the general population. The aim of the study was to determine the effect of selected PFASs on peripheral blood mononuclear cells (PBMCs) and the mechanisms of their action. PBMCs were exposed to PFOS, PFBS and PFHxS at concentrations ranging from 0.02 to 400 μM for 24 h, they were then tested for viability, apoptosis (changes in cytosolic calcium ions level and caspase-3, -8 and -9 activation), ferroptosis (changes in chelatable iron ions level and lipid peroxidation), and autophagy (LC3-II and Raptor level assay). PFOS exposure decreased cell viability, increased calcium ion level and caspase-8 activation; it also enhanced lipid peroxidation and increased the intracellular pool of chelatable iron ions as well as LC3-II protein content. In contrast, short-chain PFBS and PFHxS induced significant changes in the markers of apoptosis but had no substantial impact on ferroptosis or autophagy markers over a wide range of concentrations. Our results indicate that only PFOS demonstrated pro-ferroptotic and pro-autophagic potential but observed changes occurred at relatively high exposure. A short-chain substitute (PFBS) exhibited strong pro-apoptotic potential at concentrations related to occupational exposure. While the short-chain PFASs strongly affected the mitochondrial pathway of apoptosis, apoptosis itself was only induced by PFBS via the intrinsic and extrinsic pathways. It seems that the length of the carbon chain in PFASs appears to determine the cell death mechanisms activated in human PBMCs following exposure. Our findings provide a new insight into the immune toxicity mechanism induced by these compounds.

Atractylodes macrocephala Koidz (AMK) is a traditional herbal medicine used for thousands of years in East Asia to improve a variety of illnesses and conditions, including cancers. This study explored the effect of AMK extract on apoptosis and tumor-grafted mice using AGS human gastric adenocarcinoma cells. We investigated the compounds, target genes, and associated diseases of AMK using the Traditional Chinese Medical Systems Pharmacy (TCMSP) database platform. Cell viability assay, cell cycle and mitochondrial depolarization analysis, caspase activity assay, reactive oxygen species (ROS) assay, and wound healing and spheroid formation assay were used to investigate the anti-cancer effects of AMK extract on AGS cells. Also, in vivo studies were conducted using subcutaneous xenografts. AMK extract reduced the viability of AGS cells and increased the sub-G1 cell fraction and the mitochondrial membrane potential. Also, AMK extract increased the production of ROS. AMK extract induced the increased caspase activities and modulated the mitogen-activated protein kinases (MAPK). In addition, AMK extract effectively inhibited AGS cell migration and led to a notable reduction in the growth of AGS spheroids. Moreover, AMK extract hindered the growth of AGS xenograft tumors in NSG mice. Our results suggest that AMK has anti-cancer effects by promoting cell cycle arrest and inhibiting the proliferation of AGS cancer cells and a xenograft model through apoptosis. This study could provide a novel approach to treat gastric cancer.

Aglaia odorata, native to Guangdong, Guangxi, and Hainan provinces in China, has long been utilized as an herbal remedy in ancient China. In this study, we assembled and annotated the complete mitochondrial genome (mitogenome) of A. odorata, which spans a total length of 537,321 bp. Conformation of the A. odorata recombination was verified through PCR experiments and Sanger sequencing. We identified and annotated 35 protein-coding genes (PCGs), 22 tRNA genes, and 3 rRNA genes within the mitogenome. Analysis of repeated elements revealed the presence of 192 SSRs, 29 pairs of tandem repeats, and 333 pairs of dispersed repeats in the A. odorata mitogenome. Additionally, we analyzed codon usage and mitochondrial plastid DNAs (MTPTs). Twelve MTPTs between the plastome and mitogenome of A. odorata were identified, with a combined length of 2,501 bp, accounting for 0.47% of the mitogenome. Furthermore, 359 high-confidence C to U RNA editing sites were predicted on PCGs, and four selected RNA editing sites were specially examined to verify the creation of start and/or stop codons. Extensive genomic rearrangement was observed between A. odorata and related mitogenomes. Phylogenetic analysis based on mitochondrial PCGs were conducted to elucidate the evolutionary relationships between A. odorata and other angiosperms.

Mitostasis, the maintenance of healthy mitochondria, plays a critical role in brain health. The brain's high energy demands and reliance on mitochondria for energy production make mitostasis vital for neuronal function. Traumatic brain injury (TBI) disrupts mitochondrial homeostasis, leading to secondary cellular damage, neuronal degeneration, and cognitive deficits. Mild mitochondrial uncoupling, which dissociates ATP production from oxygen consumption, offers a promising avenue for TBI treatment. Accumulating evidence, from endogenous and exogenous mitochondrial uncoupling, suggests that mitostasis is closely regulating by mitochondrial uncoupling and cellular injury environments may be more sensitive to uncoupling. Mitochondrial uncoupling can mitigate calcium overload, reduce oxidative stress, and induce mitochondrial proteostasis and mitophagy, a process that eliminates damaged mitochondria. The interplay between mitochondrial uncoupling and mitostasis is ripe for further investigation in the context of TBI. These multi-faceted mechanisms of action for mitochondrial uncoupling hold promise for TBI therapy, with the potential to restore mitochondrial health, improve neurological outcomes, and prevent long-term TBI-related pathology.

Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure-activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors.

Cancer, ranks as the secondary cause of death, is a group of diseases that are characterized by uncontrolled tumor growth and distant metastasis, leading to increased mortality year-on-year. To date, targeted therapy to intercept the aberrant proliferation and invasion is crucial for clinical anticancer treatment, however, mutant expression of target genes often leads to drug resistance. Therefore, it is essential to identify more molecules that can be targeted to facilitate combined therapy. Previous studies showed that death associated protein 3 (DAP3) exerts a pivotal role in regulating apoptosis signaling of tumors, meanwhile, aberrant DAP3 expression is associated with the tumorigenesis and disease progression of various cancers. This review provides an overview of the molecule structure of DAP3 and the discrepant roles played by DAP3 in various types of tumors. Considering the molecular mechanism of DAP3-regulated cancer development, new potential treatment strategies might be developed in the future.