The intestine has molecular and functional diversity across the proximal-distal and the crypt-villus axes, so it is imperative to determine the common and compartment-specific molecular actions of vitamin D. However, very little work on vitamin D mediated gene regulation has been done in normal human intestine. Here, we examined the impact of 1,25-dihydroxyvitamin D (1,25(OH)2D3) on cultures of human intestinal epithelium derived from duodenum (Dd) and distal colon (Co) biopsies of 6 subjects per tissue.

This study investigates the molecular mechanisms underlying the inhibitory effects of 5-alkylresorcinol (5ARs) on colorectal cancer (CRC) growth.

Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients' survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression.

Echinacea purpurea (L.) Moench, commonly known as purple coneflower, is a significant medicinal plant renowned for its therapeutic properties, which are attributed to various phytochemical compounds, including caffeic acid derivatives (CADs). Chicoric acid is one of the CADs that has important immunostimulatory properties. This study employed a hairy roots (HRs) culture and an elicitation system to enhance the production of chicoric acid in E. purpurea. HRs cultures were established, and different concentrations (0, 1.25, 2.5, 5, and 10% v/v) of elicitors derived from Piriformospora indica culture filtrate (CF) and cell extract (CE) were added at two time points during the HRs growth period (on days 24 and 26). The effects of these treatments on the growth of HRs, chicoric acid production, and the expression of genes involved in the chicoric acid biosynthesis pathway were investigated. The highest dry weight of HRs (2.19 g/L, 1.36% higher than that in the control) was achieved in the HRs culture treated with 5% CF on the 24th day. In contrast, 5 and 10% (v/v) of P. indica CE, regardless of addition time, significantly decreased HRs growth compared to the control. The maximum production of chicoric acid (15.52 mg/g DW) was recorded after 48 h in the HRs culture treated with 5% CE on day 24, representing a 2.6-fold increase compared to the control (5.95 mg/g DW). Additionally, adding 2.5% CF to the HRs culture on day 26 resulted in a 2.3-fold increase compared to the control (13.5 mg/g DW) in chicoric acid biosynthesis. Real-time PCR assays revealed that the expression levels of the genes PAL, C4H, 4CL, C3H, and HCT were significantly upregulated after 3 and 12 h of elicitation with CE and CF. The highest gene expression was recorded for the C4H and PAL genes, 3 h after elicitation by CE (29.64 and 26.2-fold increases compared to the control culture). In contrast, the expressions of the 4CL and C3H genes peaked 12 h after elicitation with CF. The expression of the HCT gene also reached its highest level after 12 h of CE elicitation. Consistent with the chicoric acid production results, CE was found to be a more effective elicitor for inducing gene expression in the chicoric acid biosynthesis pathway. Overall, these findings indicate that HRs cultures and elicitors derived from P. indica are promising strategies to enhance chicoric acid production in E. purpurea (L.).

Temozolomide (TMZ) is an important chemotherapeutic agent for glioma treatment. However, the emergence of drug resistance impedes its application. Traditional population-level studies are limited in elucidating resistance mechanisms. Advances in single-cell and spatial transcriptomics technologies provide feasible resolution for studying the cellular composition and dynamics of tumors. In this study, we investigated the heterogeneity of gliomas associated with TMZ resistance at the single-cell and spatial transcriptome levels to identify the resistance mechanisms and potential therapeutic strategies.

Metformin has been demonstrated to extend lifespan in various model organisms, and its molecular effects are observed in the cytoplasm and multiple organelles, including mitochondria. However, its association with the unfolded protein response (UPR) and its impact on stress resistance and locomotion remain uncertain. In this study, metformin was found to exert differential influences on both UPRmt and UPRer. The correlation between metformin's lifespan-mediating effect and its interaction with UPRs was also inconsistent. We identified a metformin-mediated lifespan extension in wild-type C. elegans and in UPRmt-activated tomm-22 and cco-1 RNAi worms. Metformin suppressed the UPRmt without compromising the lifespan extension observed in tomm-22 worms. Conversely, metformin did not affect the UPRmt but extended the lifespan of long-lived cco-1 RNAi worms. Furthermore, we investigated the effects of metformin on UPRer-activated nematodes. We observed that metformin exhibited a slight increase in the UPRer in mdt-15 RNAi worms and failed to induce lifespan extension. Surprisingly, metformin appeared to mediate lifespan extension in tmem-131 RNAi worms while suppressing the UPRer. Notably, the correlation between thermotolerance, oxidative stress resistance, and the lifespan effects of metformin in UPR-activated worms was inconsistent. Activation of UPRs, but not metformin treatment, enhanced the locomotor phenotype of these worms.

Digestive system cancers, including esophageal, gastric, colorectal, pancreatic, hepatocellular, and biliary tract cancers, constitute a major global health challenge. Despite therapeutic advancements, prognosis remains poor, highlighting the urgent need for novel treatment strategies. We hypothesized that drug repositioning, facilitated by pan-cancer analyses, could lead to the identification of effective treatment strategies for these cancers.

Background: Dynamic SUMO modifications play crucial roles in orchestrating cellular response to various stimuli, including viral infection, and hold significant therapeutic potential. The Spike (S) protein, a surface glycoprotein of SARS-CoV-2 (a global health threat), serves as the key mediator for viral entry and is a critical target for drug development. However, the function of SUMOylation in the Spike protein remains largely unclear. Methods: The SUMO modification of Spike was assessed by immunoprecipitation (IP), denatured IP and immunoblotting assays in lung epithelial cells or SUMO deficient cell line models. The effect of Spike SUMOylation on viral infection was explored by site-direct mutation, cell-to-cell transmission, cell-free infection, quantitative PCR and immunofluorescence staining experiments. The role of Spike SUMOylation-derived peptides was investigated using viral intranasally infection, immunohistochemistry assay in transgenic mouse model. Results: SARS-CoV-2 infection triggers the relocation of SUMO1 to the cytoplasm and SUMO2 to the perinuclear region. Notably, SUMO1 knockout increases Spike trimer formation and its co-localization with SUMO2 at perinuclear puncta, which facilitates virion particle release. SUMO2 knockout leads to enhanced Spike cleavage and promotes viral cell-to-cell transmission. Further bioinformatic and immuno-precipitation analyses reveal that the Spike protein contains highly conserve SUMO-interacting motifs (SIMs) and selectively promotes either SUMO1 (via SIM1) or SUMO2 (via SIM3/4) modifications on lysine residues 129 and 1269, respectively. Importantly, these modifications can be efficiently disrupted by the SIM2 motif. A cell-penetrating peptide (cpSIM2), derived from the SIM2 motif, exhibits robust and broad-spectrum inhibitory activity against SARS-CoV-2 variants infection in vitro and in hACE2-transgenic mice model. Conclusions: This study uncovers critical features of SUMOylation in regulating Spike-mediated viral spread and pathogenesis, providing a potential broad-spectrum therapeutic target for drug development against emerging SARS-CoV-2 infection.

Heteroresistance is a well-known phenomenon contributing to treatment failure in bacterial infections. Previous research has traditionally linked it to genetic mechanisms, emphasizing fixed subpopulations with specific resistance mutations. Recent studies appreciated that bacterial subpopulations may not be fixed and independent, but rather dynamically changing. Heteroresistance mechanisms are likely more intricate than mere genetic predisposition alone.

Quiescent cancer cells (QCCs) are known to resist chemoradiotherapy, evade immune surveillance and have the potential to drive recurrence years after initial treatment. However, the key regulators of QCC survival during reactivation remain unclear. This study revealed that superoxide dismutase 2 (SOD2) levels are significantly greater in quiescent prostate cancer (PCa) cells than in proliferative cells. SOD2 overexpression induces apoptosis in awakening quiescent PCa cells, whereas its knockdown promotes reactivation. Elevated SOD2 also suppresses recurrent tumor growth by quiescent PCa cells and prolongs survival. Pterostilbene (PTE), a natural compound, preferentially induces apoptosis in quiescent PCa cells during awakening and reduces their long-term proliferative capacity by upregulating SOD2. Additionally, PTE inhibits tumorigenesis and significantly reduces the growth of quiescent PCa cells without apparent toxicity. Further mechanistic studies revealed that CCAAT/enhancer-binding protein beta (C/EBP-β) is critical for PTE-mediated SOD2 upregulation by enhancing SOD2 transcription. C/EBP-β knockdown significantly reduces PTE-induced apoptosis in awakening quiescent PCa cells. Clinical analysis revealed a positive correlation between CEBPB and SOD2, with low C/EBP-β expression linked to poor prognosis. Overall, the C/EBP-β-SOD2 pathway is crucial for eliminating awakening quiescent PCa cells and highlights PTE as a promising agent for preventing PCa recurrence.

Bone metastasis is a significant complication in advanced-stage cancers, especially breast and lung malignancies, profoundly influencing prognosis and quality of life. Osteolytic bone metastasis contains multiple interactions between cancer cells and the bone microenvironment, driving osteoclast-mediated bone resorption and deterioration while releasing growth factors that promote tumor progression. Current treatments, including surgery, radiation, and chemotherapy, often result in severe side effects, highlighting the need for effective, targeted therapies. Ugonin P, a natural compound derived from Helminthostachys zeylanica, known for its anti-inflammatory and anticancer properties. However, the effects of Ugonin P on osteolytic bone metastasis remain unclear. Our findings demonstrate that Ugonin P inhibits both RANKL-induced and lung and breast cancer-induced osteoclast formation. Bioinformatics analysis revealed that Midkine (MDK), a heparin-binding growth factor known to promote migration, is highly elevated in breast and lung cancer patients and is related with osteoclast formation. We further showed that MDK is involved in cancer-promoted osteoclastogenesis and that Ugonin P suppresses this process by upregulating miR-223-3p expression. Importantly, Ugonin P effectively blocks lung and breast cancer-facilitated osteolytic bone metastasis in vivo. These findings highlight Ugonin P as a promising therapeutic strategy for treating osteolytic bone metastasis.

Post-translational modifications (PTMs) are biochemical modifications that can significantly alter protein structure, function, stability, localization, and interactions with other molecules, thereby activating or inactivating intracellular processes. A growing body of research has begun to highlight the role of PTMs, including phosphorylation, ubiquitination, acetylation, and redox modifications, during virus-host interactions. Collectively, these PTMs regulate key steps in mounting the host immune response and control critical host pathways required for productive viral replication. This has led to the conception of antiviral therapeutics that focus on controlling host protein PTMs, potentially offering pathogen-agnostic treatment options and revolutionizing our capacity to prevent virus transmission. On the other hand, viruses can hijack the host cellular PTM machinery to modify viral proteins in promoting viral replication and evading immune surveillance. PTM regulation during virus-host interactions is complex and poorly mapped, and the development of effective PTM-targeted antiviral drugs will require a more comprehensive understanding of the cellular pathways essential for virus replication. In this review, we discuss the roles of PTMs in virus infection and how technological advances in mass spectrometry-based proteomics can capture systems-level PTM changes during viral infection. Additionally, we explore how such knowledge is leveraged to identify PTM-targeted candidates for developing antiviral drugs. Looking ahead, studies focusing on the discovery and functional elucidation of PTMs, either on the host or viral proteins, will not only deepen our understanding of molecular pathology but also pave the way for developing better drugs to fight emerging viruses.

Several mechanisms are involved in the resistance to endocrine therapy (ET) in estrogen receptor (ERα)-positive breast cancer (BC), including acquired mutations of ERα gene (ESR1). For example, the frequent mutation, Y537S, was shown to trigger a constitutively active receptor leading to reduced affinity for both agonist and antagonist ligands. The development of more comprehensive therapies remains a challenge in BC patients exhibiting activating mutations in ERα. Here, we show that Poly (ADP-ribose) polymerase-1 (PARP-1) may be considered as a novel therapeutic target in ERα-positive BC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with limited treatment options, and chemotherapy resistance contributes to poor prognosis. An increasing number of studies have shown that ubiquitin specific peptidases (USPs), a subtype of deubiquitinases, can affect tumor progression by regulating the stability or biological function of substrate proteins. Thus, USPs are becoming attractive targets for cancer treatment. In this study, we investigated the role of USPs in PDAC. This study illustrated significant upregulation of USP10 expression in PDAC, which was found to be correlated with unfavorable prognosis. Further evaluation showed that USP10 exhibited the ability to facilitate PDAC progression in vitro and in vivo. The assays of immunoprecipitation-mass spectrometry, CO-IP, and GST pull-down suggested that USP10 directly interacted with PLK1. Deubiquitination assays indicated that USP10 could reduce the ubiquitination of PLK1 and increase protein stability. Moreover, USP10 may promote autophagy in PDAC cells through PLK1 and further attenuate the response of PDAC cells to gemcitabine (GEM). Finally, we demonstrated that the inhibition of USP10 combined with GEM synergistically inhibited the progression of PDAC in vitro and in vivo. In summary, we revealed that USP10, as a tumor promoter, promoted the progression and attenuated GEM chemotherapy sensitivity via stabilizing PLK1 in PDAC, providing a potential target for the treatment of PDAC.

Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy that poses significant risks to both the pregnant woman and her fetus. Astragaloside IV (Ast IV) belongs to the class of triterpenoid saponins and exhibits important physiological roles in various aspects, including antidiabetic, antioxidant, and antiviral effects. The main objective of this study is to investigate the effects of Ast IV on trophoblast damage caused by high glucose (HG) and its underlying mechanism of action.

Atherosclerosis (AS) is characterized by a gradual plaque buildup within the arteries, resulting in hardened and narrowed arteries. Thus, it leads to blood flow limitation and increased risk of critical diseases. Hyperlipidemia is correlated with inflammation, as seen with increased expression of different inflammatory markers including tumor-necrosis factor-alpha (TNF-α), C-reactive protein (CRP), chemokines and interleukins. This current study explores the relationship between novel anti-hyperlipidemic compounds and the expression of specific inflammatory markers in acute hyperlipidemic rats induced by Triton WR-1339.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and resistance to conventional therapies, necessitating novel treatments. The high proliferative rate and protein synthesis in PDAC induce endoplasmic reticulum (ER) stress, with Glucose-Regulated Protein 78 (GRP78), a key regulator of ER stress and the Unfolded Protein Response (UPR), playing a pivotal role in PDAC progression. Despite its relevance, GRP78-targeted therapies remain unexplored in PDAC. BOLD-100, a novel GRP78 inhibitor, presents a potential therapeutic approach by disrupting GRP78 transcription, though its effects on PDAC have yet to be fully elucidated. Here, we found that BOLD-100 induces PDAC cell death through the UPR pathway activation, leading to CHOP-dependent apoptosis. BOLD-100 generates reactive oxygen species (ROS), inducing R-loop formation that triggers a DNA damage response via the ATR/Chk1 axis. BOLD-100 synergizes with AZD6738, an ATR inhibitor, to enhance anti-tumor efficacy compared to either agent alone in both in vitro and in vivo models. These findings suggest that BOLD-100, especially in combination with an ATR inhibitor, represents a promising therapeutic option for patients with PDAC.

Prostate cancer risk is influenced by various factors, including exposure to heavy metals like cadmium (Cd). The study reveals that the autophagy-regulating gene PLAC8 (placenta-specific 8) is significantly involved in Cd-induced prostate carcinogenesis, and NF-κB acts as the upstream transcriptional activator of PLAC8, which then selectively up-regulates BCL-xL, providing a survival advantage to Cd-transformed cells. NF-κB activation stabilizes PLAC8 in the cytosol, disrupting autophagy by allowing PLAC8 to colocalize with LC3B instead of LAMP1. Silencing NF-κB down-regulates PLAC8 and its survival function while inhibiting NF-κB or PLAC8, which restores autophagy and decreases tumor growth in xenograft models. In addition, targeting BCL-xL confirmed this signaling pathway. The findings suggest that sustained NF-κB activation regulates PLAC8 and highlights the NF-κB-PLAC8-BCL-xL axis as a potential target for early detection and therapies in metal-induced prostate cancer.

Cadmium (Cd²⁺) contamination severely threatens aquatic organisms, leading to oxidative stress, inflammation, and hepatotoxicity. Portulaca oleracea is known for its antioxidant and anti-inflammatory activities; yet, its defensive role against Cd²⁺-induced hepatotoxicity in Nile tilapia (Oreochromis niloticus) is still unclear. The current study evaluated the possible hepatoprotective effects of purslane leaf powder (PR) against Cd²⁺-induced liver damage and its mechanisms. A hepatotoxicity model was established by exposing tilapia to Cd²⁺ (50 µg/L) for 60 days, with and without PR supplementation (10 g PR/kg diet). Histopathological analysis, biochemical assays, and real-time quantitative PCR were done to assess liver tissue damage, oxidative stress markers, lipid profile, and inflammatory gene expression. Results showed that Cd²⁺ exposure induced severe hepatic alterations, including glycogen depletion, steatosis, necrosis, and inflammatory infiltration, along with increased liver indices and obvious dyslipidemia. PR supplementation significantly alleviated these changes by reducing oxidative stress, enhancing antioxidant enzyme activity, upregulating antioxidant genes (sod-1, sod-2, cat, gpx, and cyp1a), and downregulating inflammatory markers (mapk1, nf-κb, il1β, il6, il8, and tnf-α). Additionally, PR improved lipid profile and liver morphology, and reduced hepatocyte damage compared to the Cd²+-exposed group. In conclusion, PRP mitigates Cd²⁺-induced hepatotoxicity in Nile tilapia by enhancing antioxidant defenses and reducing inflammation, suggesting its potential as a dietary supplement to counteract heavy metal toxicity in aquaculture.

Cadmium (Cd) is a heavy metal widely distributed in the environment that poses a significant threat to living organisms because of its strong mobility and toxicity. In this study, a novel gene named Osß-glu from the glycosyltransferase (GT) family was investigated for its role in the Cd stress response in rice. Various experiments were conducted using the japonica cultivar Nipponbare (Nip) and its mutants (Osß-glu-1 and Osß-glu-2). The results showed that Osß-glu was specifically induced by Cd stress rather than by other mineral deficiencies. The Osß-glu mutants exhibited higher sensitivity to Cd stress, with more significant inhibition of root elongation, reduced biomass, and increased Cd accumulation in the roots, shoots, and xylem sap than Nip. Nitro-Blue Tetrazolium (NBT) staining indicated a larger acumulation of superoxide anion in the mutant roots under Cd stress, 3,3'-Diaminobenzidine (DAB) staining showed more pronounced H2O2 accumulation, and Evans Blue staining revealed more dead cells, demonstrating more severe reactive oxygen species (ROS) accumulation and cell damage in mutant roots. Moreover, the mutants had higher hemicellulose content and elevated Cd-binding capacity in the root cell wall, as well as abnormal expression of genes related to Cd absorption and translocation. Overall, multiple lines of evidence suggest that Osß-glu plays a crucial regulatory role in the response of rice to Cd stress, acting as an inhibitor of Cd accumulation. This contributes to a better understanding of the precise control network for Cd tolerance in rice, providing a basis for breeding rice varieties with lower Cd uptake.