Gibberellins (GAs) play important roles in regulating reproductive development, especially flower development. However, the regulation of GA metabolism and GA signaling component genes of flower bud development in Camellia oleifera is not entirely understood. In this study, 6-year-old C. oleifera 'Huashuo' was used as the experimental material. Exogenous GA3 and GA biosynthesis inhibitors, chlormequat chloride (CCC) and uniconazole (UCZ), were applied to investigate the flower development, levels of GA3, GA metabolism, and the expression of genes involved in GA signaling across the different treatments. Our results demonstrate that exogenous GA3 promoted flower bud growth and accelerated blooming, with the rate of petaloid-anther transformation reaching up to 64.11% during the peak blooming period. Cytological analysis showed that the anthers in the GA3-treated flowers exhibited abnormal longitudinal elongation 30 days after spraying, and gradually developed into petaloid anthers. KEGG analysis revealed that the GA3 treatment regulated the plant hormone signal transduction. The genes encoding DELLA protein accounted for the largest proportion (52.45%) of the gibberellin signal transduction pathway DEGs. GA3 enhanced gibberellin content by regulating the gibberellin biosynthesis gene CoGA20ox1 during early flower development, and GID1 also showed a significant response to GAs. Additionally, the expression of genes associated with flower development (FT, LFY, SOC1, SVP) and those involved in petaloid-anther (MADS-box family members AP1, AGL8) exhibited significant differences. These results elucidated the regulatory effects of gibberellins and their inhibitors on anther development via the GA pathway in C. oleifera, which provides a foundation for further investigation into the mechanism of flower development.

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.

A substantial rise in the less common Trichophyton tonsurans in India with notable multi-drug resistance has transformed into a reason for recalcitrant dermatophytosis and concern.

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.).

Plant development and productivity are significantly hindered by salt stress, leading to substantial financial losses in the agriculture sector. Salinity stress negatively impacts the overall growth, physiology, and metabolism of plants. Specifically, NaCl stress is particularly harmful to tomato plants, causing suppression of seedling growth, accumulation of sodium (Na+) and chloride (Cl-) ions, disrupted ion homeostasis, reduced proline and chlorophyll content, and impairment of antioxidant enzyme systems. This research aimed to investigate the role of exogenous putrescine (PUT) application on tomato (Solanum lycopersicum L.) seedlings under NaCl stress (250 mm) to determine its potential protective effects. Various physio-biochemical attributes were estimated using precise protocols for NaCl-treated, PUT-treated, and untreated controlled tomato seedlings also analyzed for the expression of ACS1, NHX1, HKT1;2, and SOS1 genes. Additionally, ACC synthase activity, ethylene content, electrolyte leakage, proline content, Na+ and potassium (K+) ion content, lycopene content, and antioxidant enzyme activities were examined. Results indicated that PUT application enhanced the expression of ACS1, NHX1, HKT1;2, and SOS1 genes increase the ACC synthase activity, ethylene content, proline content, and Na+ and K+ ion content, while reducing electrolyte leakage. Furthermore, PUT application significantly increased the activity of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR), as well as other morphological parameters. Overall, our research demonstrated the potential benefits of PUT applications for enhancing crop growth and improving salt stress tolerance, which are crucial for agronomy.

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.

Metastasis is the primary cause of death in women with breast cancer, which ranks among the most prevalent malignant diseases. Recently, we identified the significant metastatic role of hypoxanthine (HYP) in cancer cells. HYP is a naturally occurring purine derivative that actively participates in the synthesis of nucleic acids via the nucleotide salvage pathway. To gain a deeper insight onto the metastatic mechanism of HYP, integrated transcriptomics and metabolomics were conducted following the treatment of MCF-7 cells with HYP. HYP significantly activates PI3K/AKT pathway, a hallmark of cancer metastasis. Glycerolipid and fatty acid metabolisms are among the top-upregulated lipid metabolic pathways, while glycolysis is dysregulated. Seahorse real-time ATP rate analysis revealed a significant decrease in ATP production from the glycolysis pathway in HYP-treated cancer cells. On the other hand, genetic information processes including gene transcription and protein translation were downregulated. Collectively, our results highlight the contribution of HYP to cancer cell metastasis through the PI3K/AKT pathway. Consequently, manipulating HYP release could serve as a therapeutic target for the management of breast cancer.

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.

Polyamines (putrescine, spermidine, and spermine) are essential molecules for DNA stability and tumor cell proliferation, including in non-small cell lung cancer (NSCLC). AMD1 (S-adenosylmethionine decarboxylase), a critical enzyme in polyamine metabolism, decarboxylates S-adenosylmethionine, a central methyl group donor. SAM486A, an AMD1 inhibitor, has demonstrated therapeutic potential in hematologic and solid tumors.

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.