[Preparation, characterization and antitumor effect of iron-based organic framework nano preparations loaded with piperlongumine].

The preparation processes of iron-based organic framework(FeMOF) MIL-100(Fe) and MIL-101(Fe) with two different ligands were optimized and screened, and the optimized FeMOF was loaded with piperlongumine(PL) to enhance the biocompatibility and antitumor efficacy of PL. The MIL-100(Fe) and MIL-101(Fe) were prepared by solvent thermal method using the optimized reaction solvent. With particle size, polymer dispersity index(PDI), and yield as indexes, the optimal preparation processes of the two were obtained by using the definitive screening design(DSD) experiment and establishing a mathematical model, combined with the Derringer expectation function. After characterization, the best FeMOF was selected to load PL by solvent diffusion method, and the process of loading PL was optimized by a single factor combined with an orthogonal experiment. The CCK-8 method was used to preliminarily evaluate the biological safety of blank FeMOF and the antitumor effect of the drug-loaded nano preparations. The experimental results showed that the optimal preparation process of MIL-100(Fe) was as follows: temperature at 127.8 ℃, reaction time of 14.796 h, total solvent volume of 11.157 mL, and feed ratio of 1.365. The particle size of obtained MIL-100(Fe) nanoparticles was(108.84±2.79)nm; PDI was 0.100±0.023, and yield was 36.93%±0.79%. The optimal preparation process of MIL-101(Fe) was as follows: temperature at 128.1 ℃, reaction time of 6 h, total solvent volume of 10.005 mL, and feed ratio of 0.500. The particle size of obtained MIL-101(Fe) nanoparticles was(254.04±22.03)nm; PDI was 0.289±0.052, and yield was 44.95%±0.45%. The optimal loading process of MIL-100(Fe) loaded with PL was as follows: the feed ratio of MIL-100(Fe) to PL was 1∶2; the concentration of PL solution was 7 mg·mL~(-1), and the ratio of DMF to water was 1∶5. The drug loading capacity of obtained MIL-100(Fe)/PL nanoparticles was 68.86%±1.82%; MIL-100(Fe) was nontoxic to HepG2 cells at a dose of 0-120 µg·mL~(-1), and the half-inhibitory concentration(IC_(50)) of free PL for 24 h treatment of HepG2 cells was 1.542 µg·mL~(-1). The IC_(50) value of MIL-100(Fe)/PL was 1.092 µg·mL~(-1)(measured by PL). In this study, the optimal synthesis process of MIL-100(Fe) and MIL-101(Fe) was optimized by innovatively using the DSD to construct a mathematical model combined with the Derringer expectation function. The optimized preparation process of MIL-100(Fe) nanoparticles and the PL loading process were stable and feasible. The size and shape of MIL-100(Fe) particles were uniform, and the crystal shape was good, with a high drug loading capacity, which could significantly enhance the antitumor effect of PL. This study provides a new method for the optimization of the nano preparation process and lays a foundation for the further development and research of antitumor nano preparations of PL.

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer.

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

Fibroin nanodisruptor with Ferroptosis-Autophagy synergism is potent for lung cancer treatment.

Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.

Curcumin analogue EF24 prevents alveolar epithelial cell senescence to ameliorate idiopathic pulmonary fibrosis via activation of PTEN.

BACKGROUND: Treating Idiopathic pulmonary fibrosis (IPF) remains challenging owing to its relentless progression, grim prognosis, and the scarcity of effective treatment options. Emerging evidence strongly supports the critical role of accelerated senescence in alveolar epithelial cells (AECs) in driving the progression of IPF. Consequently, targeting senescent AECs emerges as a promising therapeutic strategy for IPF. PURPOSE: Curcumin analogue EF24 is a derivative of curcumin and shows heightened bioactivity encompassing anti-inflammatory, anti-tumor and anti-aging properties. The objective of this study was to elucidate the therapeutic potential and underlying molecular mechanisms of EF24 in the treatment of IPF. METHODS: A549 and ATII cells were induced to become senescent using bleomycin. Senescence markers were examined using different methods including senescence-associated ß-galactosidase (SA-ß-gal) staining, western blotting, and q-PCR. Mice were intratracheally administrated with bleomycin to induce pulmonary fibrosis. This was validated by micro-computed tomography (CT), masson trichrome staining, and transmission electron microscope (TEM). The role and underlying mechanisms of EF24 in IPF were determined in vitro and in vivo by evaluating the expressions of PTEN, AKT/mTOR/NF-κB signaling pathway, and mitophagy using western blotting or flow cytometry. RESULTS: We identified that the curcumin analogue EF24 was the most promising candidate among 12 compounds against IPF. EF24 treatment significantly reduced senescence biomarkers in bleomycin-induced senescent AECs, including SA-ß-Gal, PAI-1, P21, and the senescence-associated secretory phenotype (SASP). EF24 also effectively inhibited fibroblast activation which was induced by senescent AECs or TGF-ß. We revealed that PTEN activation was integral for EF24 to inhibit AECs senescence by suppressing the AKT/mTOR/NF-κB signaling pathway. Additionally, EF24 improved mitochondrial dysfunction through induction of mitophagy. Furthermore, EF24 administration significantly reduced the senescent phenotype induced by bleomycin in the lung tissues of mice. Notably, EF24 mitigates fibrosis and promotes overall health benefits in both the acute and chronic phases of IPF, suggesting its therapeutic potential in IPF treatment. CONCLUSION: These findings collectively highlight EF24 as a new and effective therapeutic agent against IPF by inhibiting senescence in AECs.

Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine's physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine's mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside's entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.

Targeting Ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide.

INTRODUCTION: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care. AREAS COVERED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. EXPERT OPINION: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.

Delivery of piperlongumine via hyaluronic acid/phenylboronic acid-mediated dual targetable polymersome for enhanced anticancer functionality against pancreatic tumor.

Pancreatic cancer cells highly resistance to conventional chemo drugs, resulting low survival rates. The aim of the study was to design and develop dual targeting polymersomes (DTPS) loaded with phyto alkaloid agent i.e., piperlongumine (PL) for effective pancreatic cancer treatment. Here, hyaluronic acid (HA) was functionalized with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPEPEG-NH2), poly(ethylene glycol) bis (amine) (PEG), and phenylboronic acid (PBA) moieties. The designed DTPS could selectively recognize CD44/sialic acid (SA) and deliver PL to MIA PaCa-2 pancreatic cancer cells, facilitated via HA-CD44 and PBA-SA interactions. Drug release and stability results implied sustained PL release profile and pH sensitivity. DTPS could be more efficiently bound with SA than other sugars based on fluorescence spectroscopy. The anticancer efficacy of designed polymersomes was tested with H6C7 normal pancreas cells and SA/CD44-overexpressed MIA PaCa-2 pancreatic cancer cells. DTPS showed both SA and CD44-mediated higher cellular uptake while single-targeted polymersomes showed CD44-mediated cellular uptake. The PL-loaded DTPS efficiently uptake by MIA PaCa-2 cancer cells, causing up to 80 % cell growth inhibition, reduced cell spheroids volume and increased dead cells by 58.3 %. These results indicate that the newly developed DTPS can effectively serve as a pH-responsive drug delivery system for efficient treatment of cancer.

Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/ß-Catenin in Colon Cancer Cells.

Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating ß-catenin expression, which is a pivotal protein in the Wnt/ß-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/ß-catenin pathway.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

Conjugates of 3,5-Bis(arylidene)-4-piperidone and Sesquiterpene Lactones Have an Antitumor Effect via Resetting the Metabolic Phenotype of Cancer Cells.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Design, synthesis, and biological studies of nitric oxide-donating piperlongumine derivatives triggered by lysyl oxidase as anti-triple negative breast cancer agents.

Nitric oxide (NO) is an important gas messenger molecule with a wide range of biological functions. High concentration of NO exerts promising antitumor effects and is regarded as one of the hot spots in cancer research, that have limitations in their direct application due to its gaseous state, short half-life (seconds) and high reactivity. Lysyl oxidase (LOX) is a copper-dependent amine oxidase that is responsible for the covalent bonding between collagen and elastin and promotes tumor cell invasion and metastasis. The overexpression of LOX in triple-negative breast cancer (TNBC) makes it an attractive target for TNBC therapy. Herein, novel NO donor prodrug molecules were designed and synthesized based on the naturally derived piperlongumine (PL) skeleton, which can be selectively activated by LOX to release high concentrations of NO and PL derivatives, both of them play a synergistic role in TNBC therapy. Among them, the compound TM-1 selectively released NO in highly invasive TNBC cells (MDA-MB-231), and TM-1 was also confirmed as a potential TNBC cell line inhibitor with an inhibitory concentration of 2.274 µM. Molecular docking results showed that TM-1 had a strong and selective binding affinity with LOX protein.

Identification of avaC from Human Gut Microbial Isolates that Converts 5AVA to 2-Piperidone.

2-piperidone is a crucial industrial raw material of high-value nylon-5 and nylon-6,5. Currently, a major bottleneck in the biosynthesis of 2-piperidone is the identification of highly efficient 2-piperidone synthases. In this study, we aimed to identify specific strains among 51 human gut bacterial strains capable of producing 2-piperidone and to elucidate its synthetic mechanism. Our findings revealed that four gut bacterial strains, namely Collinsella aerofaciens LFYP39, Collinsella intestinalis LFYP54, Clostridium bolteae LFYP116, and Clostridium hathewayi LFYP18, could produce 2-piperidone from 5-aminovaleric acid (5AVA). Additionally, we observed that 2-piperidone could be synthesized from proline through cross-feeding between Clostridium difficile LFYP43 and one of the four 2-piperidone producing strains, respectively. To identify the enzyme responsible for catalyzing the conversion of 5AVA to 2-piperidone, we utilized a gain-of-function library and identified avaC (5-aminovaleric acid cyclase) in C. intestinalis LFYP54. Moreover, homologous genes of avaC were validated in the other three bacterial strains. Notably, avaC were found to be widely distributed among environmental bacteria. Overall, our research delineated the gut bacterial strains and genes involved in 2-piperidone production, holding promise for enhancing the efficiency of industrial biosynthesis of this compound.

Cytotoxic glutarimide-containing polyketides isolated from Streptomyces sp. JCM 4793.

Glutarimide-containing polyketides usually exhibit anti-fungi activity, which was well exampled by cycloheximide. In our work, three new polyketide structures, 12-amidestreptimidone (1), 12-carboxylstreptimidone (2) and 3-(5S,8R)-(2-amino-2-oxoethyl-2'-methoxy-2'-oxoethyl)-8,10-dimethyl-7-oxododeca-5-hydroxy-9E,11-diolefin (3) were isolated from Streptomyces sp. JCM 4793. 3 without the glutarimide moiety is not active against fungi as expected, while 1 bearing the amide moiety is much more active than its carboxylic form 2. Here we report the isolation, structural elucidation, antifungal activity, and proposed biosynthesis pathway of 1-3.

[Research progress in anti-tumor activity and nano-drug delivery system of piperlongumine].

Piperlongumine(PL), a natural alkaloid extracted from Piperis Longi Fructus, has attracted much attention in recent years because of its strong anti-tumor activity, little toxicity to normal cells, and excellent sensitizing effect combined with chemotherapy and radiotherapy, which endow PL with unique advantages as an anti-tumor drug. However, similar to other alkaloids, PL has low water solubility and poor bioavailability. To improve the application of PL in the clinical treatment of tumors, researchers have constructed various nano-drug delivery systems to increase the efficiency of PL delivery. This paper reviewed the physicochemical properties, anti-tumor mechanism, combined therapies, and nano-drug delivery systems of PL in recent years. The review aimed to provide a reference for further research on the anti-tumor effect and nano-drug delivery system of PL. Moreover, this review is expected to provide a reference for the development and application of PL in the anti-tumor therapies.

Metabolic activation and cytochrome P450 inhibition of piperlonguminine mediated by CYP3A4.

Piperlonguminine (PLG) is a major alkaloid found in Piper longum fruits. It has been shown to possess a variety of biological activities, including anti-tumor, anti-hyperlipidemic, anti-renal fibrosis and anti-inflammatory properties. Previous studies have reported that PLG inhibits various CYP450 enzymes. The main objective of this study was to identify reactive metabolites of PLG in vitro and assess its ability to inhibit CYP450. In rat and human liver microsomal incubation systems exposed to PLG, two oxidized metabolites (M1 and M2) were detected. Additionally, in microsomes where N-acetylcysteine was used as a trapping agent, N-acetylcysteine conjugates (M3, M4, M5 and M6) of four isomeric O-quinone-derived reactive metabolites were found. The formation of metabolites was dependent on NADPH. Inhibition and recombinant CYP450 enzyme incubation experiments showed that CYP3A4 was the primary enzyme responsible for the metabolic activation of PLG. This study characterized the O-dealkylated metabolite (M1) through chemical synthesis. The IC50 shift assay showed time-dependent inhibition of CYP3A4, 2C9, 2E1, 2C8 and 2D6 by PLG. This research contributes to the understanding of PLG-induced enzyme inhibition and bioactivation.

Piperlongumine and its derivatives against cancer: A recent update and future prospective.

Piperlongumine, or piplartine (PL), is a bioactive alkaloid isolated from Piper longum L. and a potent phytoconstituent in Indian Ayurveda and traditional Chinese medicine with a lot of therapeutic benefits. Apart from all of its biological activities, it demonstrates multimodal anticancer activity by targeting various cancer-associated pathways and being less toxic to normal cells. According to their structure-activity relationship (SAR), the trimethylphenyl ring (cinnamoyl core) and 5,6-dihydropyridin-2-(1H)-one (piperdine core) are responsible for the potent anticancer activity. However, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.). As a result, pharmaceutical researchers have been trying to optimise or modify the structure of PL to improve the drug-likeness profiles. The present review selected 26 eligible research articles on PL derivatives published between 2012 and 2023, followed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format. We have thoroughly summarised the anticancer potency, mode of action, SAR and drug chemistry of the proposed PL-derivatives against different cancer cells. Overall, SAR analyses with respect to anticancer potency and drug-ability revealed that substitution of methoxy to hydroxyl, attachment of ligustrazine and 4-hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7-C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell permeability, and bioavailability, making them potential leads. Hopefully, the large-scale collection and critical drug-chemistry analyses will be helpful to pharmaceutical and academic researchers in developing potential, less-toxic and cost-effective PL-derivatives that can be used against different cancers.

Pan-cancer analysis of Sushi domain-containing protein 4 (SUSD4) and validated in colorectal cancer.

Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.

MST1/2 exerts a pivotal role in inducing neuroinflammation and Coxsackievirus-A10 replication by interacting with innate immunity.

Coxsackievirus-A10 (CV-A10), responsible for the hand, foot and mouth disease (HFMD) pandemic, could cause serious central nervous system (CNS) complications. The underlying molecular basis of CV-A10 and host interactions inducing neuropathogenesis is still unclear. The Hippo signaling pathway, historically known for a dominator of organ development and homeostasis, has recently been implicated as an immune regulator. However, its role in host defense against CV-A10 has not been investigated. Herein, it was found that CV-A10 proliferated in HMC3 cells and promoted the release of inflammatory cytokines. Moreover, pattern recognition receptors (PRRs)-mediated pathways, including TLR3-TRIF-TRAF3-TBK1-NF-κB axis, RIG-I/MDA5-MAVS-TRAF3-TBK1-NF-κB axis and TLR7-MyD88-IRAK1/IRAK4-TRAF6-TAK1-NF-κB axis, were examined to be elevated under CV-A10 infection. Meanwhile, it was further uncovered that Hippo signaling pathway was inhibited in HMC3 cells with CV-A10 infection. Previous studies have been reported that there exist complex relations between innate immune and Hippo signaling pathway. Then, plasmids of knockdown and overexpression of MST1/2 were transfected into HMC3 cells. Our results showed that MST1/2 suppressed the levels of inflammatory cytokines via interacting with TBK1 and IRAK1, and also enhanced virus production via restricting IRF3 and IFN-ß expressions. Overall, these data obviously pointed out that CV-A10 accelerated the formation of neuroinflammation by the effect of the Hippo pathway on the PRRs-mediated pathway, which delineates a negative immunoregulatory role for MST1/2 in CV-A10 infection and the potential for this pathway to be pharmacologically targeted to treat CV-A10.

Synergistic Renoprotective Effects of Green Tea Extract and Gemigliptin against Tacrolimus-Induced Nephrotoxicity in Mice / Efectos Renoprotectores Sinérgicos del Extracto de Té Verde y Gemigliptina contra la Nefrotoxicidad Inducida por Tacrolimus en Ratones

SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.

Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.