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This paper describes the synthesis and reactivity of [η5-1,3-(Me3Si)2C5H3]2U(P-2,4,6-iPr3C6H2)(OPMe3) (6) which is accessible from a ligand exchange reaction between [η5-1,3-(Me3Si)2C5H3]2U(P-2,4,6-iPr3C6H2)(OPPh3) (2) and Me3PO at ambient temperature. Phosphinidene 6 exhibits no reactivity towards internal alkynes, but readily reacts with various hetero-unsaturated molecules such as isothiocyanates, aldehydes, nitriles, isonitriles, and organic azides, forming uranium sulfido, oxido, imido, and uranaheterocyclic compounds. Nevertheless, with the bidentate ortho-dicyanobenzene o-C6H4(CN)2 the zwitterionic species [η5-1,3-(Me3Si)2C5H3]2U[NHC(N){C6H4CP(2,4,6-iPr3C6H2)CH2PMe2O}] (13) is isolated in good yield. Moreover, 6 converts with Ph2S2 to the uranium(III) phenylthiolate compound [η5-1,3-(Me3Si)2C5H3]2USPh(OPMe3) (7) in good isolated yield. Furthermore, the influence of the Lewis base on the reactivity of the uranium phosphinidene metallocenes has also been evaluated.

The Lewis base supported terminal uranium phosphinidene metallocene [η5-1,3-(Me3C)2C5H3]2U([double bond, length as m-dash]P-2,4,6-iPr3C6H2)(OPMe3) (2) could be isolated from a salt metathesis reaction in toluene at ambient temperature between [η5-1,3-(Me3C)2C5H3]2U(Cl)Me (1) and 2,4,6-iPr3C6H2PHK in the presence of Me3PO, and its structure and reactivity were probed in detail. No reaction of 2 with internal alkynes was observed, but it reacts in the presence of various heterounsaturated molecules such as CS2, isothiocyanates, aldehydes, imines, diazenes, carbodiimides, nitriles, isonitriles, diazoalkane, and organic azides, forming carbodithioates, sulfidos, oxidos, metallaheterocycles, and imido complexes, in good yields. Moreover, on reaction with the diazoalkane derivative Me3SiCHN2 the pseudophosphinimido uranium(iii) complex [η5-1,3-(Me3C)2C5H3]2U(N[double bond, length as m-dash]P-2,4,6-iPr3C6H2)(OPMe3) (20) can be isolated in good yield.

Chemotherapy has been widely used for treating the vast majority of cancer patients. Unfortunately, only a fraction of patients can respond to chemotherapies, but these patients still experience severe side effects. In this context, a wide range of nanotherapeutic platforms have been developed with the aim of improving treatment outcomes while reducing drug toxicities. Nanohydrogels are highly appealing "smart" biocompatible and biodegradable vehicles for either local or systemic delivery of bioactive compounds. Here, we developed prodrug hydrogelators that can undergo one-step distillation-precipitation polymerization to form systemically injectable nanohydrogels. The optimized nanohydrogels were capable of rapidly releasing active agents (e.g., the cytotoxic agent cabazitaxel or the PI3K molecular inhibitor PI103) in response to the reducing tumor microenvironment, while drug release was very slow in the absence of the reductive reagent glutathione. Cabazitaxel-loaded nanogels showed preferential tumor accumulation, and administration of nanogels produced durable tumor regression in a docetaxel-resistant cervical tumor xenograft-bearing mouse model. More significantly, nanogel-based therapy was proven to demonstrate a higher safety profile than solution-based free cabazitaxel. Collectively, this study provides an alternative formulation that meets the essential requirements of high stability in the blood, spontaneous drug release at diseased sites, favorable safety in vivo, and translational capacity for further investigations. STATEMENT OF SIGNIFICANCE: Chemotherapy remains a considerable challenge and only a fraction of patients can respond to chemotherapies. Here we report an intratumoral reducing agent-activatable, tumor-targeting prodrug nanogel platform for therapeutic delivery. To this end, two anticancer agents (e.g., cytotoxic cabazitaxel or PI3K molecular inhibitor PI103) are tested. Prodrug nanogels are stable in the blood but performed reduction-triggered release of chemically unmodified drug molecules in cancerous tissues. Cabazitaxel-loaded nanogels exhibit satisfactory anticancer performance in a preclinical docetaxel-resistant tumor model. This is a practical and expedient approach that combines the prodrug strategy and nanogel scaffold to re-engineer a hydrophobic and toxic anticancer drug. The approach also is broadly applicable for the formulation of other agents to improve the therapeutic index.

In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC50 values at the range of 3.3-15.0 μm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.

The first example of pyrazole-directed rhodium(III)-catalyzed unreactive C(sp3)–H alkenylation with alkynes has been described, which showed a relatively broad substrate scope with good functional group compatibility. Moreover, we demonstrated that the transitive coordinating center pyrazole could be easily removed under mild conditions.

Cardiac hypertrophy is an adaptive response against increased workload featuring by an increase in left ventricular mass and a thickening left ventricle wall. Here, we showed the expression of transient receptor potential canonical 1 (TRPC1) is higher in hearts of patients with hypertrophic cardiomyopathy (HCM) or heart failure (HF) than that of normal hearts. To better understand the mechanisms of TRPC1 in regulating cellular hypertrophy of human-based cardiomyocytes, we generated human pluripotent stem cell lines of TRPC1 knockout by CRISPR/Cas9. We demonstrated that knockout of TRPC1 significantly attenuated cardiomyocyte hypertrophy phenotype induced by phorbol 12-myristate 13-acetate, which was associated with abnormal activation of NF-κB. In contrast, overexpression of TRPC1 induced cardiomyocyte hypertrophy, which can be reversed by inhibition of NF-κB. Taken together, we established a stable human-based cardiomyocyte hypertrophy model and highlighted molecular mechanisms underlying TRPC1-mediated hypertrophy, aiding the development of therapeutic drugs for HCM and HF by targeting TRPC1.

Background Histones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive. Methods CHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods. Findings CHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent. Interpretation CHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment.

A novel palladium-catalyzed, norbornene-mediated intermolecular dehydrogenative annulation approach for the synthesis of 6-fluoroalkyl-phenanthridines from aryl iodides and fluorinated imidoyl chlorides, which are important structural motifs for bioactive molecules, is reported. Fluorinated imidoyl chlorides served as a new type of electrophilic reagent in the Catellani-type reaction, which, in turn, could be readily prepared from various anilines and fluorinated carboxylic acids. Control experiments were carried out to study the mechanism of the reaction. This transformation is scalable and tolerates a broad range of functional groups.

The Hippo tumor suppressor pathway is critical for balancing cellular differentiation and proliferation in response to cell-cell contact, mechanical signals and diffusible signals such as lysophosphatidic acid. Hippo pathway signaling is frequently dysregulated in gastric cancer (GC), as well as many other kinds of solid tumors, contributing to multiple aspects of malignant progression including unchecked cell division and metastasis. Considering the importance of this Hippo pathway in cancer, its pharmacological disruption may be of huge benefit in the fight against this disease. In this review, we summarize the components of the Hippo pathway, its crosstalk with other major oncogenic signaling pathways, common mechanisms of its dysregulation, as well as potential therapeutic approaches of targeting this pathway for cancer treatment, specifically in a GC context.

Reactions of 2-benzoylpyridine or 2-benzylpyridine with [Cp*MCl2]2 (M = Ir, Rh) have been carried out in the presence of NaOAc in refluxing methanol, which form the corresponding six-membered cyclometalated products (1–3) except for the reaction of 2-benzylpyridine with [Cp*RhCl2]2. Insertion reactions of two six-membered cyclometalated pyridine iridium complexes (1 and 2) with terminal or internal aromatic alkynes were studied. Terminal alkynes p-XC6H4CCH (X = H, MeO, and F) with 1 give the corresponding five- and seven-membered doubly cycloiridated complexes 4a–c, internal alkynes p-XC6H4CCC6H4X-p (X = H, MeO, and Br) form the similar five- and seven-membered doubly cycloiridated complexes (5a,b) and/or di-insertion products (6a,c), whereas the acyl alkyne PhCCCOPh affords the novel spiro-metalated complex 7. For complex 2, internal alkynes p-XC6H4CCC6H4X-p (X = H, MeO, and Br) form similar five- and seven-membered doubly cycloiridated complexes (8a–c). However, in the case of PhCCCOPh, the reaction gives the novel four-membered cyclometalated complex 9. These results suggest that the products formed by alkyne insertion reactions of the six-membered cycloiridated pyridine complexes are very diverse. Plausible pathways for the formation of these novel insertion products were proposed. Molecular structures of seven cyclometalated complexes were determined by X-ray diffraction.

Background: Drug resistance continues to be a major clinical challenge in achieving cures in cancer patients. Cabazitaxel has shown the ability to surmount drug resistance through bypassing the transporter-mediated drug expulsion; however, the substantially high toxicity in patients hampered its clinical application. In addition, upregulation of certain self-defense proteins (e.g, Akt) was reportedly involved in drug resistance, which may further compromise the activity of cabazitaxel. We have previously developed several prodrug-based strategies to deliver nanoparticles encapsulating cabazitaxel derivatives in tumors with enhanced efficacy and improved in vivo tolerability. Therefore, we hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically eliminate the resistant cancers with reduced systemic toxicity.Methods: Activation of Akt in resistant cancers upon cabazitaxel treatment was determined by western blotting assay. The effect of combing MK-2206 with cabazitaxel on cell viability was evaluated by CCK-8 assay. To improve the in vivo biocompatibility, the delivery of potent cabazitaxel was feasibly achieved via the integration of oligolactide-conjugated cabazitaxel into the PEG-b-PLA matrix. Both the synergism and safety of cabazitaxel nanomedicine-based combination were evaluated through a series of in vitro and in vivo experiments, including Western blotting assay, CCK-8 assay, EdU assay, flow cytometry, migration assay, transwell assay, MTD study, myelosuppression study, nude mouse xenograft, and immunostaining analyses. Results: We found that resistant cells adapted to activate Akt signaling upon cabazitaxel treatment, which potentially discounts the efficacy of cabazitaxel. The addition of MK-2206 reversed this situation and potentiated the activity of cabazitaxel nanomedicine against resistant cells. Mechanistically, suppression of the Akt pathway increased the microtubule-stabilizing effect of cabazitaxel. Their collaboration was demonstrated to maximize the efficacy in a xenograft model bearing paclitaxel-resistant tumors. In particular, the nanoformulation substantially improved drug tolerability in animals, and combined treatment with MK-2206 was proven to be safe for synergistic cancer therapy. Conclusion: The preclinical studies demonstrate the therapeutic efficacy of our binary system consisting of a better-tolerated nanotherapy and a specific pathway modulator against resistant cells, thereby highlighting the potential applications for the clinical treatment of patients with multidrug-resistant malignancies.

Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3′ or 5′ overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.

The synthesis of highly unsaturated fatty acids (HUFAs) from C18 fatty acids in the Pacific white shrimp, Litopenaeus vannamei, has long been debated in terms of the limited capacity or even the existence of fatty acid desaturase and elongase. In the present study, a Δ6 fatty acyl desaturase (Fad)-like gene was identified and characterized with a full length of 1,491 bp, including a 39-bp 5′-UTR (untranslated region), a 108-bp 3′-UTR, and a 1,344 bp open reading frame encoding a 448 amino acid protein. The protein contained a cytochrome b5-like heme/steroid binding domain and a Fad domain. The Δ6 Fad-like protein of L. vannamei shared 70%–77% sequence homology with those of Macrobrachium nipponense, Scylla paramamosain, Portunus trituberculatus and Eriocheir sinensis. When salinity was reduced from 30 to 3, Δ6 Fad-like gene expression significantly increased in the gills, muscles, eyestalk, and hepatopancreas (P < 0.05). The highest expression was observed in the hepatopancreas under salinity 3 i...

There is an urgent need for more effective, less toxic cancer therapy agents. Motivated by this need, we synthesized a small panel of N-heterocyclic carbene (NHC)-coordinated ruthenium(II) arene complexes Ru1–Ru6 with the formula [Ru(p-cymene)(L)Cl]PF6 (L = NHC ligand with varying substituents). Cell-based in vitro studies revealed that despite the structural similarity, Ru1–Ru6 exhibited distinct cytotoxic activities against cancer cells. In particular, Ru4 and Ru6, which bear n-octyl and pentamethylbenzyl motifs, respectively, were the most active at inducing apoptosis. In human ovarian A2780 cancer cells, Ru4 and Ru6 showed the highest cytotoxicities with IC50 values of 2.74 ± 0.15 μM and 1.98 ± 0.10 μM, respectively, and they were approximately 2-fold more potent than cisplatin (IC50 = 5.55 ± 0.37 μM). In addition to the cell killing capacity, inhibition of cell migration was validated by using these two optimized complexes. Mechanistic studies revealed that Ru4 and Ru6 complexes induced apoptosis in a caspase-dependent manner, primarily through intracellular reactive oxygen species (ROS) overproduction and cell cycle arrest at G1 phase. Furthermore, in a preclinical metastatic model of A2780 tumor xenograft, administration of Ru4 and Ru6 (20 μmol/kg) resulted in a marked inhibition of tumor progression and metastasis. Finally, a substantially alleviated systemic toxicity was observed for both complexes in comparison with cisplatin in animals. Overall, this study greatly increases our understanding of NHC-coordinated Ru(II) arene metallodrugs, aiding further investigation of their therapeutic potential in the treatment of metastatic cancers.

The utilization of nonionic surfactants is a practical way to formulate hydrophobic chemotherapeutics, facilitating the clinical translation of drug candidates during the development process. However, since the drug toxicity in patients is primarily determined by the cytotoxic drugs themselves, such a formulation approach is unable to improve the drug tolerability. Therefore, additional strategies for enhancing drug safety profiles are necessary when considering the use of surfactants as formulation excipients. Using cabazitaxel as a target agent, we show that the miscibility of α-linolenic acid (LNA)tethered cabazitaxel conjugate 1 with polysorbate 80 (Tween 80) was enhanced. Upon further blending with aqueous solutions, conjugate 1 formed stable colloidal nanoemulsions with Tween 80. Thus, the nanoemulsions are systemically injectable and suitable for preclinical studies. Compared with parent cabazitaxel, conjugate 1 displayed a substantial improvement in its safety profile in animals. Therapeutic studies in a mouse xenograft model of human cancer further demonstrated the effectiveness of conjugate 1 in suppressing tumor growth. These results suggest that attaching flexible lipid chains to the highly toxic cabazitaxel generates a new drug entity that is more compatible with Tween 80-based formulations than its free drug form. This new entity retains its antitumor activity while improving its tolerability in vivo.

Macrobrachium nipponense is an economically and nutritionally important species threatened by ambient superfluous nitrite. De novo RNA-Seq was used to explore the molecular mechanism in M. nipponense exposed to the acute nitrite stress (26.05 mg/L nitrite-N) for 24 h and the chronic nitrite stress (1.38 mg/L nitrite-N) for 28 d A total of 175.13 million reads were obtained and assembled into 58,871 unigenes with an average length of 1028.7 bp and N50 of 1294 bp. Under the acute and chronic nitrite stress trials, 2824 and 2610 unigenes were significantly expressed. In GO analysis and KEGG pathway analysis, 30 pathways were significantly different between the two treatments while four pathways were in common and the markedly altered pathways were divided into four sections as immunity, metabolism, cell and others. The immunity section revealing the different depth of immunity provoked by nitrite stress contained the most pathways including the important pathways as phagosome, folate biosynthesis, glycerolipid metabolism, glycine, serine and threonine metabolism, amino sugar and nucleotide sugar metabolism under the acute nitrite stress, and lysosome, alanine, aspartate and glutamate metabolism, arginine and proline metabolism under the chronic nitrite stress. This is the first report of responses of M. nipponense under acute and chronic nitrite stress through de novo transcriptome sequencing on the transcriptome level. The results of transcriptome analysis improve our understanding on the underlying molecular mechanisms coping with nitrite stress in crustacean species.

Sulfide is a natural and widely distributed toxicant. It can be commonly found on the interface between water and sediment in the aquatic environment. The Pacific white shrimp Litopenaeus vannamei starts life in the benthic zone soon after the mysis stage, an early stage of post larvae. Therefore, L. vannamei is inevitably affected by exposure to sulfide released from pond sediment. This study explored the toxicant effect of different concentrations of sulfide on the intestinal health and microbiota of Pacific white shrimp by monitoring the change of expression of inflammatory, immune related cytokines, and the structure of the intestinal microbiota. The gut histology, expressions of inflammatory and immune related cytokines (tumor necrosis factor-alpha, C-type lectin 3, myostatin and heat shock transcription factor 1), and the microbiota were determined in L. vannamei after exposure to 0 (control), 425.5 (1/10 LC 50-96 h), and 851 μg/L (1/5 LC 50-96 h) of sulfide for 21 days. With the increase of sulfide concentration, intestinal injury was aggravated and the inflammatory and immune related cytokines generated a range of reactions. The expression of myostatin (MSTN) was significantly down-regulated by the concentration of sulfide exposure. No difference in the expression of heat shock transcription factor 1 (HSF1) was found between the control and shrimp exposed to 425.5 μg/L, but significantly higher HSF1 expression was found in shrimp exposed to 851 μg/L of sulfide. Significantly higher values of tumor necrosis factor-alpha (TNF-α) and C-type lectin 3 (CTL3) were found in the shrimp exposed to 425.5 μg/L of sulfide compared to the control, but a lower value was found in the shrimp exposed to 851 μg/L (P 0.05). Sulfide also changed the intestinal microbial communities. The abundance of pathogenic bacteria, such as Cyanobacteria, Vibrio and Photobacterium, increased significantly with exposure to the increasing concentration of sulfide. The abundance of some anti-stress bacteria, such as Chlorobi and Fusobacterium, increased. Nitrospirae which can alleviate nitrite toxicity decreased. Microbacterium, Parachlamydia, and Shewanella were all commonly found and down-regulated in both sulfide groups, which is associated with an adaptation to sulfide stimulation. This study indicates that chronic exposure to sub-lethal levels of sulfide could lead to damage of the gut structure, stimulate the response of the inflammatory and immune systems, and shape the structure of the gut microbiota in L. vannamei.

The toxicity and poisoning mechanisms of sulfide were studied in Litopenaeus vannamei from the perspective of energy metabolism and metabolomics. The lethal concentrations of sulfide in L. vannamei (LC50) at 24 h, 48 h, 72 h, and 96 h were determined. Sulfide at a concentration of 0, 1/10 (425.5 μg/L), and 1/5 (851 μg/L) of the LC50 at 96 h was used to test the metabolic responses of L. vannamei for 21 days. The chronic exposure of shrimp to a higher sulfide concentration of 851 μg/L decreased shrimp survival but did not affect weight gain or the hepatopancreas index. The glycogen content in the hepatopancreas and muscle and the activity of hepatopancreas cytochrome C oxidase of the shrimp exposed to all sulfide concentrations were significantly lower, and the serum glucose and lactic acid levels and lactic acid dehydrogenase activity were significantly lower than those in the control. Metabolomics assays showed that shrimp exposed to sulfide had lower amounts of serum pyruvic acid, succinic acid, glycine, alanine, and proline in the 425.5 μg/L group and phosphate, succinic acid, beta-alanine, serine, and l-histidine in the 851 μg/L group than in the control. Chronic sulfide exposure could disturb protein synthesis in shrimp but enhance gluconeogenesis and substrate absorption for ATP synthesis and tricarboxylic acid cycles to provide extra energy to cope with sulfide stress. Chronic sulfide exposure could adversely affect the health status of L. vannamei, as indicated by the high amounts of serum n-ethylmaleamic acid, pyroglutamic acid, aspartic acid and phenylalanine relative to the control. This study indicates that chronic exposure of shrimp to sulfide can decrease health and lower survival through functional changes in gluconeogenesis, protein synthesis and energy metabolism.

AMP-activated protein kinase (AMPK) serves as a major regulator of cellular energy metabolism by activating ATP production pathways and blocking ATP consumption. However, information on AMPK genes in aquatic animals is limited. In this study, three subunits of AMPK were cloned from the Pacific white shrimp Litopenaeus vannamei. The full-length cDNAs of the α, β and γ subunits were 1617, 1243 and 3467bp long, respectively, with open reading frames of 1566, 873 and 2988bp encoding for 521, 290 and 996 amino acids, respectively. Amino acid sequence alignments of the three subunits showed that the functional domains in the L. vannamei proteins retained the highest similarity with those of other animals, at 89%, 58%, and 75%, respectively. The expression levels of the three subunits were higher in the muscle and gills than in the eyestalk and hepatopancreas. The mRNA levels of AMPK-α and AMPK-β were up-regulated in the hepatopancreas and muscle after acute low-salinity stress at 3psu for 6h compared with control salinity at 20psu. After 8-week salinity stress at 3psu, AMPK-α and AMPK-β mRNA levels in the hepatopancreas were significantly higher than those of the control at 30psu. However, in the muscle only AMPK-γ mRNA was significantly up-regulated at low salinity relative to controls. Muscle and hepatopancreas showed increases in AMPK protein after 6h exposure to low salinity, but there were no differences seen after long term acclimation. The change patterns of protein were slightly differing from the mRNA patterns due to the distinguishing function of individual subunits of AMPK. These findings confirm that three AMPK subunits are present in L. vannamei and that all encode proteins with conserved functional domains. The three AMPK subunits are all regulated at the transcriptional and protein levels to manage excess energy expenditure during salinity stress.