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PubMed2026

The mighty microproteins: from versatile cellular regulators to precision medicine therapeutics.

Microproteins, are tiny proteins encoded by small open reading frame (sORF), translation of these non-canonical open reading frames (ncORFs) has been implicated in diverse biological processes and diseases. This review summarizes recent developments in the discovery, biogenesis, and functional characterization of microproteins, and their involvement in various disease, with special focus on their roles in cancer, cardiovascular, metabolic, neurodegenerative and immune-related disorders. We emphasize the regulation of key cellular pathways by microproteins, including mitochondrial homeostasis, apoptosis, metabolic reprogramming, and immune signaling, all of which affect disease initiation and progression. Emerging evidence also supports their potential as disease biomarkers and therapeutic candidates for precision medicine. Finally, the review critically discusses the current challenges including discrepancies in microprotein annotation, the limitations of ribosome profiling and proteogenomic approaches, the gap between computationally predicted and experimentally validated microproteins, and the need for rigorous orthogonal validation by means of CRISPR-based genome editing, ribosome release assays, mutational analysis, high-resolution mass spectrometry, and functional studies. Finally, we review recent development of AI-assisted ORF prediction, single-cell translatomics, spatial proteomics, and integrated multi-omics as emerging technologies reshaping. Microprotein discovery and functional annotation. Finally, we discuss the translational potential of microproteins and highlight the remaining challenges to clinical application, including peptide stability, pharmacokinetics, tissue-specific delivery, immunogenicity, and the need for rigorous preclinical and clinical validation. Together, this review provides an updated and critical overview of the rapidly evolving microprotein field and highlights future research priorities for translating these molecules into clinically useful biomarkers and precision therapeutics.

Microproteins↗
PubMed2025

Phytocompounds of Honey mesquite (Prosopis glandulosa) and Lodhra (Symplocos racemosa) in the management of COVID-19 associated rheumatoid arthritis (CARA).

COVID-19 persists globally with profound social and economic consequences, and its complex interplay with other diseases makes it a syndemic. Rheumatoid arthritis (RA), a chronic autoimmune disorder, has shown increased incidence during the pandemic, with patients displaying higher susceptibility to COVID-19. This overlap prompted the hypothesis of 'COVID-19-associated rheumatoid arthritis (CARA)'. The present study explores phytocompounds with anti-inflammatory and immunomodulatory properties as potential CARA therapeutics. Compounds from Prosopis glandulosa and Symplocos racemosa, both used in traditional medicine, were evaluated through molecular docking and simulation studies. Six inflammatory targets relevant to RA and COVID-19 -interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), human leukocyte antigen DR4 (HLA-DR4), signal transducer and activator of transcription 4 (STAT4), and peptidyl arginine deiminase 4 (PAD4) were selected. Among the tested ligands, salidroside showed the strongest binding affinity, with energies of - 8.20 kcal/mol (IL-6), - 7.67 kcal/mol (TNF-α), - 8.53 kcal/mol (GM-CSF), - 8.80 kcal/mol (HLA-DR4), - 8.18 kcal/mol (STAT4), and - 7.91 kcal/mol (PAD4), indicating stable interactions. These findings suggest salidroside could modulate key inflammatory pathways and potentially reduce cytokine storms in COVID-19 patients. Existing RA and COVID-19 treatments often cause immunosuppression, increasing vulnerability to opportunistic infections (Datta et al in J Biomol Struct Dyn 41(8):3281-3294, 2022). Immunomodulatory phytocompounds like salidroside may offer safer, targeted alternatives without compromising immune defenses. However, this study is based on in silico analyses, and warrants in vitro and in vivo validation. Nevertheless, present work may represent an important step towards novel therapeutic strategies for COVID-19 Associated Rheumatoid Arthritis (CARA).

COVID-19↗
PubMed1995

Heterologous desensitization of bombesin- and vasopressin-stimulated phospholipase D activity in Swiss 3T3 fibroblasts.

Bombesin- and vasopressin-stimulated phospholipase D (PLD) activities are rapidly desensitized in 3T3 cells, in addition both agonists are subject to heterologous desensitization. Binding studies showed that homologous desensitization was partly a result of loss of cell surface receptors, whilst heterologous desensitization was independent of receptor changes. Pretreatment with either agonist reduced subsequent GTP gamma S-stimulated PLD activity by 50% whereas a pretreatment with GTP gamma S did not attenuate the response, suggesting that the G-protein or downstream effector systems were affected by receptor activation resulting in desensitization. The desensitization of receptor-stimulated PLD activation provides support for the phospholipase functioning in a key signalling pathway.

3T3 Cells↗
PubMed1995

Determinants of hydroperoxide detoxification in diabetic rat intestine: effect of insulin and fasting on the glutathione redox cycle.

The capacity for hydroperoxide detoxification in diabetic (DM) intestine was studied in streptozocin-induced DM rats by quantification of the intestinal glutathione (GSH) redox cycle, a key cellular pathway for peroxide elimination. A role for luminal glucose in regulation of redox cycle activity was examined in insulin-treated or 24-hour-fasted DM animals. Intestinal activities of the redox enzymes, GSH peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase (G6PD), were significantly decreased by 17 hours' insulin treatment, whereas only G6PD was decreased by fasting. Mucosal GSH levels were also markedly decreased under these conditions. These results are consistent with an overall suppression of intestinal GSH redox cycle function by short-term administration of insulin. Insulin treatment for 7 consecutive days increased hepatic G6PD activity by fourfold but was without effect on intestinal G6PD, suggesting tissue specificity in insulin regulation of G6PD. The rate of metabolism of tert-butyl hydroperoxide (tBH) in isolated enterocytes was low in the absence of substrates (0.51 +/- 0.07 nmol/10(6) cells/min) but was increased fivefold by exogenous glucose (2.70 +/- 0.11 nmol/10(6) cells/min), indicating that glucose availability is an important contributor to intestinal detoxification of toxic hydroperoxides. Collectively, the current results show that GSH redox cycle enzymes in DM intestine are under coordinate insulin control, and that this control appears to be downregulated by short-term insulin treatment.

Animals↗
PubMed1986

The relative role of PAF-acether and icosanoids in septic shock.

Endotoxemia and gram negative sepsis remain a clinically important problem since mortality rate is still high in these diseases. Recently, the participation of some new potential mediators in this pathology is beginning to be demonstrated but the results obtained on animal models with specific inhibitors are contradictory. In order to clarify the pathological importance of icosanoids and PAF-acether in the septicemic process, we investigated the effects of indomethacin (IND) a cyclooxygenase inhibitor, NDGA and EP 10045 two lipoxygenase inhibitors, dexamethasone (DXM) a phospholipase A2 inhibitor and BN 52021 a PAF-acether receptor antagonist, on the Salmonella enteritidis-induced endotoxic shock (E.S.) in the rat. Injected subcutaneously 15 min before the test, NDGA, EP 10045 and IND were moderately effective when DXM completely prevented the endotoxin lethality. BN 52021 decreased the death rate in a dose-related manner and exerted at a non-active dose a synergistic effect on IND treatment. Furthermore, given orally 1 hour before endotoxin, it provided a potent protective effect. Our results seem to confirm that PAF-acether exerted alone, or in conjunction with products of the cyclooxygenase pathway, a key role in E.S. when LTs seem to play a role of minor importance.

Animals↗
PubMed1983

Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations.

The salient features of nonketotic hyperglycinemia include apnea, feeding difficulties, lethargy, seizures, abnormal muscle tone and reflex activity, significant developmental delay, and, in most instances, early death. The pathogenesis of the biochemical defect leading to increased glycine concentration in blood, urine, and CSF is likely to concern derangements of the glycine cleavage enzyme and/or transport mechanisms of glycine. Our current state of knowledge of this disorder is incomplete. Therapeutic attempts, as described in Table 2, have been largely unsuccessful. Further basic research on the underlying biochemical perturbation, including additional documentation of the glycine cleavage enzyme deficiency patterns, of substrate inhibition of key metabolic pathways, and of glycine transport aberrations, as well as investigations of new pharmacologic approaches, will be a challenge for investigators in this field. It is hoped that new knowledge in these areas will eventually lead to reduction of morbidity and mortality in children with nonketotic hyperglycinemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed1985

Combination chemotherapy directed at the components of nucleoside diphosphate reductase.

It would be expected that drugs directed at the rate-limiting step in a key metabolic pathway in tumor cell proliferation would provide a useful basis for therapy of neoplasms. Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of dNTP's for DNA synthesis. Further, ribonucleotide reductase is composed of two non-identical protein subunits (non-heme iron and effector-binding subunits) which can be specifically and independently inhibited. As a result, combinations of drugs specifically directed at each of the subunits of ribonucleotide reductase have been shown to cause synergistic inhibition of L1210 cell growth in culture and synergistic cell kill. This approach offers a novel basis for the design of combination chemotherapy.

Animals↗
PubMed1990

Expression, purification, biochemical characterization and inhibition of recombinant Plasmodium falciparum aldolase.

The energy metabolism of the blood stage form of the human malaria parasite Plasmodium falciparum is adapted to the host cell. Like erythrocytes, P. falciparum merozoites lack a functional citric acid cycle. Generation of ATP depends therefore fully on the glycolytic pathway. Aldolase is a key enzyme of this pathway and a high degree of sequence diversity between parasite and host makes it a potential drug target. We have expressed the enzyme in its tetrameric form in Escherichia coli and the catalytic constants Vmax and Km of the recombinant enzyme correspond to the constants of parasite-derived aldolase. Rabbit antibodies against the recombinant P. falciparum aldolase inhibit the natural enzyme and no cross-reaction with human aldolase is detectable. Both the recombinant and the natural protein bind to the cytosolic domain of the band 3 membrane protein in vitro. A 19-residue synthetic peptide corresponding to the sequence of the binding domain of band 3 is an inhibitor when included in the binding assay. In addition, this peptide inhibits the catalytic activity of recombinant P. falciparum aldolase when assayed in a buffer system devoid of anions such as chloride or phosphate. The band 3-derived peptides compete with the aldolase substrate fructose-1,6-diphosphate for binding, suggesting that both reagents have a high affinity for the substrate pocket. A similar sequence motif exists in P. falciparum actin II. A 19-residue peptide corresponding to this sequence is also an inhibitor which could suggest that the P. falciparum aldolase can associate with the cytoskeleton of the parasite or of the host.

Amino Acid Sequence↗
PubMed1986

A histochemical examination of the metabolic profiles of rat ventral tegmental area and substantia nigra arterioles.

To determine the metabolic profiles of arterioles of the rat ventral tegmental area and zona compacta and zona reticulata of the substantia nigra (SN), the distribution of selected enzymes, or by-products, of key metabolic pathways were examined histologically. Arterioles of all three regions expressed the enzymes required for aerobic and anaerobic metabolism. However, the relative abundance of the enzymes and byproducts suggests a lower metabolic capacity for the SN than the ventral tegmentum, while lipid catabolism in both regions appears non-operative. Moreover, the larger ventral tegmental arterioles possess a greater potential for nucleic acid and protein synthesis. Together, these results suggest the larger ventral tegmental arterioles possess a greater capacity for proliferation and repair.

Animals↗
PubMed1994

Enhancing central and peripheral insulin activity as a strategy for the treatment of endogenous depression--an adjuvant role for chromium picolinate?

Depression is often associated with insulin resistance, owing to cortisol overproduction; conversely, many studies suggest that diabetics are at increased risk for depression. Recent evidence indicates that insulin is transported through the blood-brain barrier and influences brain function via widely distributed insulin receptors on neurons. These receptors are particularly dense on catecholaminergic synaptic terminals, and, while effects are variable dependent on brain region, several studies indicate that insulin promotes central catecholaminergic activity, perhaps by inhibiting synaptic re-uptake of norepinephrine. Additionally, it is well known that insulin enhances serotonergic activity in increasing blood-brain barrier transport of tryptophan. Since impaired monoaminergic activity in key brain pathways is believed to play an etiological role in depression, techniques which promote effective insulin activity, both centrally and peripherally, may be therapeutically beneficial in this disorder. This may rationalize anecdotal reports of improved mood in clinical depressives and diabetics receiving the insulin-sensitizing nutrient chromium picolinate. This nutrient, perhaps in conjunction with other insulin-sensitizing measures such as low-fat diet and aerobic exercise training (already shown to be beneficial in depression), should be tested as an adjuvant for the treatment and secondary prevention of depression.

Brain↗
PubMed1996

Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells.

Valproic acid (VPA) is an anticonvulsant drug with demonstrated efficacy in the treatment of mania. In the present study, we found that chronic exposure of rat C6 glioma cells to VPA induces a coordinate decrease in multiple components of the beta-adrenergic receptor- (beta-AR) coupled cyclic adenosine 3'-5'monophosphate (cAMP) generating system. Chronic VPA decreased the number of beta-ARs in a time- and concentration-dependent manner; the decrease of beta-ARs was largely beta 1-AR selective and affected beta-ARs in both the high- and low-affinity states. Chronic VPA also significantly attenuated receptor- and postreceptor-stimulated cAMP production, [3H]forskolin binding sites, immunolabeling of G alpha s 45, and cholera toxin catalyzed ADP-ribosylation of G alpha s 52 and 45. Although the precise underlying mechanisms remain to be elucidated, such profound long-term changes in the functioning of this key signaling pathway may help explain the antimanic effects of chronic VPA treatment and are worthy of further study.

Adenylyl Cyclases↗
PubMed2004

High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity.

The molecular chaperone heat-shock protein 90 (HSP90) plays a key role in the cell by stabilizing a number of client proteins, many of which are oncogenic. The intrinsic ATPase activity of HSP90 is essential to this activity. HSP90 is a new cancer drug target as inhibition results in simultaneous disruption of several key signaling pathways, leading to a combinatorial approach to the treatment of malignancy. Inhibitors of HSP90 ATPase activity including the benzoquinone ansamycins, geldanamycin and 17-allylamino-17-demethoxygeldanamycin, and radicicol have been described. A high-throughput screen has been developed to identify small-molecule inhibitors that could be developed as therapeutic agents with improved pharmacological properties. A colorimetric assay for inorganic phosphate, based on the formation of a phosphomolybdate complex and subsequent reaction with malachite green, was used to measure the ATPase activity of yeast HSP90. The Km for ATP determined in the assay was 510+/-70 microM. The known HSP90 inhibitors geldanamycin and radicicol gave IC(50) values of 4.8 and 0.9 microM respectively, which compare with values found using the conventional coupled-enzyme assay. The assay was robust and reproducible (2-8% CV) and used to screen a compound collection of approximately 56,000 compounds in 384-well format with Z' factors between 0.6 and 0.8.

Adenosine Triphosphatases↗
PubMed2006

Challenges and prospects for the establishment of embryonic stem cell lines of domesticated ungulates.

Embryonic stem (ES) cell lines provide an invaluable research tool for genetic engineering, developmental biology and disease models. These cells can be maintained indefinitely in culture and yet maintain competence to produce all the cells within a fetus. While mouse ES cell lines were first established over two decades ago and primate ES cells in the 1990 s, validated ES cell lines have yet to be established in ungulates. Why competent, pluripotent ES cells can be established from certain strains of mice and from primates, and not from cows, sheep, goats or pigs is an on-going topic of interest to animal reproduction scientists. The identification of appropriate stem cell markers, functional cytokine pathways, and key pluripotency-maintaining factors along with the release of more comprehensive bovine and porcine genomes, provide encouragement for establishment of ungulate ES cell lines in the near future.

Animals↗
PubMed2004

RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis.

The emergence of the molecular triad osteoprotegerin (OPG)/Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL) has helped elucidate a key signalling pathway between stromal cells and osteoclasts. The interaction between RANK and RANKL plays a critical role in promoting osteoclast differentiation and activation leading to bone resorption. OPG is a soluble decoy receptor for RANKL that blocks osteoclast formation by inhibiting RANKL binding to RANK. The OPG/RANK/RANKL system has been shown to be abnormally regulated in several malignant osteolytic pathologies such as multiple myeloma [MM, where enhanced RANKL expression (directly by tumour cells or indirectly by stromal bone cells or T-lymphocytes)] plays an important role in associated bone destruction. By contrast, production of its endogenous counteracting decoy receptor OPG is either inhibited or too low to compensate for the increase in RANKL production. Therefore, targeting the OPG/RANK/RANKL axis may offer a novel therapeutic approach to malignant osteolytic pathologies. In animal models, OPG or soluble RANK was shown both to control hypercalcaemia of malignancy and the establishment and progression of osteolytic metastases caused by various malignant tumours. To this day, only one phase I study has been performed using a recombinant OPG construct that suppressed bone resorption in patients with multiple myeloma or breast carcinoma with radiologically confirmed bone lesions. RANK-Fc also exhibits promising therapeutic effects, as revealed in animal models of prostate cancer and multiple myeloma. If the animal results translate to similar clinical benefits in humans, using RANK-Fc or OPG may yield novel and potent strategies for treating patients with established or imminent malignant bone diseases and where standard therapeutic regimens have failed.

Antineoplastic Agents↗
PubMed2005

Negative and positive regulation of HIF-1: a complex network.

Hypoxia inducible factor-1 (HIF-1) is as a key transcriptional mediator of the hypoxic response in eukaryotic cells, regulating the expression of a myriad of genes involved in oxygen transport, glucose uptake and glycolysis and angiogenesis. Deregulation of HIF-1 activity occurs in many human cancers, usually at the level of the HIF-1alpha subunit. HIF-1 is regulated by a variety of mechanisms including transcription, translation post-translational modification, protein-protein interaction and degradation. Our understanding of the key signalling pathways that regulate HIF-1 has significantly progressed in recent years and has highlighted the potential for targeting the HIF-1 pathway as a basis for the development of new cancer therapies.

Animals↗
PubMed2004

Androgen suppresses PML protein expression in prostate cancer CWR22R cells.

The ability of PML to modulate key suppressive pathways in tumor cells suggests that PML may act as a tumor suppressor. The detailed mechanism of how PML functions in prostate cancer progression, however, remains unknown. Here we demonstrate that in the presence of androgen, PML protein expression can be suppressed in CWR22R prostate cancer cells. Further studies reveal that PML can selectively suppress AR transactivation and PML protein expression positively correlates with increased p21 protein level and enhances p53 transcription ability in CWR22R cells. We also found that PML strongly inhibits CWR22R cell colony formation, while PML siRNA enhances AR activity and CWR22R cell colony formation. Together our results suggest that PML may suppress prostate cancer cell growth by inhibiting AR transactivation and/or enhancing p53 activity.

Androgens↗
PubMed2004

Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis.

Hepatic stellate cells (HSCs) and transdifferentiated myofibroblasts are the principal producers of excessive extracellular matrix in liver fibrosis and cirrhosis. Activation of HSC is regulated by several cytokines and growth factors, including platelet-derived growth factor B-chain (PDGF-B), a potent mitogen for HSC, and overexpressed during hepatic fibrogenesis. Previous studies showed that MAPK and phosphatidylinositol 3' kinase are key signaling pathways involved in PDGF-induced stimulation of HSC. Based on the involvement of PDGF-B in fibrogenesis, reducing ligand stimulation of proliferative cytokine- or growth factor receptors interfering with receptor signaling therefore presents an interesting strategy for hepatic fibrosis prevention or interruption. We therefore generated an adenoviral vector serotype 5 (Ad5) expressing an antisense mRNA of the PDGF B-chain (Ad5-CMV-asPDGF) for application in an experimentally induced liver fibrogenesis model. The transgene clearly showed the ability to down-regulate endogenous PDGF B-chain and PDGFRbeta mRNA in culture-activated HSC and rat livers. The asPDGF mRNA also attenuates experimental liver fibrogenesis indicated by reduced levels of alpha-SMA and collagen type I expression.

Actins↗
PubMed2004

Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3.

Prostaglandin-induced cAMP elevation restrains key signaling pathways in platelet activation including Ca(2+) mobilization and integrin alphaIIbbeta3 affinity regulation. We investigated how cAMP turnover by cyclic nucleotide phosphodiesterases (PDEs) regulates platelet activation. In washed human platelets, inhibition of all PDEs and also specific inhibition of PDE3 but not of PDE5 suppressed thrombin-induced Ca(2+) responses. The effect of general PDE or PDE3 inhibition was accompanied by an increase in cAMP, and potentiated by Gs stimulation with prostaglandin E(1). In platelet-rich plasma, general or PDE3 inhibition blocked platelet aggregation, integrin activation, secretion and thrombin generation. In contrast, inhibition of PDE5 increased the cGMP level, but without significant influence on aggregation, alphaIIbbeta3 activation, secretion or procoagulant activity. Nitroprusside (nitric oxide) potentiated the effect of PDE5 inhibition in elevating cGMP. Nitroprusside inhibited platelet responses, but this was accompanied by elevation of cAMP. Together, these results indicate that cAMP is persistently formed in platelets, independently of agonist-induced Gs stimulation. PDE3 thus functions to keep cAMP at a low equilibrium level and reduce the cAMP-regulated threshold for platelet activation. This crucial role of PDE3, but not of PDE5, extends to all major processes in thrombus formation: assembly of platelets into aggregates, secretion of autocrine products, and procoagulant activity.

3',5'-Cyclic-AMP Phosphodiesterases↗