Understanding Long COVID; Mitochondrial Health and Adaptation-Old Pathways, New Problems.

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery.

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing.

Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a "cytokine storm" and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response.

Immune-Modulating Drug MP1032 with SARS-CoV-2 Antiviral Activity In Vitro: A potential Multi-Target Approach for Prevention and Early Intervention Treatment of COVID-19.

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm.

Consensus-interferon and platelet-derived growth factor adversely regulate proliferation and migration of Kaposi's sarcoma cells by control of c-myc expression.

Platelet-derived growth factor-B (PDGF-B) is a potent paracrine-acting mitogen in Kaposi's sarcoma (KS) lesions. Interferon-alpha is widely used for clinical treatment of KS. Here we show that platelet-derived growth factor-B activates proliferation and migration of cultivated AIDS-KS spindle cells whereas interferon-alpha acts as an inhibitor.

Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice.

We examined the dynamics of removal from circulation, tissue distribution, and persistence of phosphorothioate oligodeoxynucleotides (S-ODN) anti-tumor-necrosis-factor and a control of random sequence (randomer) in mice. After intravenous injection, the majority (96%) of S-ODN cleared rapidly from the circulation in the first two phases. In the first phase, 37.

Changes in the expression of synapsin I and II messenger RNA during postnatal rat brain development.

Synapsin Ia, Ib, IIa, and IIb are neuronal phosphoproteins, which are supposed to play a role in the short-term regulation of neurotransmitter release. Besides a high degree of homology among the four synapsin subtypes, there are structural differences in the 3'end of their coding region. Here we present the first extensive study of the expression of their gene transcripts by using in situ hybridization and northern blot analysis.

Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides.

Transforming growth factors-beta 1 and -beta 2 (TGF-beta 1 and -beta 2) are important growth-regulatory proteins for astroglial neoplasms. We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-beta 1-mRNA and TGF-beta 2-mRNA. TGF-beta 1-S-ODNs inhibited cell proliferation in 5 of 12 gliomas, whereas TGF-beta 2-S-ODNs reduced the cell proliferation in all glioma cell lines, compared to nonsense-S-ODN-treated and S-ODN-untreated cells as controls.

Antisense-mediated inhibition of protein synthesis : rational drug design, pharmacokinetics, intracerebral application, and organ uptake of phosphorothioate oligodeoxynucleotides.

There is hardly any class of drugs for which the term "ratronal drug design" is more appropriate than for the currently developing antisense therapeutics. The specrficlty of the hybridization reaction and the surprisingly efficient uptake of synthetrc oligonucleotide derivatives provide a new class of selective protein synthesis inhibitors. Concurrently with the development of the antisense technology, elucidation of the pathogenetic role of mdrvrdual proteins for certain diseases is rapidly progressing, most notably in the fields of cancer research and virology.

Transforming growth factor-beta-mediated regulation of human peripheral blood mononuclear cell proliferation as detected with phosphorothioate antisense oligodeoxynucleotides.

Transforming growth factor-beta (TGF-beta) is a potent cytokine that has influence upon immunosuppressive as well as proinflammatory processes. In this context we have investigated the role of endogenous TGF-beta in human peripheral blood mononuclear cells (PBMCs) by TGF-beta 1 phosphorothioate antisense oligodeoxynucleotides (TGF-beta 1-S-ODNs). In short-term cultures (up to 3 days), TGF-beta 1-S-ODNs-treated, interleukin 2-activated PBMCs displayed a growth advantage (up to 148%) compared to nonsense or untreated controls as measured by cell counting and [3H]thymidine incorporation.

Inhibition of memory consolidation after active avoidance conditioning by antisense intervention with ependymin gene expression.

A rapid increase in ependymin mRNA expression demonstrated by semiquantitative in situ hybridization after avoidance conditioning on goldfish suggested a molecular demand for newly synthesized ependymin translation product. To inhibit de novo synthesis of ependymin molecules without interference with preexisting ones, 18 mer anti-ependymin mRNA-phosphorothioate oligodeoxynucleotides (S-ODNs) were injected into the perimeningeal brain fluid before active avoidance training. S-ODN-injected animals learned the avoidance response; however, they were amnesic in the test.

Learning-induced expression of meningeal ependymin mRNA and demonstration of ependymin in neurons and glial cells.

The turnover of a CNS-specific cell adhesion glycoprotein, ependymin, has earlier been found to increase during periods of neuronal plasticity. Here, ependymin mRNA expression was analyzed by semiquantitative in situ hybridization in goldfish. Learning of an active avoidance response resulted in a significant increase in ependymin mRNA expression 20 min to 4 h after acquisition of the task.

Effects of transforming growth factor-beta 1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells.

Transforming growth factor-beta 1 (TGF-beta 1) as a potent modulator of cell-extracellular matrix (ECM) interactions may be related to poorly understood ECM-associated features of glioblastomas, such as diffuse brain invasion, rarity of extracranial metastasis and marked ECM production in vitro. We therefore studied TGF-beta 1 expression in glioblastoma biopsy specimens and cell lines by using reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were also examined by Western blotting and immunocytochemistry.

Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock.

Light-induced phase shifts of circadian rhythmic locomotor activity are associated with the expression of c-Jun, JunB, c-Fos and FosB transcription factors in the rat suprachiasmatic nucleus, as shown in the present study. In order to explore the importance of c-Fos and JunB, the predominantly expressed AP-1 proteins for the phase-shifting effects of light, we blocked the expression of c-Fos and JunB in the suprachiasmatic nucleus of male rats, housed under constant darkness, by intracerebroventricular application of 2 microliters of 1 mM antisense phosphorothioate oligodeoxynucleotides (ASO) specifically directed against c-fos and junB mRNA. A light pulse (300 lux for 1 h) at circadian time 15 induced a significant phase shift (by 125 +/- 15 min) of the circadian locomotor activity rhythm, whereas application of ASO 6 h before the light pulse completely prevented this phase shift.

Reversal of multiple drug resistance in vitro by phosphorothioate oligonucleotides and ribozymes.

In the present study we investigated the effectiveness of 14, 15 and 18 nucleotide antisense phosphorothioate oligonucleotides (S-ODNs) directed to four different regions of the published mdr-1 gene sequence to reduce the level of mdr-1 gene product (p170, P-glycoprotein) and its function in the over-expressing cell lines Lo-VoDxR, S180DxR and KBChR8-5. The highest efficiency in reduction of multiple drug resistance was obtained at a concentration of 2 microM. In proliferation assays a growth reduction of 50% was observed after exposure of doxorubicin-resistant cells to S-ODN3.

Differential expression of c-jun, junB and junD in rat hippocampal slices.

The temporal expression pattern of jun genes was studied in the hippocampal slice preparation. Slices were kept either in a physiological Ringer solution or a modified medium, substituting calcium (Ca2+) by magnesium (Mg2+). All three jun genes were expressed in a circumscribed, independent fashion with respect to distribution, intensity and time course.

Design and application of antisense oligonucleotides in cell culture, in vivo, and as therapeutic agents.

1. Synthetic oligonucleotides can inhibit the expression of a gene in a sequence specific manner on the transcriptional and translational level. These molecules are usually referred to as antisense oligonucleotides.

The role of Jun transcription factor expression and phosphorylation in neuronal differentiation, neuronal cell death, and plastic adaptations in vivo.

1. To investigate the role of the Jun transcription factors in neuronal differentiation, programmed neuronal cell death, and neuronal plasticity, we used phosphorothioate oligodeoxynucleotides (S-ODN) to inhibit selectively the expression of c-Jun, JunB, and JunD. 2.

Sequence-specific impairment of learning by c-jun antisense oligonucleotides.

Hybridization studies revealed a differential accumulation of c-jun and jun B mRNA in the hippocampus and cerebral cortex of rats trained on a foot-shock-motivated brightness discrimination. Supposing that early gene expression is functionally significant for plastic changes in the brain, we used antisense phosphorothioate oligodeoxynucleotides (S-ODN) in vivo to study effects of specific inhibition of c-jun and jun B gene expression on learning and memory formation in rat brain. Discrimination performance of rats was impaired after intrahippocampal injection of anti-c-jun S-ODN but not of anti-jun B S-ODN.

Inhibition of p185c-erbB-2 proto-oncogene expression by antisense oligodeoxynucleotides down-regulates p185-associated tyrosine-kinase activity and strongly inhibits mammary tumor-cell proliferation.

The c-erbB-2 proto-oncogene codes for a 185-kd putative growth factor receptor that is highly homologous to but distinct from the epidermal growth factor (EGF) receptor. Amplification and overexpression of c-erbB-2 occurs in a number of human tumors, in some of which it is a negative prognostic factor. This study investigates the possibility of inhibiting tumor-cell proliferation by blocking c-erbB-2 expression in the human mammary carcinoma cell line SK-Br-3 using chemically modified antisense oligodeoxynucleotides.

Reduction of erbB2 gene product in mamma carcinoma cell lines by erbB2 mRNA-specific and tyrosine kinase consensus phosphorothioate antisense oligonucleotides.

A considerable reduction of up to 75% at the protein level of the erbB2 gene product was observed using phosphorothioate antisense oligonucleotides directed against specific sequences of the erbB2 mRNA. Antisense oligonucleotides used were the 14-mer (translation start region) and the 17-mer (3' translated region) all-phosphorothioate oligonucleotides (S-ODNs). Sense or random sequences were used as a control.

Developmental expression of the transcription factor zif268 in rat brain.

Changes in the distribution pattern of mRNA encoding the zif268 transcription factor (also referred to as NGFI-A, Krox-24 or EGR-1) were investigated by in situ hybridization histochemistry during postnatal rat brain development. Marked changes in zif268 expression patterns were seen in particular in the cerebral cortex and the hippocampal formation during the first 3 wk. In the 1st postnatal week, zif268 mRNA levels were highest in the corpus striatum and the piriform cortex.

Changes of synapsin I messenger RNA expression during rat brain development.

Synapsin I is a synaptic phosphoprotein that is involved in the short-term regulation of neurotransmitter release. In this report we present the first extensive study of the developmental expression of its corresponding messenger ribonucleic acid (mRNA) by in situ hybridization and northern blot analysis in rat brain. Synapsin I mRNA showed pronounced differences in expression in different brain regions during postnatal development.

Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules.

The cell lines of three neuroectodermal tumors, two glioblastomas (HTZ-146, HTZ-17) and one melanoma (HTZ-19) were established and screened for the expression of growth factors by northern blotting and immunochemical methods. All three tumors were positive for platelet-derived growth factor- (PDGF-) A-, -B-chain, and basic fibroblast growth factor (bFGF) messenger ribonucleic acids. Cultured cells as well as original tumor material were also positive for PDGF-AA-, PDGF-BB, and bFGF protein, as shown by immunochemistry.