[Exercise and diet in colorectal cancer prevention and therapy]. / Körperliche Aktivität und Ernährung in der Prävention und Therapie des Kolorektalen Karzinoms.

INTRODUCTION: Colorectal carcinoma is a leading cause of cancer diseases in Europe. Due to modern therapies survival rate is increasing. Nevertheless, cancer and its treatment is associated with significant morbidity. Physical activity appears as having a positive impact on cancer risk, as well as, reducing peri- and postoperative morbidity and mortality. METHODS: We searched pubmed and googlescholar for English- and German-language studies from inception to September 2022. The search terms physical activity, colon cancer, colorectal cancer, diet, survivors. prehabilitation, postoperative morbidity, quality of life and outcome were used. Guidelines of national advisory commmittees and Cochrane reviews were included. RESULTS: There is considerable evidence that physical activity is associated with reduced risk of colon cancer, epigenetic mechanisms play a central role in connection. Different studies showed a risk reduction of 12 to 27 percent. A prehabilitation programme consisting of exercise, nutritional intervention, and psychosocial rehabilitation can reduce peri- and postoperative complications. Aerobic exercise and strength training can improve survival rates and overall mortality. However, a causal relationship between nutritional treatment and cancer related symptoms (e.g. fatigue) is missing. CONCLUSION: There is a wide range of scientific papers on the influence of physical activity and nutrition; nevertheless, its influence on the various stages of colorectal disease are not addressed adequately. Recommendations concerning prehabilitation and tertiary prevention can only be given on the basis of heterogeneous trial data.

[Bowel preparation in patients with Diabetes mellitus: Development of a procedure model]. / Koloskopievorbereitung bei Patienten mit Diabetes mellitus: Entwicklung einer Handlungsempfehlung.

BACKGROUND: Adequate bowel preparation prior to colonoscopy is the key factor for high quality preparation for colonoscopy. Inadequate preparation can result in prolonged procedure time, incomplete colonoscopy and an increased risk of procedural adverse events. Diabetes mellitus has been identified as a predictor of inadequate colonoscopy bowel preparation. Currently, standard recommendations for diabetes patients before colonoscopy are missing. METHODS: This review is based on a selective literature search in PubMed and Google Scholar carried out in June 2021. Systematic reviews, guidelines, expert opinions, and recommendations from German and international societies were also considered. RESULTS: The currently available preparations comprise two different groups: High-, medium- and low- volume polyethylene glycol (PEG) preparations and hyperosmotic agents. So far, a couple of reviews tried to identify outcome related differencies. Results are heterogeneous. In practise, preparation agents and timing of preparation as well as a thorough patient information before the preparation process are considered the most relevant items. In diabetes patients, preinterventional dietary recommendations are of paramount importance. CONCLUSION: Split dosing of PEG preparations are recommended in diabetes patients with expected motility disorders. Extensive counseling about preparation intake and dietary recommendations should be offered.

Severe Hyperglycemia Due to Protein Kinase Inhibitor Therapy in a Patient With Poorly Controlled Diabetes Mellitus.

The efficacy and safety of zanubrutinib, a highly selective next-generation Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia and lymphoplasmocytoides immunocytoma seems favorable. Adverse events comprise neutropenia, thrombocytopenia, infection, anemia, and atrial fibrillation. This report describes a 75-year-old man suffering from polydipsia, polyuria, and blurred vision for 10 days. He was diagnosed with lymphoplasmocytoides immunocytoma in 2003. After various therapies, he was started on zanubrutinib in October 2022. A diagnosis of diabetes mellitus had never been established before. On arrival in the emergency department, his plasma glucose was 37.2 mmol/L (671 mg/dL) and glycated hemoglobin (HbA1c) was 14.2%. Circulating antibodies showed positivity for glutamic acid decarboxylase (GAD-65), and his C-peptide level was 1.3 nmol/L (normal range, 0.37-1.47 nmol/L), equivalent to 3.9 ng/mL (normal range 1.1-5.0 ng/mL). From the patient's medical history, it became obvious that the metabolic situation had been problematic for many years, and that diabetes could have been taken into account at least in the summer of 2020 when HbA1c was 6.7%. In patients on tyrosine kinase inhibitors, careful assessment of glycemic control (monitoring HbA1c and blood glucose levels periodically even for nondiabetic patients) is recommended to prevent a major diabetic emergency.

Paleolithic occupation of arid Central Asia in the Middle Pleistocene.

Central Asia is positioned at a crossroads linking several zones important to hominin dispersal during the Middle Pleistocene. However, the scarcity of stratified and dated archaeological material and paleoclimate records makes it difficult to understand dispersal and occupation dynamics during this time period, especially in arid zones. Here we compile and analyze paleoclimatic and archaeological data from Pleistocene Central Asia, including examination of a new layer-counted speleothem-based multiproxy record of hydrological changes in southern Uzbekistan at the end of MIS 11. Our findings indicate that Lower Palaeolithic sites in the steppe, semi-arid, and desert zones of Central Asia may have served as key areas for the dispersal of hominins into Eurasia during the Middle Pleistocene. In agreement with previous studies, we find that bifaces occur across these zones at higher latitudes and in lower altitudes relative to the other Paleolithic assemblages. We argue that arid Central Asia would have been intermittently habitable during the Middle Pleistocene when long warm interglacial phases coincided with periods when the Caspian Sea was experiencing consistently high water levels, resulting in greater moisture availability and more temperate conditions in otherwise arid regions. During periodic intervals in the Middle Pleistocene, the local environment of arid Central Asia was likely a favorable habitat for paleolithic hominins and was frequented by Lower Paleolithic toolmakers producing bifaces.

Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner.

Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular, the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, in our analyses, within a timescale of minutes, mitochondrial respiration and glycolysis were hampered, which occurred in a pH-independent manner. Using metabolomics, an accumulation of glucose and numerous amino acids, including branched chain amino acids, was observed. Metabolomic tracking of 15N-labeled ammonia showed rapid incorporation of 15N into glutamate and glutamate-derived amino acids. Downregulating human GLUD2 [encoding mitochondrial glutamate dehydrogenase 2 (GDH2)], inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Metabolomic tracking of 13C-glutamine showed that hyperammonemia can inhibit anaplerosis of tricarboxylic acid (TCA) cycle intermediates. Contrary to its classical anaplerotic role, we show that, under hyperammonemia, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate, which efficiently and rapidly inhibits the TCA cycle. Overall, we propose a critical GDH2-dependent mechanism in HE models that helps to remove ammonia, but also impairs energy metabolism in mitochondria rapidly.

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein.

The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD+-dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is present in the cytosol and predominantly localizes to centrosomes. Confocal spinning disk microscopy revealed that SIRT4 is found during the cell cycle dynamically at centrosomes with an intensity peak in G2 and early mitosis. Moreover, SIRT4 precipitates with microtubules and interacts with structural (α,ß-tubulin, γ-tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components as detected by co-immunoprecipitation and mass spectrometric analyses of the mitotic SIRT4 interactome. Overexpression of SIRT4 resulted in a pronounced decrease of acetylated α-tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(ΔN28), which is unable to translocate into mitochondria, delayed mitotic progression and reduced cell proliferation. This study extends the functional roles of SIRT4 beyond mitochondrial metabolism and provides the first evidence that SIRT4 acts as a novel centrosomal/microtubule-associated protein in the regulation of cell cycle progression. Thus, stress-induced SIRT4 may exert its role as tumor suppressor through mitochondrial as well as extramitochondrial functions, the latter associated with its localization at the mitotic spindle apparatus.

Gαi3 signaling is associated with sexual dimorphic expression of the clock-controlled output gene Dbp in murine liver.

The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). However, the signaling mechanism mediating CREB-dependent regulation of DBP expression in the peripheral clock remains elusive. In this study, we examined the role of the GPCR (G-protein-coupled receptor)/Gαi3 (Galphai3) controlled cAMP-CREB signaling pathway in the regulation of hepatic expression of core clock and clock-regulated genes, including Dbp. Analysis of circadian gene expression revealed that rhythmicity of hepatic transcript levels of the majority of core clock (including Per1) and clock-regulated genes were not affected by Gαi3 deficiency. Consistently, the period length of primary Gαi3 deficient tail fibroblasts expressing a Bmal1-Luciferase reporter was not affected. Interestingly, however, Gαi3 deficient female but not male mice showed a tendentiously increased activation of CREB (nuclear pSer133-CREB) accompanied by an advanced peak in Dbp gene expression and elevated mRNA levels of the cytochrome P450 family member Cyp3a11, a target gene of DBP. Accordingly, selective inhibition of CREB led to a strongly decreased expression of DBP and CYP3A4 (human Cyp3a11 homologue) in HepG2 liver cells. In summary, our data suggest that the Gαi3-pCREB signalling pathway functions as a regulator of sexual-dimorphic expression of DBP and its xenobiotic target enzymes Cyp3a11/CYP3A4.

SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy.

The stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD+-dependent manner and is implicated in cellular senescence and aging. Here we reveal a novel function of SIRT4 in mitochondrial morphology/quality control and regulation of mitophagy. We report that moderate overexpression of SIRT4, but not its enzymatically inactive mutant H161Y, sensitized cells to mitochondrial stress. CCCP-triggered dissipation of the mitochondrial membrane potential resulted in increased mitochondrial ROS levels and autophagic flux, but surprisingly led to increased mitochondrial mass and decreased Parkin-regulated mitophagy. The anti-respiratory effect of elevated SIRT4 was accompanied by increased levels of the inner-membrane bound long form of the GTPase OPA1 (L-OPA1) that promotes mitochondrial fusion and thereby counteracts fission and mitophagy. Consistent with this, upregulation of endogenous SIRT4 expression in fibroblast models of senescence either by transfection with miR-15b inhibitors or by ionizing radiation increased L-OPA1 levels and mitochondrial fusion in a SIRT4-dependent manner. We further demonstrate that SIRT4 interacts physically with OPA1 in co-immunoprecipitation experiments. Overall, we propose that the SIRT4-OPA1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle.