Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose ...producing large volumes of lactate even in the presence of oxygen, this process is known as “Warburg effect or aerobic glycolysis.” As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.
Background and Purpose
Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown.
Experimental Approach
To address ...this, TGR (mRen2)27 rats (angiotensin II‐dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry.
Key Results
MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver‐specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis.
Conclusion and Implications
Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver‐derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.
ABSTRACT
We study the star formation rate (SFR), stellar mass (M⋆), and the gas metallicity (Z) for 4636 galaxy pairs using the Galaxy And Mass Assembly (GAMA) survey. Our galaxy pairs lie in a ...redshift range of 0 < z < 0.35, mass range of 7.5 < log(M⋆/M⊙) < 11.5 and ΔV < 1000 km s−1. We explore variations in SFR and Z from three point of views: multiplicity, pair separation, and dynamics. We define multiplicity as the number of galaxies paired with a single galaxy, and analyzed for the first time variations in SFR and Z for both, single pairs and pairs with higher multiplicity. For the latter, we find SFR enhancements from 0.025–0.15 dex, that would shift the M–SFR relation of single pairs by 27${{\ \rm per\ cent}}$ to higher SFRs. The effect of Z, on the other hand, is of only 4${{\ \rm per\ cent}}$. We analyse the most and least massive galaxy of major/minor pairs as a function of the pair separation. We define major pairs those with mass ratios of 0.5 < M1/M2 < 2, while pairs with more discrepant mass ratios are classified as minor pairs. We find SFR enhancements of up to two and four times with respect to their control sample, for major and minor pairs. For the case of Z, we find decrements of up to 0.08 dex for the closest pairs. When we focus on dynamics, Z enhancements are found for minor pairs with high-velocity dispersion $(\sigma _p \gt 250 \,\, \mathrm{km\, s ^{-1}})$ and high multiplicity.
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape ...phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent
-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Fire has been an integral part of ecosystem functioning in many biomes for a long time, but the increased intensity and frequency of wildfires often affect plant diversity and carbon storage. ...Prescribed burning is one of the alternatives to forest fuel management where the fire is controlled and carried out under a determined set of weather conditions and objectives. The effect of prescribed burning on plant diversity and carbon (C) storage has not been studied widely. The objective of this study was to evaluate the effect of prescribed burning on plant diversity indices, biomass stocks, and soil C storage in the tropical highland forests of Southern Mexico. We assessed plant diversity and carbon stocks at 21 sampling sites: seven with prescribed burning, seven non-burning, and seven with wildfires. We calculated tree biodiversity indices, stand structural properties, and species composition among burning treatments. We quantified C stocks in vegetation biomass by using an allometric equation and forest litter by direct sampling. We analyzed 252 soil samples for soil organic C content and other properties. The results showed that the biodiversity index was higher in sites with prescribed burning (Shannon index, H = 1.26) and non-burning (H = 1.14) than in wildfire sites (H = 0.36). There was a greater similarity in plant species composition between non-burning and prescribed burning sites compared to wildfire sites. Prescribed burning showed a positive effect on soil carbon storage (183.9 Mg C ha−1) when compared to wildfire (144.3 Mg C ha−1), but the difference was not statistically significant (p > 0.05) in biomass stocks. Prescribed burning in this study conserved plant diversity as well as soil carbon stocks compared to non-burning, the opposite of what we found in wildfires.
ABSTRACT
We investigate several panchromatic scaling relations (SRs) for the dwarf irregular galaxy NGC 1569 using Integral Field Unit (IFU) data from the Metal-THINGS Survey. Among the spatially ...resolved properties analysed, we explore SRs between the stellar mass, SFR, molecular gas, total gas, baryonic mass, gas metallicity, gas fraction, SFE, and effective oxygen yields. Such multiwavelength SRs are analysed at a spatial resolution of 180 pc, by combining our IFU observations with data from the surveys THINGS, CARMA, and archival data from DustPedia. Although we recover several known relations, our slopes are different to previously reported ones. Our star formation main sequence, Kennicutt–Schmidt (KS), and molecular KS relations show higher SFRs, lower scatter, and higher correlations, with steeper (1.21), and flatter slopes (0.96, 0.58), respectively. The shape of the SRs including metallicity, stellar mass, and gas fraction are flat, with an average value of 12 + log(O/H) ∼ 8.12 dex. The baryonic mass versus effective oxygen yields, and the stellar, gas and baryonic mass versus SFE show higher dispersions and lower correlations. Since we use the dust mass as a tracer of gas mass, we derive the dust-to-gas ratio and the CO luminosity-to-molecular gas mass conversion factors, showing differences of 0.16 and 0.95 dex for the total and molecular gas surface density, respectively, in comparison to previously reported values. We use a self-regulated feedback model to conclude that stellar feedback plays an important role generating outflows in NGC 1569.
Context.
NGC 6946, also known as the “Fireworks Galaxy”, is an unusual galaxy that hosts a total of 225 supernova remnant (SNR) candidates, including 147 optically identified with high S
II
/H
α
...line ratios. In addition, this galaxy shows prominent H
I
holes, which have been analyzed in previous studies. Indeed, the connection between SNRs and H
I
holes along with their physical implications in the surrounding gas are worthy of attention.
Aims.
This paper explores the connection between the SNRs and the H
I
holes, including an analysis of their physical link to observational optical properties inside and around the rims of the holes, using new integral field unit (IFU) data from the Metal-THINGS survey.
Methods.
We present an analysis combining previously identified H
I
holes, SNR candidates, and new integral field unit (IFU) data from Metal-THINGS of the spiral galaxy NGC 6946. We analyzed the distributions of the oxygen abundance, star formation rate surface density, extinction, ionization, and diffuse ionized gas, as well as the Baldwin-Phillips-Terlevich classification throughout the galaxy.
Results.
By analyzing the optical properties of the 121 previously identify H
I
holes in NGC 6946 in detail, we find that the SNRs are concentrated at the rims of the H
I
holes. Furthermore, our IFU data show that the star formation rate and extinction are enhanced at the rims of the holes. To a lesser degree, the oxygen abundance and ionization parameter show hints of enhancement on the rims of the holes. Altogether, this provides evidence of induced star formation taking place at the rims of the holes, whose origin can be explained by the expansion of superbubbles created by multiple supernova explosions in large stellar clusters dozens of Myr ago.
Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic ...hypertensive (mREN2)27 rats.
Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry.
Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II but not angiotensin-(1-7) upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney.
RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.
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