induction-an-inflammatory-response-primary-hepatocyte-cultures-from

Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice

The liver plays a decisive role in the regulation of systemic inflammation. In chronic kidney disease in particular, the liver reacts in response to the ...

University of Miami Leonard M. Miller School of Medicine

Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological, emerging as a consequence of the tumor's physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an "ion trapping" phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed.

Drug resistance and cellular adaptation to tumor acidic pH microenvironment.

&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x751F;&#x5B58;&#x4F9D;&#x8D56;&#x4E8E;&#x5BF9;&#x9178;&#x6027;&#x6761;&#x4EF6;&#x7684;&#x80BF;&#x7624;&#x5FAE;&#x73AF;&#x5883;&#x7684;&#x9002;&#x5E94;&#x3002;&#x82E5;&#x8981;&#x8C03;&#x67E5;&#x6027;&#x9178;&#x4E2D;&#x6BD2;&#x751F;&#x5B58;&#x7684;&#x6F5C;&#x5728;&#x673A;&#x5236;&#xFF0C;&#x6211;&#x4EEC;&#x5BA1;&#x67E5;&#x4E86;&#x5BF9;&#x4EBA;&#x7C7B;&#x4E73;&#x817A;&#x764C;&#x7EC6;&#x80DE;&#x4F4E; ph &#x503C; (6.7) &#x7684;&#x5F71;&#x54CD;&#x3002;&#x6025;&#x6027;&#x4F4E; pH &#x66DD;&#x5149;&#x6269;&#x6563;&#x7387;&#x964D;&#x4F4E;&#x3001; &#x8BF1;&#x5BFC; G1 &#x7EC6;&#x80DE;&#x5468;&#x671F;&#x902E;&#x6355;&#xFF0C;&#x548C;&#x589E;&#x52A0;&#x7EC6;&#x80DE;&#x8D28;&#x65E0;&#x673A;&#x76D0;&#x3002;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x5206;&#x6790;&#x63ED;&#x793A; ATG5 &#x6C34;&#x5E73;&#x5347;&#x9AD8;&#x548C; BNIP3 &#x4E2D;&#x9178;&#x6761;&#x4EF6;&#x7684;&#x5355;&#x5143;&#x683C;&#xFF0C;&#x8FD9;&#x8868;&#x660E;&#x66B4;&#x9732;&#x4E8E;&#x4F4E; ph &#x503C;&#x7684;&#x5355;&#x5143;&#x683C;&#x53EF;&#x5229;&#x7528;&#x81EA;&#x4F53;&#x541E;&#x566C;&#x4F5C;&#x4E3A;&#x4E00;&#x79CD;&#x751F;&#x5B58;&#x673A;&#x5236;&#x3002;&#x652F;&#x6301;&#x8FD9;&#x4E00;&#x5047;&#x8BBE;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#xFF0C;&#x6025;&#x6027;&#x4F4E; pH &#x523A;&#x6FC0;&#x81EA;&#x566C;&#x6240;&#x754C;&#x5B9A;&#x7684;&#x4FBF;&#x662F; LC3 &#x9633;&#x6027;&#x6613;&#x8D1D;&#x6C34;&#x6CE1;&#xFF0C;&#x53CC;&#x819C;&#x6CE1;&#xFF0C;&#x589E;&#x52A0;&#x548C;&#x51CF;&#x5C11;&#x78F7;&#x9178;&#x5316; AKT &#x548C;&#x6838;&#x7CD6;&#x4F53;&#x86CB;&#x767D; S6&#x3002;&#x503C;&#x5F97;&#x6CE8;&#x610F;&#x7684;&#x662F;&#xFF0C;&#x5927;&#x7EA6; 3 &#x4E2A;&#x6708;&#x66B4;&#x9732;&#x4E8E;&#x4F4E; ph &#x503C;&#x7684;&#x5355;&#x5143;&#x683C;&#x540C;&#x65F6;&#x4FDD;&#x6301;&#x7EC6;&#x80DE;&#x8D28;&#x8868;&#x76AE;&#x8868;&#x578B;&#x6062;&#x590D;&#x5176;&#x589E;&#x6B96;&#x80FD;&#x529B;&#x3002;&#x867D;&#x7136;&#x81EA;&#x566C;&#x662F;&#x901A;&#x5E38;&#x662F;&#x77AC;&#x6001;&#x7684;&#x63D0;&#x5347;&#x81EA;&#x566C;&#x6807;&#x8BB0;&#x4FDD;&#x6301;&#x957F;&#x671F;&#x5728;&#x4F4E; ph &#x503C;&#x6761;&#x4EF6;&#x7684;&#x5355;&#x5143;&#x683C;&#x6240;&#x8BBE;&#x60F3;&#x7684;&#x4FBF;&#x662F; LC3-&#x4E8C;&#x3001; &#x53CC;&#x819C;&#x6CE1;&#x589E;&#x52A0;&#x7684;&#x86CB;&#x767D;&#x8868;&#x8FBE;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x8FD9;&#x4E9B;&#x5355;&#x5143;&#x683C;&#x7531; 3 methyladenine &#x5C55;&#x51FA;&#x808C;&#x9187;&#x7C7B;&#x4E09;&#x6291;&#x5236;&#x9AD8;&#x67B6;&#x7684;&#x654F;&#x611F;&#x6027;&#x3002;&#x5728;&#x5C0F;&#x9F20;&#x80BF;&#x7624;&#xFF0C;&#x4FBF; LC3 &#x8868;&#x8FBE;&#x51CF;&#x5C11;&#x4E86;&#x78B3;&#x9178;&#x6C22;&#x94A0;&#xFF0C;&#x5F15;&#x53D1;&#x7624;&#x5185; ph &#x503C;&#x7684;&#x5168;&#x8EAB;&#x6CBB;&#x7597;&#x3002;&#x4E24;&#x8005;&#x5408;&#x8BA1;&#xFF0C;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8BA4;&#x4E3A;&#x80BF;&#x7624;&#x5FAE;&#x73AF;&#x5883;&#x4E2D;&#x7684;&#x9178;&#x6027;&#x6761;&#x4EF6;&#x4FC3;&#x8FDB;&#x81EA;&#x566C;&#xFF0C;&#x4F5C;&#x4E3A;&#x6B64;&#x8BBE;&#x7F6E;&#x4E2D;&#x8BBE;&#x7F6E;&#x7684;&#x751F;&#x5B58;&#x9002;&#x5E94;&#x8FD9;&#x6162;&#x6027;&#x81EA;&#x566C;&#x53D1;&#x751F;&#x3002;

&#x6162;&#x6027;&#x81EA;&#x566C;&#x662F;&#x7EC6;&#x80DE;&#x9002;&#x5E94;&#x80BF;&#x7624;&#x9178;&#x6027; ph &#x503C;&#x5FAE;&#x89C2;&#x73AF;&#x5883;&#x3002;

Tumor cell survival relies upon adaptation to the acidic conditions of the tumor microenvironment. To investigate potential acidosis survival mechanisms, we examined the effect of low pH (6.7) on human breast carcinoma cells. Acute low pH exposure reduced proliferation rate, induced a G1 cell cycle arrest, and increased cytoplasmic vacuolization. Gene expression analysis revealed elevated levels of ATG5 and BNIP3 in acid-conditioned cells, suggesting cells exposed to low pH may utilize autophagy as a survival mechanism. In support of this hypothesis, we found that acute low pH stimulated autophagy as defined by an increase in LC3-positive punctate vesicles, double-membrane vacuoles, and decreased phosphorylation of AKT and ribosomal protein S6. Notably, cells exposed to low pH for approximately 3 months restored their proliferative capacity while maintaining the cytoplasmic vacuolated phenotype. Although autophagy is typically transient, elevated autophagy markers were maintained chronically in low pH conditioned cells as visualized by increased protein expression of LC3-II and double-membrane vacuoles. Furthermore, these cells exhibited elevated sensitivity to PI3K-class III inhibition by 3-methyladenine. In mouse tumors, LC3 expression was reduced by systemic treatment with sodium bicarbonate, which raises intratumoral pH. Taken together, these results argue that acidic conditions in the tumor microenvironment promote autophagy, and that chronic autophagy occurs as a survival adaptation in this setting.

Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments.

La survie des cellules tumorales se fonde sur l&#39;adaptation aux conditions acides du microenvironnement de la tumeur. Afin d&#39;&eacute;tudier les m&eacute;canismes de survie acidose possibles, nous avons examin&eacute; l&#39;effet d&#39;un faible pH (6,7) sur les cellules de carcinome mammaire humain. Exposition aigu&euml; faible pH r&eacute;duit la vitesse de prolif&eacute;ration, induite par un arr&ecirc;t en G1 du cycle cellulaire et augment&eacute; la vacuolisation cytoplasmique. Analyse de l&#39;expression g&eacute;nique a r&eacute;v&eacute;l&eacute; des niveaux &eacute;lev&eacute;s de ATG5 et BNIP3 dans les cellules conditionn&eacute; par l&#39;acide, ce qui sugg&egrave;re des cellules expos&eacute;es &agrave; des pH faibles peuvent utiliser autophagie comme un m&eacute;canisme de survie. &Agrave; l&#39;appui de cette hypoth&egrave;se, nous avons constat&eacute; qu&#39;aigu&euml;s pH faible stimul&eacute;e par autophagie, telle que d&eacute;finie par une augmentation des v&eacute;sicules ponctu&eacute;es LC3-positives, &agrave; double membrane vacuoles et a diminu&eacute; la phosphorylation de l&#39;AKT et prot&eacute;ine ribosomale S6. Leur capacit&eacute; de prolif&eacute;ration a &eacute;t&eacute; restaur&eacute; tout en conservant le ph&eacute;notype des vacuoles cytoplasmique notamment, des cellules expos&eacute;es &agrave; des pH faibles pendant environ 3 mois. Bien que l&#39;autophagie est g&eacute;n&eacute;ralement transitoire, marqueurs d&#39;autophagie &eacute;lev&eacute;es ont &eacute;t&eacute; maintenues chroniquement dans les cellules de faible pH conditionn&eacute; comme visualis&eacute;s par l&#39;expression de la prot&eacute;ine accrue de LC3-II et double membrane vacuoles. En outre, ces cellules chez &eacute;lev&eacute;e de sensibilit&eacute; &agrave; l&#39;inhibition de PI3K-classe III 3-m&eacute;thylad&eacute;nine. Dans les tumeurs de souris, LC3 expression a &eacute;t&eacute; r&eacute;duite par un traitement syst&eacute;mique avec bicarbonate de sodium, ce qui soul&egrave;ve le pH intratumorale. Pris ensemble, ces r&eacute;sultats soutiennent que des conditions acides dans le microenvironnement de la tumeur promouvoir autophagie et que l&#39;autophagie chronique se produit comme une adaptation de survie dans ce param&egrave;tre.

Autophagie chronique est une adaptation cellulaire aux microenvironnements pH acide de tumeur.

Tumor Zelle &Uuml;berleben h&auml;ngt von Anpassung an die sauren Bedingungen die Tumor-Untersuchungsverfahren. Um m&ouml;gliche Azidose-&Uuml;berlebens-Mechanismen zu untersuchen, haben wir die Auswirkung der niedrigen pH (6,7) auf menschlichen Brust-Karzinom-Zellen gepr&uuml;ft. Akute niedriger pH-Wert Belichtung reduzierte Verbreitung Rate, induziert eine G1 Zellzyklus Verhaftung und zytoplasmatische Vakuolisierung erh&ouml;ht. Genexpressionsanalyse ergab erh&ouml;hte Konzentrationen von ATG5 und BNIP3 in S&auml;ure konditionierten Zellen, Zellen ausgesetzt niedriger pH-Wert vorschlagen kann Autophagy als &Uuml;berlebens-Mechanismus zu nutzen. Zur Unterst&uuml;tzung dieser Hypothese, die wir fanden, dass akute niedriger pH-Wert Autophagy angeregt, wie durch eine Erh&ouml;hung der LC3-positivem punctata Bl&auml;schen, Doppel-Membran-Vakuolen, definiert und verringerte die Phosphorylierung von AKT und ribosomal Protein S6. Insbesondere wiederhergestellt Zellen ausgesetzt niedriger pH-Wert f&uuml;r ca. 3 Monate ihre proliferative Kapazit&auml;t unter Beibehaltung der zytoplasmatischen vakuolisierten Ph&auml;notyp. Obwohl Autophagy normalerweise vor&uuml;bergehend ist, wurden erh&ouml;hte Autophagy Marker chronisch in niedrigen pH konditioniert Zellen aufrechterhalten, als durch erh&ouml;hte Proteinexpression LC3-II und Doppel-Membran-Vakuolen sichtbar gemacht. Dar&uuml;ber hinaus stellte diese Zellen erh&ouml;hte Empfindlichkeit gegen&uuml;ber PI3K-Klasse III-Hemmung durch 3-Methyladenine. Maus-Tumoren reduzierte LC3 Ausdruck durch die systemische Behandlung mit Natriumbicarbonat, die intratumorale pH-Wert erh&ouml;ht. Zusammengenommen argumentieren diese Ergebnisse saure Bedingungen in den Tumor Mikromilieu f&ouml;rdern Autophagy, dass diese chronische Autophagy tritt als eine Anpassung &Uuml;berleben in dieser Einstellung.

Chronische Autophagy ist eine zellul&auml;re Anpassung an Tumor sauren pH-Wert Mikroumgebungen.

La sopravvivenza delle cellule tumorali si basa su adattamento alle condizioni acide del microambiente del tumore. Per indagare su possibili meccanismi di sopravvivenza di acidosi, abbiamo esaminato l&#39;effetto del pH basso (6,7) sulle cellule di carcinoma mammario umano. L&#39;esposizione acuta a basso pH ridotto tasso di proliferazione, indotta da un arresto del ciclo cellulare G1 e vacuolizzazione citoplasmatica &egrave; aumentato. Analisi di espressione genica ha rivelato livelli elevati di ATG5 e BNIP3 nelle cellule acido-condizionato, suggerendo le cellule esposte a basso pH pu&ograve; utilizzare autophagy come un meccanismo di sopravvivenza. A sostegno di questa ipotesi, abbiamo trovato che acute pH basso stimolato autophagy come definita da un aumento in vescicole punctate LC3-positivo, doppia membrana vacuoli e diminuito la fosforilazione di AKT e proteina ribosomiale S6. In particolare, le cellule esposte a basso pH per circa 3 mesi restaurato loro capacit&agrave; proliferativa mantenendo il fenotipo vacuolato citoplasmatico. Sebbene autophagy &egrave; in genere transitoria, marcatori elevati autophagy erano mantenuti cronicamente in cellule pH basso condizionata visualizzati da espressione aumentata della proteina LC3-II e la doppia membrana vacuoli. Inoltre, queste cellule esposte elevata sensibilit&agrave; all&#39;inibizione della PI3K-classe III da 3-polymerase. Nei tumori del mouse, LC3 espressione &egrave; stata ridotta dal trattamento sistemico con bicarbonato di sodio, che genera intratumoral pH. Presi insieme, questi risultati sostengono che condizioni di acidit&agrave; nel microambiente del tumore promuovere autophagy, e che autophagy cronica si verifica come un adattamento di sopravvivenza in questa impostazione.

Autophagy cronica &egrave; un adattamento cellulare a microambienti di pH acido del tumore.

&#x816B;&#x760D;&#x7D30;&#x80DE;&#x306E;&#x751F;&#x5B58;&#x304C;&#x3093;&#x5FAE;&#x5C0F;&#x74B0;&#x5883;&#x306E;&#x9178;&#x6027;&#x6761;&#x4EF6;&#x3078;&#x306E;&#x9069;&#x5FDC;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x307E;&#x3059;&#x3002;&#x6F5C;&#x5728;&#x6027;&#x30A2;&#x30B7;&#x30C9;&#x30FC;&#x30B7;&#x30B9;&#x751F;&#x5B58;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x8ABF;&#x3079;&#x308B;&#x305F;&#x3081;, &#x4F4E; pH &#xFF08;6.7&#xFF09; &#x304C;&#x4EBA;&#x9593;&#x306E;&#x4E73;&#x764C;&#x7D30;&#x80DE;&#x306B;&#x53CA;&#x307C;&#x3059;&#x5F71;&#x97FF;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x6025;&#x6027;&#x4F4E; pH &#x9732;&#x51FA;&#x5897;&#x6B96;&#x7387;&#x306E;&#x6E1B;&#x5C11;&#x3001;G1 &#x7D30;&#x80DE;&#x5468;&#x671F;&#x306E;&#x505C;&#x6B62;&#x3092;&#x8A98;&#x767A;&#x3057;&#x3001;&#x7A7A;&#x80DE;&#x5316;&#x304C;&#x5897;&#x52A0;&#x3057;&#x307E;&#x3059;&#x3002;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x89E3;&#x6790; ATG5 &#x306E;&#x9AD8;&#x5024;&#x3068;&#x4F4E; pH &#x306B;&#x7D30;&#x80DE;&#x3092;&#x793A;&#x5506; BNIP3 &#x9178;&#x8ABF;&#x7BC0;&#x7D30;&#x80DE;&#x3067;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC;&#x751F;&#x5B58;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3068;&#x3057;&#x3066;&#x5229;&#x7528;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;.&#x3053;&#x306E;&#x4EEE;&#x8AAC;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3059;&#x308B;&#x6211;&#x3005; &#x306F;&#x6025;&#x6027;&#x767A;&#x898B;&#x4F4E; pH &#x523A;&#x6FC0;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC; LC3 &#x6B63;&#x70B9;&#x72B6;&#x5C0F;&#x80DE;&#x3001;&#x4E8C;&#x91CD;&#x819C;&#x6DB2;&#x80DE;&#x306E;&#x5897;&#x52A0;&#x306B;&#x3088;&#x3063;&#x3066;&#x5B9A;&#x7FA9;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3068;&#x30EA;&#x30F3;&#x9178;&#x5316; AKT &#x3068;&#x30EA;&#x30DC;&#x30BD;&#x30FC;&#x30E0;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA; S6 &#x306E;&#x6E1B;&#x5C11;&#x3057;&#x307E;&#x3059;&#x3002;&#x7279;&#x306B;&#x3001;&#x4F4E; pH &#x306B;&#x7D04; 3 &#x30F6;&#x6708;&#x9593;&#x7D30;&#x80DE;&#x306E;&#x5897;&#x6B96;&#x80FD;&#x529B;&#x7D30;&#x80DE;&#x8CEA;&#x80DE;&#x8868;&#x73FE;&#x578B;&#x3092;&#x7DAD;&#x6301;&#x3057;&#x306A;&#x304C;&#x3089;&#x5FA9;&#x5143;&#x3002;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC;&#x306F;&#x901A;&#x5E38;&#x3001;&#x4E00;&#x6642;&#x7684;&#x3067;&#x3059;&#x304C;&#x3001;LC3 II &#x3068;&#x4E8C;&#x91CD;&#x819C;&#x6DB2;&#x80DE;&#x306E;&#x5897;&#x52A0;&#x86CB;&#x767D;&#x8CEA;&#x767A;&#x73FE;&#x306B;&#x3088;&#x3063;&#x3066;&#x53EF;&#x8996;&#x5316;&#x9AD8;&#x67B6;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC; &#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x306F;&#x6162;&#x6027;&#x7684;&#x306A;&#x4F4E; pH &#x6761;&#x4EF6;&#x306E;&#x30BB;&#x30EB;&#x3092;&#x7DAD;&#x6301;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D30;&#x80DE;&#x306F; 3-&#x30E1;&#x30C1;&#x30EB;&#x30A2;&#x30C7;&#x30CB;&#x30F3; PI3K &#x30AF;&#x30E9;&#x30B9; III &#x963B;&#x5BB3;&#x3059;&#x308B;&#x611F;&#x6027;&#x306E;&#x9AD8;&#x307E;&#x308A;&#x3092;&#x51FA;&#x5C55;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30DE;&#x30A6;&#x30B9;&#x816B;&#x760D;&#x306E; LC3 &#x5F0F;&#x5168;&#x8EAB;&#x30C8;&#x30EA;&#x30FC;&#x30C8;&#x30E1;&#x30F3;&#x30C8;&#x816B;&#x760D;&#x5185; pH &#x3092;&#x767A;&#x751F;&#x3055;&#x305B;&#x307E;&#x3059;&#x91CD;&#x70AD;&#x9178;&#x30CA;&#x30C8;&#x30EA;&#x30A6;&#x30E0;&#x3068;&#x6E1B;&#x5C11;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x53D6;&#x3089;&#x308C;&#x3066;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC;, &#x816B;&#x760D;&#x5FAE;&#x5C0F;&#x74B0;&#x5883;&#x306B;&#x304A;&#x3051;&#x308B;&#x9178;&#x6027;&#x6761;&#x4EF6;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x3001;&#x6162;&#x6027;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC;&#x751F;&#x5B58;&#x9069;&#x5FDC;&#x3053;&#x306E;&#x8A2D;&#x5B9A;&#x3068;&#x3057;&#x3066;&#x767A;&#x751F;&#x3092;&#x4E3B;&#x5F35;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x6162;&#x6027;&#x30AA;&#x30FC;&#x30C8;&#x30D5;&#x30A1;&#x30B8;&#x30FC;&#x306B;&#x9178;&#x6027; pH &#x5FAE;&#x5C0F;&#x306E;&#x816B;&#x760D;&#x7D30;&#x80DE;&#x306E;&#x9069;&#x5FDC;&#x3067;&#x3059;&#x3002;

&#xC885;&#xC591; &#xC138;&#xD3EC; &#xC0DD;&#xC874; &#xC885;&#xC591; microenvironment&#xC758; &#xC0B0; &#xC131; &#xC870;&#xAC74;&#xC5D0; &#xC801;&#xC751;&#xC5D0; &#xC758;&#xC874; &#xD569;&#xB2C8;&#xB2E4;. &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC99D; &#xC0DD;&#xC874; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC870;&#xC0AC;, &#xC6B0;&#xB9AC; &#xC778;&#xAC04;&#xC758; &#xC720; &#xBC29; &#xC554; &#xC885; &#xC138;&#xD3EC;&#xC5D0; &#xB0AE;&#xC740; pH (6.7)&#xC758; &#xC601;&#xD5A5;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xAE09;&#xC131; &#xB0AE;&#xC740; pH &#xB178;&#xCD9C; &#xD655;&#xC0B0; &#xC18D;&#xB3C4; &#xAC10;&#xC18C; &#xD558; &#xACE0; G1 &#xC138;&#xD3EC; &#xC8FC;&#xAE30;&#xC758; &#xCCB4;&#xD3EC; &#xC720;&#xB3C4; &#xC138;&#xD3EC;&#xC9C8; vacuolization &#xC99D;&#xAC00;. &#xC9C4; &#xC2DD; &#xBD84;&#xC11D; ATG5 &#xB192;&#xC740; &#xC218;&#xC900;&#xC758; &#xADF8;&#xB9AC;&#xACE0; BNIP3 &#xC140; &#xC0B0; &#xC131; &#xC870;&#xAC74;&#xC5D0;&#xC11C; &#xC81C;&#xC548; &#xD558;&#xB294; &#xB0AE;&#xC740; Ph&#xC5D0; &#xB178;&#xCD9C; &#xC140; autophagy &#xC0DD;&#xC874; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC73C;&#xB85C; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xAC00;&#xC124;&#xC744; &#xC9C0; &#xC6D0;&#xD558;&#xB294; &#xC6B0;&#xB9AC;&#xAC00; &#xBC1C;&#xACAC; &#xADF8; &#xAE09;&#xC131; &#xB0AE;&#xC740; pH LC3 &#xC591;&#xC131; punctate &#xC18C;&#xD3EC;, &#xC774;&#xC911; &#xBA64;&#xBE0C;&#xB808;&#xC778; vacuoles &#xC99D;&#xAC00; &#xC758;&#xD574; &#xC815;&#xC758; &#xB41C; &#xB300;&#xB85C; autophagy&#xB97C; &#xC790;&#xADF9; &#xD558; &#xACE0; ribosomal &#xB2E8;&#xBC31;&#xC9C8; S6 AKT&#xC758; &#xC778; &#xC0B0;&#xD654;&#xB97C; &#xAC10;&#xC18C;. &#xD2B9;&#xD788;, &#xC57D; 3 &#xAC1C;&#xC6D4;&#xC5D0; &#xB300; &#xD55C; &#xB0AE;&#xC740; Ph&#xC5D0; &#xB178;&#xCD9C; &#xC140; &#xC138;&#xD3EC;&#xC9C8; vacuolated &#xD45C;&#xD604; &#xD615;&#xC744; &#xC720;&#xC9C0; &#xD558;&#xBA74;&#xC11C; &#xADF8;&#xB4E4;&#xC758; &#xC99D;&#xC2DD; &#xB2A5;&#xB825;&#xC744; &#xBCF5;&#xC6D0;. Autophagy &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xC77C;&#xC2DC;&#xC801; &#xC774;&#xC9C0;&#xB9CC; &#xB192;&#xC740; autophagy &#xB9C8;&#xCEE4; &#xD588;&#xB2E4; &#xC720;&#xC9C0; &#xB9CC;&#xC131; &#xB0AE;&#xC740; pH &#xC870;&#xAC74; &#xC140;&#xC5D0;&#xC11C; LC3 II&#xC640; &#xB354;&#xBE14; &#xBA64;&#xBE0C;&#xB808;&#xC778; vacuoles &#xC99D;&#xAC00; &#xB2E8;&#xBC31;&#xC9C8; &#xD45C;&#xC815;&#xC5D0; &#xC758;&#xD574; &#xC2DC;&#xAC01;. &#xB610;&#xD55C;, &#xC774;&#xB7EC;&#xD55C; &#xC140; 3-methyladenine&#xC5D0; &#xC758;&#xD574; PI3K &#xD074;&#xB798;&#xC2A4; III &#xC800;&#xD574;&#xC5D0; &#xB192;&#xC740; &#xAC10;&#xB3C4; &#xC804;&#xC2DC;. &#xB9C8;&#xC6B0;&#xC2A4; &#xC885;&#xC591; LC3 &#xC2DD; &#xB098;&#xD2B8;&#xB968; &#xC911; &#xD0C4;&#xC0B0;&#xC5FC;, intratumoral &#xC0B0;&#xB3C4; &#xAC00;&#xC9C4; &#xC870;&#xC9C1;&#xC758; &#xCE58;&#xB8CC;&#xC5D0; &#xC758;&#xD574; &#xAC10;&#xC18C; &#xD588;&#xB2E4;. &#xD568;&#xAED8; &#xCC0D;&#xC740;, &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xC885;&#xC591; microenvironment &#xC0B0; &#xC131; &#xC870;&#xAC74; autophagy, &#xC99D;&#xC9C4;&#xACFC; &#xB9CC;&#xC131; autophagy &#xADF8; &#xBC1C;&#xC0DD;&#xC774; &#xC124;&#xC815;&#xC5D0; &#xC0DD;&#xC874; &#xC801;&#xC751;&#xC73C;&#xB85C; &#xC8FC;&#xC7A5; &#xD55C;&#xB2E4;.

&#xB9CC;&#xC131; autophagy &#xC885;&#xC591; &#xC0B0; &#xC131; pH microenvironments &#xC140;&#xB8F0;&#xB7EC; &#xC801;&#xC751; &#xC774;&#xB2E4;.

Supervivencia de la c&eacute;lula del tumor depende de la adaptaci&oacute;n a las condiciones &aacute;cidas del microambiente tumoral. Para investigar los posibles mecanismos de supervivencia de la acidosis, examinamos el efecto de pH bajo (6,7) en c&eacute;lulas de carcinoma de mama humano. Exposici&oacute;n aguda pH bajo redujo tasa de proliferaci&oacute;n, inducida por una detenci&oacute;n del ciclo celular G1 y aument&oacute; la vacuolizaci&oacute;n citoplasm&aacute;tica. An&aacute;lisis de expresi&oacute;n g&eacute;nica revelaron niveles elevados de ATG5 y BNIP3 en c&eacute;lulas de &aacute;cido-condicionada, sugiriendo las c&eacute;lulas expuestas a bajo pH puede utilizar autofagia como un mecanismo de supervivencia. En apoyo de esta hip&oacute;tesis, encontramos que aguda pH bajo estimula la autofagia definida por un aumento en las ves&iacute;culas punteadas LC3-positivo, vacuolas de doble membrana y disminuy&oacute; la fosforilaci&oacute;n de AKT y prote&iacute;na ribosomal S6. En particular, las c&eacute;lulas expuestas a pH bajo, durante aproximadamente 3 meses restauran su capacidad proliferativa manteniendo el fenotipo vacuolated citopl&aacute;smico. Aunque autofagia es t&iacute;picamente transitoria, marcadores elevados de la autofagia se mantuvieron cr&oacute;nico en c&eacute;lulas de pH bajo acondicionado como visualizado por la expresi&oacute;n de la prote&iacute;na mayor de LC3-II y vacuolas de doble membrana. Adem&aacute;s, estas c&eacute;lulas exhibieron elevada sensibilidad a la inhibici&oacute;n de PI3K-clase III por 3-methyladenine. En tumores de rat&oacute;n, LC3 expresi&oacute;n se redujo con un tratamiento sist&eacute;mico con bicarbonato de sodio, que eleva pH intratumoral. Tomados en conjunto, estos resultados sostienen que las condiciones &aacute;cidas en el microentorno del tumor promoci&oacute;n autofagia, y esa autofagia cr&oacute;nica se presenta como una adaptaci&oacute;n de la supervivencia en este ajuste.

Autofagia cr&oacute;nica es una adaptaci&oacute;n celular a microambientes de pH &aacute;cido del tumor.

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.

Case reports have linked childhood nephrotic syndrome to food sensitivity, including gluten. We report our experience with 8 children (6 boys, 2 girls; age at implementation of special diet 2-14 years) with difficult-to-manage nephrotic syndrome who were placed on a gluten-free diet for 3.4 ± 4.3 years (range, 0.6-14 years) and who had clinical improvement enabling reduction or discontinuation in steroid dosage.

The Effect of a Gluten-Free Diet in Children With Difficult-to-Manage Nephrotic Syndrome.

Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature that predicts poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 coreceptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.

Karla Schramm

Katz Family Drug Discovery Center and Division of Nephrology and Hypertension,
Department of Medicine,
Department of Cell Biology and Anatomy,
Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine

University of Miami Leonard M. Miller School of Medicine

Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice

Karla Schramm

Katz Family Drug Discovery Center and Division of Nephrology and Hypertension,Department of Medicine,Department of Cell Biology and Anatomy,Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine

University of Miami Leonard M. Miller School of Medicine

Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice

Katz Family Drug Discovery Center and Division of Nephrology and Hypertension,
Department of Medicine,
Department of Cell Biology and Anatomy,
Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine