EMBO/soda-nel huggingface dataset:
PGE2-EP3 axis promotes brown adipose tissue formation through 
stabilization of WTAP RNA methyltransferase (2022)
Figure 3

Figure 3. EP3 deficiency suppresses BA differentiation by reducing WTAP protein levels in brown pre-adipocytes.

(A) N6-methyladenosine (m6A) modification levels of mRNAs in normal and EP3-deficient brown pre-adipocytes with or without brown adipogenesis induction, detected by m6A RNA Methylation Quantification Kit (Colorimetric) (n = 4-6).

(B) qRT-PCR analysis of the relative mRNA levels of m6A writers (METTL3, METTL4, METTL14 and WTAP) and erasers (FTO and ALKBH5) in normal and EP3-deficient brown pre-adipocytes with or without brown adipogenesis induction (n = 6-9).

(C) Western blotting analysis of m6A writers and erasers in normal and EP3-deficient brown pre-adipocytes with or without brown adipogenesis induction.

(D) Quantification of protein levels in C (n = 4-6).

(E) Western blotting analysis of WTAP in iBAT from EP3F/F and EP3F/FMyf5Cre mice fed HFD for 1 week.

(F) Western blotting analysis of WTAP in BAs differentiated from EP3γ-expressed brown pre-adipocytes.

(G) Relative mRNA levels of WTAP gene in BAs differentiated from EP3γ-expressed brown pre-adipocytes detected by RT-qPCR (n = 6-7).

(H) qRT-PCR analysis of the relative mRNA levels of EP3γ gene in BAs differentiated from EP3γ-expressed EP3-/- brown pre-adipocytes after transfection with WTAP siRNA (n = 8).

(I) qRT-PCR analysis of the relative mRNA levels of WTAP gene in BAs differentiated from EP3γ-expressed EP3-/- brown pre-adipocytes after transfection with WTAP siRNA (n = 8).

(J) Representative picture of oil red O-stained BAs differentiated from EP3γ-expressed EP3-/- brown pre-adipocytes with WTAP siRNA treatment. Scale bar: 50 μm.

(K-Q) qRT-PCR analysis of the relative mRNA levels of brown marker genes in BAs differentiated from EP3γ-expressed EP3-/- brown pre-adipocytes after transfection with WTAP siRNA (n = 6-8).

Data information: Data represent the mean ± standard error of mean (SEM). Data are representative of two independent experiments with biological replicates (A-B, D, G, H-Q). Statistical significance was evaluated by unpaired two-tailed student's t test (A, B, D, H), two-way ANOVA followed by Tukey's test for post-hoc comparisons (G, I, K-Q). *P < 0.05, **P < 0.01, ***P < 0.001 and ns, not significant (P > 0.05).
PGE2-EP3 axis promotes brown adipose tissue formation through 
stabilization of WTAP RNA methyltransferase (2022)
Figure 6

Figure 6. EP3 prevents ubiquitin-dependent degradation of WTAP in brown pre-adipocytes by attenuating PKA-mediated ERK1/2 inhibition.

(A) Western blotting analysis of ubiquitination of WTAP in the control and EP3-deficient brown pre-adipocytes with or without sulprostone treatment.

(B) Western blotting analysis of ERK1/2 phosphorylation in the control and EP3-deficient brown pre-adipocytes.

(C) Effect of ERK1/2 inhibitor, ravoxertinib, on ubiquitin-dependent degradation of WTAP in sulprostone-treated brown pre-adipocytes.

(D) Effect of wortmannin (Wor), pertussis toxin (PTX), U73122, barbadin, and melittin on ubiquitin-dependent degradation of WTAP in sulprostone-treated brown pre-adipocytes.

(E) Analysis of PKA activity in the control and EP3-deficient brown pre-adipocytes (n = 4).

(F) Effect of PKA inhibitor, H89, on ubiquitin-dependent degradation of WTAP in EP3-/- brown pre-adipocytes.

(G) Effect of ERK1/2 phosphorylation site mutation (HA-WTAP-2A) on EP3-mediated ubiquitin-dependent degradation of WTAP in brown pre-adipocytes.

(H) Representative picture of oil red O-stained BAs differentiated from sulprostone-treated brown pre-adipocyte with treatment of PTX, dbcAMP, or ravoxertinib. Scale bar: 50 μm.

(I) Western blotting assay of ERK1/2, WTAP, ZFP410, PRDM16, and UCP1 in BAs differentiated from sulprostone-treated brown pre-adipocyte with treatment of PTX, dbcAMP, or ravoxertinib.

(J) Schematic illustration of EP3-mediated BA differentiation via the PKA/ERK1/2/WTAP/ZFP410 signaling pathway.

Data information: Data represent the mean ± standard error of mean (SEM). Data are representative of two independent experiments with biological replicates (A-I). Statistical significance was evaluated by Mann-Whitney U tests (E).
PGE2-EP3 axis promotes brown adipose tissue formation through 
stabilization of WTAP RNA methyltransferase (2022)
Figure 7

Figure 7. Inhibition of EP3 retards the differentiation of human embryonic stem cells (hESCs) into BAs.

(A)Experimental scheme for the differentiation of hESCs into BAs.

(B)Representative pictures of nile red-stained human BAs differentiated from hESC-derived brown progenitors. Scale bar: 50 μm.

(C) Time course analysis of the relative mRNA levels of EP3 receptors in hESC-derived BAs during BA differentiation detected by RT-qPCR (n = 7-8).

(D) Representative pictures of hESC-derived BAs treated with L798106 alone or combined with H89. Scale bar: 50 μm.

(E) Effect of H89 on the relative mRNA level of brown marker gene in hESC-derived BAs treated with L798106 detected by RT-qPCR (n = 6-8).

(F) Effect of H89 on WTAP mRNA expression in hESC-derived BAs treated with L798106 (n = 6-7).

(G) Effect of H89 on ZNF410 mRNA expression in hESC-derived BAs treated with L798106 (n = 8).

(H) Western blotting assay of ERK1/2, WTAP, ZNF410, PRDM16, and UCP1 in hESC-derived BAs treated with L798106 alone or combined with H89.

Data information: Data represent the mean ± standard error of mean (SEM). Data are representative of two independent experiments with biological replicates (C, D-G). Statistical significance was evaluated by Welch ANOVA test followed by Tamhane's T2 test for post-hoc comparisons (C), two-way ANOVA followed by Tukey's test for multiple comparisons (E, F, G). *P < 0.05, **P < 0.01, ***P < 0.001 and ns, not significant (P > 0.05).

Figure EV Legends
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 1

Figure 1. BES1 is activated by heat and contributes to heat stress resistance.

A-C. Immunodetection of BES1-CFP from heat-treated plants. Plants pre-grown at 21°C were (A) exposed for 60 minutes to the indicated temperatures, (B) to 45°C for the indicated period of time, or (C) to 45°C and, following sampling after 30 minutes (lane 2) and 60 minutes (lane 3), returned to 21°C for 3 hours (lane 4). CBB, Coomassie Brilliant Blue stained gel.

D. Subcellular localization of BES1-CFP in roots of 7-day-old plants after heat shock. 35S:BES1-CFP seedlings were grown at 21°C and either left untreated or exposed for 60 minutes to 45°C. Left: representative photos. Right: quantification of the nuclear/cytoplasmic signal. Data show the mean ±SD. n=25. The asterisks indicate significant differences to the untreated plants by Student's t-test (***P≤0.001).

E. Expression of the BES1-repressed BR biosynthetic genes ROT3, DWF4 and BR6ox2 (the basic regulatory pathway is illustrated) after a heat shock of 45°C. Plants were treated as in C, samples were harvested and qPCR analyses were performed. Data show the mean ±SD. n=4 biological repeats, each measured in 3 technical replicates, normalized to UBC. The asterisks indicate significant differences compared to the control condition at 21 °C by Student's t-test (*P≤0.05; **P≤0.01; ***P≤0.001).

F. Heat stress resistance of bes1-1, bes1-2 and bes1-D as compared to wild-type. For basal resistance assays (top charts) plants were directly exposed to 45°C for the indicated time. For acquired resistance (bottom charts), plants were primed with the respective temperatures for 120 minutes before transfer to 45°C for 150 minutes. Data show the mean ±SE. n=7. The asterisks indicate significant differences compared to wild-type by Student's t-test (*P≤0.05; **P≤0.01; ***P≤0.001).
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 2

Figure 2. Canonical BR signaling is not required for heat-induced BES1 de-phosphorylation.

A. Basal and acquired heat stress resistance of bri1-1. For basal resistance assays (left) plants were directly exposed to 45°C for the indicated time. For acquired resistance (right), plants were primed with the respective temperatures for 120 minutes before transfer to 45°C for 150 minutes. The data are shown as means ±SE; n=8.

B. Immunodetection of BES1-CFP from heat-stressed plants, treated with epiBL or BRZ. 35S:BES1-CFP plants were treated for 24 hours with DMSO (control), 1 μM 24-epiBL or 5 μM BRZ and then heat-stressed as follows: lane 1: untreated control; lane 2: 45°C for 30 minutes; lane 3: 45°C for 60 minutes; lane 4: 45°C for 60 minutes and recovery at 21°C for 180 minutes.

C, D. Immunodetection of BES1-CFP from heat-treated bri1-1 or det2-1 plants. Left: phenotypes of 10-day-old plants of all lines as compared to wild-type Col-0 (wt). Right: Immunoblots from the lines grown and treated as in B.

E. Basal and acquired heat stress resistance of bin2-1. The experiment was performed as in A.

F. Immunodetection of BES1-CFP from heat-treated bin2-1 plants. The experiment was performed as in C and D.
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 3

Figure 3. ABA represses BES1 de-phosphorylation by heat.

A. Immunodetection of BES1-CFP from heat-stressed plants, treated with ABA or Fluridone (Flu). 35S:BES1-CFP plants were treated for 24 hours with DMSO (control), 5 μM ABA or 10 μM Fluridone and heat-stressed as follows: lane 1: untreated control; lane 2: 45°C for 30 minutes; lane 3: 45°C for 60 minutes. The non-phosphorylated BES1 bands were quantified with ImageJ and the obtained values are shown in blue.

B. Basal and acquired heat stress resistance of abi1tM. For basal resistance assays (top) plants were directly exposed to 45°C for the indicate time. For acquired resistance (bottom), plants were primed with the respective temperatures for 120 minutes before transfer to 45°C for 150 minutes. Data show the mean ±SE. n=7. The asterisks indicate significant differences compared to wild-type by Student's t-test (*P≤0.05; **P≤0.01).

C. Immunodetection of native BES1 from heat-stressed and epiBL-treated abitM plants. abitM and wild-type plants were grown on ½ MS medium either containing DMSO as a control or 1 μM epiBL and either left untreated or exposed to 45°C for 60 minutes. The non-phosphorylated BES1 bands were quantified with ImageJ and the obtained values are shown in blue.
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 4

Figure 4. BES1 binds to HSP promoters.

A. Illustration of the promoters of HSP70.3, HSP70.4 and HSP90.1. Relevant regulatory motifs and promoter regions that were assessed in ChIP experiments (C) or in vitro DNA-binding studies (Fig 5A) are shown with purple and grey lines, respectively.

B. Relative expression changes of HSP70.3, HSP70.4 and HSP90.1 in bes1-D as compared to wild-type following heat shock. 14-day-old plants were exposed to 45°C for 60 minutes, expression was analyzed by qPCR and the results were normalized to UBC. Data show the mean ±SD. n=3 biological replicates measured in 3 technical repeats. Significant differences as compared to wild-type at 45°C, calculated by Student's t-test, are shown (*P≤0.05).

C. ChIP to determine BES1-CFP enrichment on the promoters of HSP70.3, HSP70.4 and HSP90.1 following heat stress. 35S:BES1-CFP and wild-type plants grown at 21°C were either left untreated or treated with 45°C for 60 minutes. BES1-CFP was immuno-precipitated with α-GFP beads. Fragments were quantified in the precipitates with qPCR and the ratios of samples with antibody to without antibody were calculated. TA3 (70.3p and 90.1p) or 5s rRNA (70.4p) were used for normalization. UBQ5 served as an internal control. Data show the mean ±SE. n=3 biological replicates measured in 3 technical repeats. Significant differences as compared to wild-type at 21°C, calculated by Student's t-test, are shown (*P≤0.05; **P≤0.01; ***P≤0.001).
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 5

Figure 5. HSFA1s promote BES1 activity in HSP induction and heat stress resistance.

A. EMSAs showing in vitro DNA interaction of recombinant BES1 and/or HSFA1 with HSE-containing fragments of the HSP70.3 and HSP90.1 promoters. Unlabeled competitor fragments with functional HSEs (C1 +HSE) or mutated versions (C2 -HSE) were used for competition studies in 100x molar access (lanes 6 and 7).

B. BiFC assays showing cells co-transformed with nYFP-BES1 and cYFP-HSFA1a. The fusion proteins were co-expressed in N. benthamiana leaves and fluorescence was visualized. Two nuclei are highlighted and shown in a 6-fold magnification. Scale bar=20 μm.

C. LUC assays in protoplasts of wild-type, bes1-D or the hsfA1qM plants. LUC reporter constructs, driven by 2 kb of the HSP70.3, HSP70.4 and HSP90.1 promoters, were tested either alone (0, with empty effector plasmid) or with BES1 or HSFA1a as effectors and LUC transactivation was analyzed. Data show the mean ±SD. n=5. Statistically significant difference at P≤0.05 of results is indicated with different letters and was determined by Student's t-test.

D. Basal heat stress resistance of hsfA1qM and bes1-DxhsfA1qM plants. Plants were directly exposed to 45°C for the indicated time. Data show the mean ±SE. n=8.

E. Working model for the contribution of BES1 to heat stress signaling. BES1 is de-phosphorylated and activated by heat stress, utilizing ABI1 and redundant ABA-repressed PP2C phosphatases. It then interacts with HSFA1s, which are also activated by heat, for binding to HSEs in promoters of HSP70s and HSP90s genes, which induces them and increases heat stress resistance. BRs, while not needed for the activity, can promote it.
The transcription factor BES1 interacts with HSFA1 to promote heat stress resistance of plants (2021)
Figure 6

Figure 6. HSFA1s repress bes1-D activity in BR responses.

A, B. Constitutive and BR-responsive growth of bes1-DxhsfA1qM seedlings. Hypocotyl elongation of 7-day-old dark-grown (A) and light-grown (B) seedlings on medium containing either 1 μM epi-BL, 1 μM BRZ or DMSO as a control (c). Left: Mean and SD of 30 plants. Significant difference at P≤0.05 of results is indicated with different letters and was determined with a Student's t-test. Right: photos of representative plants.

C. Expression of BR-regulated genes in bes1-DxhsfA1qM, as compared to its parents and respective wild-types analyzed by qPCRs. Data show the mean ±SD. n=3 biological repeats, each measured in 3 technical replicates, normalized to UBC. Statistically significant difference at P≤0.05 of results is indicated with different letters and was determined by Student's t-test.
HER3 targeting with an Antibody Drug Conjugate Bypasses Resistance to anti-HER2 therapies (2020)
Figure 1

Figure 1. EV20/MMAF efficiently acts on naïve and trastuzumab-resistant cells.

(A) Schematic representation of the generation of trastuzumab resistant cell lines. Low density cultures of BT474 (5,000 cells/150 mm dish) were incubated with trastuzumab (50 nM, replenished weekly) for 12 months and resistant pools and clones selected.

(B) Cell counting experiments analyzing the response to trastuzumab (50 nM, 5 days) of naïve BT474 as well as the resistant BTRH pool and the BTRH#10 clone. *** P<0.001. Exact P‐values of all comparisons and the statistical test used are indicated in Appendix Table S2.

(C) Western blot analyses of the expression of HER2, pHER2, HER3 and pHER3 in BT474, BTRH and BTRH#10 cells. HER2 and HER3 were immunoprecipitated from 100 or 500 μg of cell extracts, respectively, and blots probed with anti-HER2, anti-HER3 or anti-phosphotyrosine. Calnexin was used as a loading control. Numbers below the blots show the quantitation of the signal of each band, referred to BT474 cells (intensity of band in BT474 cells=1).

(D) Analyses of cell surface levels of HER2 and HER3 in BT474 and BTRH cells by surface immunoprecipitation.

(E) Response of BT474, BTRH and BTRH#10 to EV20/MMAF. Cells treated with the indicated doses of EV20/MMAF for 5 days were counted.

(F) Action of the nude EV20 antibody or EV20/MMAF (10 nM each, 5 days) on BT474, BTRH and BTRH#10 cells. *** P<0.001. Exact P‐values of all comparisons and the statistical test used are indicated in Appendix Table S3.

(G) Comparison of the effect of MMAF and EV20/MMAF on the proliferation of BT474 and BTRH cells after five days of treatment with the drugs.

Data information: Data in (B, E, F and G) represent mean + SD of triplicates of an experiment that was repeated at least twice and normalized to untreated controls. In (B, E, F and G), when error bars are invisible, that is because they are small and are covered by the graphic's symbols.
HER3 targeting with an Antibody Drug Conjugate Bypasses Resistance to anti-HER2 therapies (2020)
Figure 2

Figure 2. Action of EV20/MMAF on various models of primary and secondary resistance to trastuzumab.

(A) Response to trastuzumab (50 nM, 5 days) of BT474, BTRH, patient derived cells (PDX118) and their trastuzumab-resistant derivatives TR1 and TR2. *** P<0.001. Exact P‐values of all comparisons and the statistical test used are indicated in Appendix Table S4.

(B) HER2, HER3 and pHER3 levels in BT474, BTRH, PDX118, TR1 and TR2. pHER3 levels were analyzed by a specific anti-pHER3 antibody.

(C) Effect of EV20/MMAF on BT474, BTRH, PDX118, TR1 and TR2. Cells were counted after 5 days of treatment with the indicated doses of EV20/MMAF.

(D) Effect of trastuzumab (50 nM, 5 days) in HER2 positive breast cancer cell lines (SKBR3, BT474, BTRH, MDA-MB-361, HCC1419, HCC1569 and HCC1954). The blue line indicates the threshold (established from BTRH) used to consider a cell line resistant to trastuzumab.

(E) Analyses of HER2, HER3 and pHER3 in the cells used in (D). Numbers below the blots show the quantitation of the signal of each band, referred to SKBR3 cells (intensity of band in SKBR3 cells=1). pHER3 levels were analyzed by a specific anti-pHER3 antibody. Note that the pHER3 blot is the same as the first one showed in EV2E.

(F) Effect of EV20/MMAF on the cell lines used in (D). Cells were counted after 5 days of treatment with the indicated doses of EV20/MMAF.

(G) Knockdown of HER3 in BT474 cells. Control and HER3-targeted short hairpin sequences were transduced in BT474 cells and HER3, pHER3 and pAKT levels analyzed by Western. Levels of pHER3 were analyzed by a specific anti-pHER3 antibody.

(H) Effect of HER3 knockdown on the antiproliferative action of EV20/MMAF analyzed by cell counting after 5 days of treatment with the ADC. *** P<0.001. Exact P‐values and the statistical test used are indicated in Appendix Table S5.

Data information: Data in (A, C, D, F and H) represent mean + SD of triplicates of an experiment that was repeated at least twice and normalized to untreated controls. In (A, C, D, F, and H), when error bars are invisible, that is because they are covered by the graphic's symbols.
HER3 targeting with an Antibody Drug Conjugate Bypasses Resistance to anti-HER2 therapies (2020)
Figure 3

Figure 3. Internalization of EV20/MMAF in BT474 and BTRH.

(A) Internalization of EV20/MMAF (10 nM) at indicated times in BT474 and BTRH cells. Scale bar: 20 µm. HER3 staining: red; DAPI: blue.

(B) Internalization of biotin-S-S-EV20/MMAF in BT474 and BTRH cells. These cell lines were pulsed with 10 nM of biotin-S-S-EV20/MMAF for 1 hour at 4°C and chased at 37°C at the indicated times. Subsequently, surface accessible biotin was cleaved, cells were lysed, and extracts precipitated with streptavidin-sepharose. EV20/MMAF was analyzed by Western blotting using anti-human-HRP.

(C) Quantitative plot of the Western studies shown in (B). Data are presented as the mean + SD of two independent experiments.

(D) Co-localization (yellow) between EV20/MMAF and LAMP1 at the indicated incubation times with EV20/MMAF in BT474 and BTRH cells. Scale bar: 5 µm. HER3 staining: red; LAMP1: green, DAPI: blue.

(E) Western blot analyses of the effect of EV20/MMAF (10 nM) on the levels of HER2 and HER3 in BT474 and BTRH cells at the indicated incubation times with the ADC. The same Western was probed for HER2 or HER3 expression using two differently labelled species-specific secondary fluorescent antibodies.

(F) Quantitative representation of the Western studies shown in (E).
HER3 targeting with an Antibody Drug Conjugate Bypasses Resistance to anti-HER2 therapies (2020)
Figure 4

Figure 4. Mechanism of action of EV20/MMAF.

(A) Cell cycle analysis by flow cytometry of BT474 and BTRH cells (50,000 events) treated with EV20/MMAF (10 nM) for the indicated times.

(B) BT474 and BTRH cells were treated for the indicated days with EV20/MMAF (10 nM), lysed and the amount of different proteins analyzed by Western. Numbers below the blots show the quantitation of the signal of each band, referred to time 0.

(C) Action of EV20/MMAF on mitotic spindle formation. BT474 and BTRH cells were treated (10 nM, 48 hours), fixed, stained for β-tubulin (green) and DAPI (blue). Scale bar: 7.5 μm.

(D) Quantitative analysis of mitotic cells with abnormal spindles treated or not with EV20/MMAF (10 nM, 48 hours) in BT474 and BTRH cells. Bars represent the mean + SD of two independent experiments, calculated as follows: (number of mitotic cells with abnormal spindles/total number of mitotic cells) ×100 (%). ** P<0.01. Exact P‐values and the statistical test used are indicated in Appendix Table S6.

(E) Cell death induction by EV20/MMAF (10 nM) analyzed by double annexin V and PI staining in BT474 and BTRH cells (50,000 events).

(F) Time-course analysis of the effect of EV20/MMAF (10 nM) on cleaved-caspase-3, analyzed by Western blotting in BT474 and BTRH cells. GAPDH was used as a loading control. Samples with intensity values of 1 were used as reference.

(G) Fluorimetric analyses of caspase-3 activity in BT474 and BTRH cells treated with 10 nM EV20/MMAF. Data show the mean + SD of triplicates of an experiment that was repeated twice.
HER3 targeting with an Antibody Drug Conjugate Bypasses Resistance to anti-HER2 therapies (2020)
Figure 5

Figure 5. In vivo effect of EV20/MMAF.

(A) In vivo effect of EV20 (10 mg/kg, n=4), untreated control (PBS, n=4) and EV20/MMAF (3.3 mg/kg, n=5; 10 mg/kg, n=4) on tumor growth in mice injected with BTRH cells. Mice were treated when tumors reached a volume of 500 mm3. Data are represented as mean + SEM. Exact P‐values of all comparisons of the last measurements and the statistical test used are indicated in Appendix Table S7.

(B) In vivo effect of single-dose EV20 (10 mg/kg, n=3) untreated control (PBS, n=4), single-dose EV20/MMAF (10 mg/kg, n=4) or weekly trastuzumab (30 mg/kg, n=4) on tumor growth in mice injected with BTRH#10 cells. Data are represented as mean + SEM. Exact P‐values of all comparisons of the last measurements and the statistical test used are indicated in Appendix Table S8.

(C) In vivo effect of single-dose EV20 (10 mg/kg, n=4), untreated control (PBS, n=4), single-dose EV20/MMAF (10 mg/kg, n=4) or weekly trastuzumab (30 mg/kg, n=4) on tumor growth in mice injected with HCC1954 cells. Data are represented as mean + SEM. Exact P‐values of all comparisons of the last measurements and the statistical test used are indicated in Appendix Table S9.

(D) Analysis of pHistone H3, HER3, pHER3 and cleaved caspase-3 in tumors of mice injected with BTRH and treated (T) or not (C) with EV20/MMAF (3.3 mg/kg for 24 hours or two weeks). Numbers below the blots show the quantitation of the signal of each band, referred to that of a control untreated tumor.

(E) Long-term monitoring of mice injected with BTRH cells and treated with EV20/MMAF (3.3 mg/kg, n=5; 10 mg/kg, n=4). Where indicated, mice were treated with EV20/MMAF. Data were represented as mean + SD of the different mice groups.

Data information: In (A, B, C and E), when error bars are invisible, that is because they are small and are covered by the graphic's symbols.