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Fig. 2. Ovulation rate declines with increasing body weight but is improved by treatment with ER stress inhibitors. (A) Hematoxylin and Eosin-stained ovary sections from 14-week-old gonadotropin-treated lean (+/+ or +/bbb) and obese Blobby (bbb/bbb) mice. Arrows indicate unruptured follicles, which are prevalent in ovaries from obese mice. Representative examples from n=4 mice per genotype are shown. Panels a-c are higher magnifications of the indicated follicles of the Blobby mouse. (B) The number of ovulated oocytes in 14-week-old lean and obese mice treated with saline vehicle (Veh.), <t>salubrinal</t> (Sal) or BGP-15 i.p. once per day for 4 days. Values are means+s.e.m. (lean mice+Veh, n=19; lean+Sal, n=5; lean+BGP-15, n=10; obese mice+Veh, n=22; obese+Sal, n=16; obese+BGP-15, n=14). Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test; P<0.0001. Right panel: the number of ovulated oocytes in oviducts is not reduced in bbb/bbb mice prior to the onset of obesity, at 6 weeks of age (+/+; +/bbb: n=11; bbb/bbb n=4; Student’s t-test).

Salubrinal, supplied by Thermo Fisher, used in various techniques. Bioz Stars score: 93/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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salubrinal - by Bioz Stars, 2026-08

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1) Product Images from "Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors."

Article Title: Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors.

Journal: Development (Cambridge, England)

doi: 10.1242/dev.114850

Figure Legend Snippet: Fig. 2. Ovulation rate declines with increasing body weight but is improved by treatment with ER stress inhibitors. (A) Hematoxylin and Eosin-stained ovary sections from 14-week-old gonadotropin-treated lean (+/+ or +/bbb) and obese Blobby (bbb/bbb) mice. Arrows indicate unruptured follicles, which are prevalent in ovaries from obese mice. Representative examples from n=4 mice per genotype are shown. Panels a-c are higher magnifications of the indicated follicles of the Blobby mouse. (B) The number of ovulated oocytes in 14-week-old lean and obese mice treated with saline vehicle (Veh.), salubrinal (Sal) or BGP-15 i.p. once per day for 4 days. Values are means+s.e.m. (lean mice+Veh, n=19; lean+Sal, n=5; lean+BGP-15, n=10; obese mice+Veh, n=22; obese+Sal, n=16; obese+BGP-15, n=14). Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test; P<0.0001. Right panel: the number of ovulated oocytes in oviducts is not reduced in bbb/bbb mice prior to the onset of obesity, at 6 weeks of age (+/+; +/bbb: n=11; bbb/bbb n=4; Student’s t-test).

Techniques Used: Staining, Saline

Fig. 5. Treatment with salubrinal or BGP-15 induces mtDNA replication and normalizes mitochondrial membrane potential (ΔΨm) and autophagy in oocytes from obese mice. Obese mice (bbb/bbb) or lean littermates (+/+ or +/bbb) were treated with vehicle (Veh), salubrinal (Sal) or BGP-15 i.p. once daily for 4 days, and oocytes were collected from the oviducts. (A) Live oocytes stained with JC-1, where red fluorescence indicates high ΔΨm, and green indicates low ΔΨm. (B) Ratio of red to green fluorescence, an indicator of mitochondrial activity. Data are presented as means+s.e.m., n=6-30 oocytes from four mice per group. (C) Live oocytes were assessed for autophagic vacuoles, visualized as green fluorescence. Hoechst 33342 (blue). (D) Autophagy levels were quantified as the sum total of green fluorescence within each oocyte. Data are presented as means+s.e.m., n=8-10 oocytes from three mice per group. (E) mtDNA copy number in individual oocytes collected from treated mice. Data are presented as means+s.e.m.; n=19-38 oocytes from six mice per group over three independent experiments. (F) Representative examples of oocytes from three or four mice per treatment group immunostained for TFAM or DRP1 (green) and Hoechst 33342 (blue). Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test, P<0.0001.

Figure Legend Snippet: Fig. 5. Treatment with salubrinal or BGP-15 induces mtDNA replication and normalizes mitochondrial membrane potential (ΔΨm) and autophagy in oocytes from obese mice. Obese mice (bbb/bbb) or lean littermates (+/+ or +/bbb) were treated with vehicle (Veh), salubrinal (Sal) or BGP-15 i.p. once daily for 4 days, and oocytes were collected from the oviducts. (A) Live oocytes stained with JC-1, where red fluorescence indicates high ΔΨm, and green indicates low ΔΨm. (B) Ratio of red to green fluorescence, an indicator of mitochondrial activity. Data are presented as means+s.e.m., n=6-30 oocytes from four mice per group. (C) Live oocytes were assessed for autophagic vacuoles, visualized as green fluorescence. Hoechst 33342 (blue). (D) Autophagy levels were quantified as the sum total of green fluorescence within each oocyte. Data are presented as means+s.e.m., n=8-10 oocytes from three mice per group. (E) mtDNA copy number in individual oocytes collected from treated mice. Data are presented as means+s.e.m.; n=19-38 oocytes from six mice per group over three independent experiments. (F) Representative examples of oocytes from three or four mice per treatment group immunostained for TFAM or DRP1 (green) and Hoechst 33342 (blue). Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test, P<0.0001.

Techniques Used: Membrane, Staining, Fluorescence, Activity Assay

Fig. 6. Oocytes from obese Blobby mice exhibit impaired embryo development that is restored by treatment with salubrinal or BGP-15. Obese Blobby (bbb/bbb) mice or lean littermates (+/+ or +/bbb) at 14 weeks of age (except where indicated) were treated with vehicle (Veh; saline), salubrinal (Sal) or BGP-15 daily for 4 days. Ovulated oocytes were collected from oviducts 16 h following hCG injection and fertilized in vitro. (A) At 4 h after in vitro fertilization, many degenerate oocytes (arrows) from untreated obese mice were observed. (B) The percentage of viable oocytes presented as means+s.e.m. Embryo development was assessed on day 2 and day 5 following IVF and is presented as the mean percentage of embryos exhibiting appropriate (‘on-time’) development+s.e.m. (C) Two-cell embryos developed from viable oocytes by day 2. (D) Blastocysts developed from two-cell embryos by day 5. Lean, n=24; lean+Sal, n=7; lean+BGP- 15, n=6; Blobby, n=15; Blobby+Sal, n=6; Blobby+BGP-15, n=7 pools of oocytes from animals within same group. [C,D, right-hand panels are identical assessments of oocytes from 6-week-old (non-obese) mice. +/+, n=13; Blobby, n=10.] (E) Blastocysts were collected at day 5 and the mtDNA copy number of individual blastocysts was measured by using quantitative PCR. Data are expressed as mean copy number+s.e.m.; lean, n=22 blastocysts; lean+Sal, n=10 blastocysts; lean+BGP-15, n=7 blastocysts; Blobby, n=14 blastocysts; Blobby+Sal, n=10 blastocysts; Blobby+BGP-15, n=7 blastocysts collected from three independent IVF experiments. Different letters indicate significant differences by one-way ANOVA, Tukey’s post hoc test; P<0.0001.

Figure Legend Snippet: Fig. 6. Oocytes from obese Blobby mice exhibit impaired embryo development that is restored by treatment with salubrinal or BGP-15. Obese Blobby (bbb/bbb) mice or lean littermates (+/+ or +/bbb) at 14 weeks of age (except where indicated) were treated with vehicle (Veh; saline), salubrinal (Sal) or BGP-15 daily for 4 days. Ovulated oocytes were collected from oviducts 16 h following hCG injection and fertilized in vitro. (A) At 4 h after in vitro fertilization, many degenerate oocytes (arrows) from untreated obese mice were observed. (B) The percentage of viable oocytes presented as means+s.e.m. Embryo development was assessed on day 2 and day 5 following IVF and is presented as the mean percentage of embryos exhibiting appropriate (‘on-time’) development+s.e.m. (C) Two-cell embryos developed from viable oocytes by day 2. (D) Blastocysts developed from two-cell embryos by day 5. Lean, n=24; lean+Sal, n=7; lean+BGP- 15, n=6; Blobby, n=15; Blobby+Sal, n=6; Blobby+BGP-15, n=7 pools of oocytes from animals within same group. [C,D, right-hand panels are identical assessments of oocytes from 6-week-old (non-obese) mice. +/+, n=13; Blobby, n=10.] (E) Blastocysts were collected at day 5 and the mtDNA copy number of individual blastocysts was measured by using quantitative PCR. Data are expressed as mean copy number+s.e.m.; lean, n=22 blastocysts; lean+Sal, n=10 blastocysts; lean+BGP-15, n=7 blastocysts; Blobby, n=14 blastocysts; Blobby+Sal, n=10 blastocysts; Blobby+BGP-15, n=7 blastocysts collected from three independent IVF experiments. Different letters indicate significant differences by one-way ANOVA, Tukey’s post hoc test; P<0.0001.

Techniques Used: Saline, Injection, In Vitro, Real-time Polymerase Chain Reaction

Fig. 7. Altered fetal outcomes of oocytes from obese Blobby mice are alleviated after treatment with salubrinal or BGP-15. Obese mice (bbb/bbb) and lean littermates (+/+) were treated with vehicle (Veh; saline), salubrinal (Sal) or BGP-15 for 4 days, followed by the isolation of oocytes from oviducts and fertilization by using IVF. Blastocysts were collected at day 5 of culture and transferred to non-obese pseudo-pregnant recipient mice with six blastocysts per uterine horn. On embryonic day 14.5, fetuses were collected and weighed (A). Liver (B), heart (C) and kidney (D) were dissected and the relative mtDNA copy number normalized to β-actin nuclear DNA was determined. Data are presented as means+s.e.m.; lean+Veh, n=18 fetuses from six surrogates; Blobby+Veh, n=20 fetuses from six surrogates; Blobby+Sal, n=22 fetuses from six surrogates; Blobby+BGP-15, n=15 fetuses from four surrogates. (E) Liver mtDNA samples (n=4 fetuses from each treatment group) were analyzed by using next generation sequencing, and rearrangements were identified. Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test; P<0.01.

Figure Legend Snippet: Fig. 7. Altered fetal outcomes of oocytes from obese Blobby mice are alleviated after treatment with salubrinal or BGP-15. Obese mice (bbb/bbb) and lean littermates (+/+) were treated with vehicle (Veh; saline), salubrinal (Sal) or BGP-15 for 4 days, followed by the isolation of oocytes from oviducts and fertilization by using IVF. Blastocysts were collected at day 5 of culture and transferred to non-obese pseudo-pregnant recipient mice with six blastocysts per uterine horn. On embryonic day 14.5, fetuses were collected and weighed (A). Liver (B), heart (C) and kidney (D) were dissected and the relative mtDNA copy number normalized to β-actin nuclear DNA was determined. Data are presented as means+s.e.m.; lean+Veh, n=18 fetuses from six surrogates; Blobby+Veh, n=20 fetuses from six surrogates; Blobby+Sal, n=22 fetuses from six surrogates; Blobby+BGP-15, n=15 fetuses from four surrogates. (E) Liver mtDNA samples (n=4 fetuses from each treatment group) were analyzed by using next generation sequencing, and rearrangements were identified. Different letters indicate significant differences calculated by one-way ANOVA, Tukey’s post hoc test; P<0.01.

Techniques Used: Saline, Isolation, Next-Generation Sequencing

Image Search Results

Effects of the selective eIF2α dephosphorylation inhibitor salubrinal on ferroptosis‐related protein expression in HASMCs and AoSMCs. (A) Alterations in Ferroptosis‐Related Protein Expression Following Treatment with the eIF2α Dephosphorylation Inhibitor Salubrinal in HASMCs and AoSMCs. (B) Glucose‐regulated protein 78 (GRP78) expression, reflecting the activation status of ER chaperone machinery under conditions of altered eIF2α signalling. (C) Western blot analysis of phosphorylated protein kinase RNA‐like ER kinase (p‐PERK) in HASMCs and AoSMCs after 24 h treatment with salubrinal (25 μM), showing modulation of the ER stress response via inhibition of eIF2α dephosphorylation. (D) Phosphorylated eukaryotic initiation factor 2α (p‐EIF2α) protein levels, demonstrating sustained phosphorylation in both cell types following salubrinal treatment. (E) Activating transcription factor 4 (ATF4) protein levels, upregulated in response to persistent eIF2α phosphorylation, consistent with activation of downstream stress signalling. (F) ChaC glutathione‐specific γ‐glutamylcyclotransferase 1 (CHAC1) protein expression, indicating potential enhancement of glutathione degradation following eIF2α pathway activation. (G) Glutathione peroxidase 4 (GPX4) protein levels, showing a trend toward reduction, suggestive of compromised antioxidant defence and potential promotion of ferroptotic processes. Densitometric quantification of protein bands from panels (A–F), normalized to β‐Actin and expressed as fold change relative to control, confirming significant alterations in ferroptosis‐related proteins in response to salubrinal treatment. Data are presented as mean ± SD ( n = 3 independent experiments). * p < 0.05, ** p < 0.01 vs. Control.

Journal: Journal of Cellular and Molecular Medicine

Article Title: EIF2α – ATF4 – CHAC1 Signalling Links ER Stress to Ferroptosis in Human Aortic Smooth Muscle Cells: Mechanistic Insights and Therapeutic Implications

doi: 10.1111/jcmm.71104

Figure Lengend Snippet: Effects of the selective eIF2α dephosphorylation inhibitor salubrinal on ferroptosis‐related protein expression in HASMCs and AoSMCs. (A) Alterations in Ferroptosis‐Related Protein Expression Following Treatment with the eIF2α Dephosphorylation Inhibitor Salubrinal in HASMCs and AoSMCs. (B) Glucose‐regulated protein 78 (GRP78) expression, reflecting the activation status of ER chaperone machinery under conditions of altered eIF2α signalling. (C) Western blot analysis of phosphorylated protein kinase RNA‐like ER kinase (p‐PERK) in HASMCs and AoSMCs after 24 h treatment with salubrinal (25 μM), showing modulation of the ER stress response via inhibition of eIF2α dephosphorylation. (D) Phosphorylated eukaryotic initiation factor 2α (p‐EIF2α) protein levels, demonstrating sustained phosphorylation in both cell types following salubrinal treatment. (E) Activating transcription factor 4 (ATF4) protein levels, upregulated in response to persistent eIF2α phosphorylation, consistent with activation of downstream stress signalling. (F) ChaC glutathione‐specific γ‐glutamylcyclotransferase 1 (CHAC1) protein expression, indicating potential enhancement of glutathione degradation following eIF2α pathway activation. (G) Glutathione peroxidase 4 (GPX4) protein levels, showing a trend toward reduction, suggestive of compromised antioxidant defence and potential promotion of ferroptotic processes. Densitometric quantification of protein bands from panels (A–F), normalized to β‐Actin and expressed as fold change relative to control, confirming significant alterations in ferroptosis‐related proteins in response to salubrinal treatment. Data are presented as mean ± SD ( n = 3 independent experiments). * p < 0.05, ** p < 0.01 vs. Control.

Article Snippet: Erastin (Targetmol, Cat. No. T1765, China); BSO (Targetmol, Cat. No. T5371, China); Salubrinal (Targetmol, Cat. No. 405060‐95‐9, China); Ferrostatin‐1 (Fer‐1) (Targetmol, Cat. No. T6500, China); TRIzol reagent (Invitrogen, Cat. No. 15596026, USA); CCK‐8 kit (Abbkine, Cat. No. BMU106‐CN, China); BCA Protein Assay Kit (Thermo Fisher Scientifi, Cat. No. 23225, USA); C11‐BODIPY 581/591 (Beyotime, Cat. No. S0043S, China); FerroOrange (Maokangbio, Cat. No. MX4559, China); MDA Assay Kit (Abbkine, Cat. No. KTB1050, China); TUNEL Apoptosis Detection Kit (Abbkine, Cat. No. KTA2010, China).

Techniques: De-Phosphorylation Assay, Expressing, Activation Assay, Western Blot, Inhibition, Phospho-proteomics, Control

GR-mediated suppression of cGAS-STING signaling is executed by PPP1CB and reversed by DXM. ( A ) High-throughput mass spectrometry revealed distinct IRF3 interactomes before and after DXM treatment, including enriched protein kinases, phosphatases, and ubiquitin E3 ligases (eg, PPP1CB and RIOK1) in the untreated condition. ( B ) Activation of the cGAS-STING pathway in ARP1 cells treated with DXM in combination with the PP1 inhibitor salubrinal or the RIOK1 inhibitor toyocamycin was assessed by Western blot. ( C ) qPCR analysis of ISG15 mRNA levels in ARP1 cells treated with DXM and either toyocamycin or salubrinal. ( D ) Activation of the cGAS-STING pathway in MM cells treated with DXM in combination with the indicated siRNA transfection was assessed by Western blot. ( E ) qPCR analysis of ISG15 mRNA levels in MM cells treated with DXM in combination with the indicated siRNA transfection. ( F ) Dose-dependent effect of salubrinal or toyocamycin (0–20 μM) on cGAS-STING pathway activation in MM cells, evaluated by Western blot. ( G ) qPCR analysis of IFNB , ISG15 , and CXCL9 mRNA in MM cells treated with or without salubrinal. ( H ) IF quantification of IRF3 colocalized with PPP1CB is shown in ( H ). ( I ) Co-IP in MM cells demonstrating interactions among PPP1CB, GR, TBK1, and IRF3 under DXM treatment or control conditions. ( G ) IF analysis of the interaction between PPP1CB and IRF3 with or without DXM treatment. Scale bar: 5 µm. ( K ) Co-IP in HEK-293 cells demonstrating interactions among PPP1CB, GR, and IRF3 under DXM treatment or control conditions. ( L, M ) Co-IP in MM cells demonstrating interactions among PPP1CB, GR, TBK1, and IRF3 under DXM treatment or control conditions. ( N ) Crystal structure of DXM (green sticks) bound to the GR (PDB 1M2Z). GR is shown in a pale-yellow cartoon representation. Key binding residues are displayed as sticks (wild-type in gray, mutated in pink), with critical interactions indicated by yellow dashed lines. ( O ) Co-IP showed that mutation or truncation of NR3C1 (GR) abolishes the DXM-induced modulation of interactions among GR, PPP1CB, and IRF3. ( P, Q ) Activation of the cGAS-STING pathway in MM cells treated with DXM in combination with the indicated siRNA and plasmid transfection was assessed by Western blot. ( R ) qPCR analysis of ISG15 mRNA levels in MM cells treated with DXM in combination with the indicated siRNA and plasmid transfection. Data are representative of at least three independent repeated experiments without any inclusion or exclusion. Data are presented as mean ± SEM and were analyzed by using the Student’s t-test and ANOVA with Tukey’s test (> two groups) (n.s. for no significance, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ANOVA, analysis of variance; cGAS-STING, cyclic GMP-AMP synthase/stimulator of interferon genes; Co-IP, Co-immunoprecipitation; DBD, DNA-binding domain; DXM, dexamethasone; DMSO, Dimethyl Sulfoxide ; GR, glucocorticoid receptor; HT-DNA, herring-testis DNA; IF, immunofluorescence; MM, multiple myeloma; PBS, phosphate buffered saline; qPCR, quantitative real-time PCR.

Journal: Journal for Immunotherapy of Cancer

Article Title: Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling

doi: 10.1136/jitc-2026-015256

Figure Lengend Snippet: GR-mediated suppression of cGAS-STING signaling is executed by PPP1CB and reversed by DXM. ( A ) High-throughput mass spectrometry revealed distinct IRF3 interactomes before and after DXM treatment, including enriched protein kinases, phosphatases, and ubiquitin E3 ligases (eg, PPP1CB and RIOK1) in the untreated condition. ( B ) Activation of the cGAS-STING pathway in ARP1 cells treated with DXM in combination with the PP1 inhibitor salubrinal or the RIOK1 inhibitor toyocamycin was assessed by Western blot. ( C ) qPCR analysis of ISG15 mRNA levels in ARP1 cells treated with DXM and either toyocamycin or salubrinal. ( D ) Activation of the cGAS-STING pathway in MM cells treated with DXM in combination with the indicated siRNA transfection was assessed by Western blot. ( E ) qPCR analysis of ISG15 mRNA levels in MM cells treated with DXM in combination with the indicated siRNA transfection. ( F ) Dose-dependent effect of salubrinal or toyocamycin (0–20 μM) on cGAS-STING pathway activation in MM cells, evaluated by Western blot. ( G ) qPCR analysis of IFNB , ISG15 , and CXCL9 mRNA in MM cells treated with or without salubrinal. ( H ) IF quantification of IRF3 colocalized with PPP1CB is shown in ( H ). ( I ) Co-IP in MM cells demonstrating interactions among PPP1CB, GR, TBK1, and IRF3 under DXM treatment or control conditions. ( G ) IF analysis of the interaction between PPP1CB and IRF3 with or without DXM treatment. Scale bar: 5 µm. ( K ) Co-IP in HEK-293 cells demonstrating interactions among PPP1CB, GR, and IRF3 under DXM treatment or control conditions. ( L, M ) Co-IP in MM cells demonstrating interactions among PPP1CB, GR, TBK1, and IRF3 under DXM treatment or control conditions. ( N ) Crystal structure of DXM (green sticks) bound to the GR (PDB 1M2Z). GR is shown in a pale-yellow cartoon representation. Key binding residues are displayed as sticks (wild-type in gray, mutated in pink), with critical interactions indicated by yellow dashed lines. ( O ) Co-IP showed that mutation or truncation of NR3C1 (GR) abolishes the DXM-induced modulation of interactions among GR, PPP1CB, and IRF3. ( P, Q ) Activation of the cGAS-STING pathway in MM cells treated with DXM in combination with the indicated siRNA and plasmid transfection was assessed by Western blot. ( R ) qPCR analysis of ISG15 mRNA levels in MM cells treated with DXM in combination with the indicated siRNA and plasmid transfection. Data are representative of at least three independent repeated experiments without any inclusion or exclusion. Data are presented as mean ± SEM and were analyzed by using the Student’s t-test and ANOVA with Tukey’s test (> two groups) (n.s. for no significance, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ANOVA, analysis of variance; cGAS-STING, cyclic GMP-AMP synthase/stimulator of interferon genes; Co-IP, Co-immunoprecipitation; DBD, DNA-binding domain; DXM, dexamethasone; DMSO, Dimethyl Sulfoxide ; GR, glucocorticoid receptor; HT-DNA, herring-testis DNA; IF, immunofluorescence; MM, multiple myeloma; PBS, phosphate buffered saline; qPCR, quantitative real-time PCR.

Article Snippet: Salubrinal and toyocamycin were obtained from MedChemExpress.

Techniques: High Throughput Screening Assay, Mass Spectrometry, Ubiquitin Proteomics, Activation Assay, Western Blot, Transfection, Co-Immunoprecipitation Assay, Control, Binding Assay, Mutagenesis, Plasmid Preparation, Immunoprecipitation, Immunofluorescence, Saline, Real-time Polymerase Chain Reaction

Pharmacological PP1 inhibition enhances anti-myeloma immunity by boosting NK cell cytotoxicity and M1 macrophage polarization. ( A ) Schematic of the Transwell co-culture system (0.4 µm pore size) for MM cells and NK92MI cells, with or without salubrinal treatment. ( B ) qPCR analysis of mRNA expression of Perforin 1 , Granzyme A , and Granzyme B in NK92MI cells, cultured alone or with MM cells, and treated with or without salubrinal. ( C ) Schematic of the experimental setup for assessing ADCC: MM cells co-cultured with NK cells and daratumumab, with or without salubrinal. ( D ) ADCC activity against MM cells in the presence of DXM, evaluated by LDH release assay. ( E ) IFN-γ and TNF-α release in the supernatant of NK92MI and MM cell co-cultures, measured by ELISA, with or without salubrinal treatment. ( F ) Schematic of the Transwell co-culture system (0.4 µm pore size) for MM cells and macrophages, with or without salubrinal. ( G ) qPCR analysis of CD40 , NOS2 , IL-10 , and TGF-β mRNA levels in macrophages under the indicated conditions. ( H, I ) Surface expression of CD206 ( H ), CD80, and CD86 ( I ) on macrophages, analyzed by flow cytometry. ( J ) Schematic of the treatment regimen in the 5TMM3VT/C57BL/KaLwRij mouse model: vehicle control, bortezomib alone, salubrinal alone, and bortezomib+salubrinal combination. ( K ) Kaplan-Meier survival curves of 5TMM3VT-bearing mice treated as indicated (CTRL, bortezomib, salubrinal, and bortezomib+salubrinal) (n =7 per group). ( L ) Representative micro-CT images, IHC staining, and corresponding quantitative analysis for plasma cells (CD138 + ), CD8 + T cells, cytotoxic NK cells (NKp46 + ), M1-like macrophages (CD80 + ), and M2-like macrophages (CD206 + ) in mouse bone tissues. Scale bar: 100 µm. Data are representative of at least 3 independent repeated experiments without inclusion/exclusion. Animals were randomly assigned to experimental groups using a computer-generated random number sequence. The investigator was blinded to group allocation during the assignment process. Data are presented as mean ± SEM and were analyzed by using the Student’s t-test and ANOVA with Tukey’s test (> two groups) (n.s. for no significance, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ADCC, antibody-dependent cellular cytotoxicity; ANOVA, analysis of variance; DXM, dexamethasone; IHC, immunohistochemical; i.v., intravenous; LDH, lactate dehydrogenase; MM, multiple myeloma; NK, natural killer; qPCR, quantitative real-time PCR.

Journal: Journal for Immunotherapy of Cancer

Article Title: Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling

doi: 10.1136/jitc-2026-015256

Figure Lengend Snippet: Pharmacological PP1 inhibition enhances anti-myeloma immunity by boosting NK cell cytotoxicity and M1 macrophage polarization. ( A ) Schematic of the Transwell co-culture system (0.4 µm pore size) for MM cells and NK92MI cells, with or without salubrinal treatment. ( B ) qPCR analysis of mRNA expression of Perforin 1 , Granzyme A , and Granzyme B in NK92MI cells, cultured alone or with MM cells, and treated with or without salubrinal. ( C ) Schematic of the experimental setup for assessing ADCC: MM cells co-cultured with NK cells and daratumumab, with or without salubrinal. ( D ) ADCC activity against MM cells in the presence of DXM, evaluated by LDH release assay. ( E ) IFN-γ and TNF-α release in the supernatant of NK92MI and MM cell co-cultures, measured by ELISA, with or without salubrinal treatment. ( F ) Schematic of the Transwell co-culture system (0.4 µm pore size) for MM cells and macrophages, with or without salubrinal. ( G ) qPCR analysis of CD40 , NOS2 , IL-10 , and TGF-β mRNA levels in macrophages under the indicated conditions. ( H, I ) Surface expression of CD206 ( H ), CD80, and CD86 ( I ) on macrophages, analyzed by flow cytometry. ( J ) Schematic of the treatment regimen in the 5TMM3VT/C57BL/KaLwRij mouse model: vehicle control, bortezomib alone, salubrinal alone, and bortezomib+salubrinal combination. ( K ) Kaplan-Meier survival curves of 5TMM3VT-bearing mice treated as indicated (CTRL, bortezomib, salubrinal, and bortezomib+salubrinal) (n =7 per group). ( L ) Representative micro-CT images, IHC staining, and corresponding quantitative analysis for plasma cells (CD138 + ), CD8 + T cells, cytotoxic NK cells (NKp46 + ), M1-like macrophages (CD80 + ), and M2-like macrophages (CD206 + ) in mouse bone tissues. Scale bar: 100 µm. Data are representative of at least 3 independent repeated experiments without inclusion/exclusion. Animals were randomly assigned to experimental groups using a computer-generated random number sequence. The investigator was blinded to group allocation during the assignment process. Data are presented as mean ± SEM and were analyzed by using the Student’s t-test and ANOVA with Tukey’s test (> two groups) (n.s. for no significance, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). ADCC, antibody-dependent cellular cytotoxicity; ANOVA, analysis of variance; DXM, dexamethasone; IHC, immunohistochemical; i.v., intravenous; LDH, lactate dehydrogenase; MM, multiple myeloma; NK, natural killer; qPCR, quantitative real-time PCR.

Article Snippet: Salubrinal and toyocamycin were obtained from MedChemExpress.

Techniques: Inhibition, Co-Culture Assay, Pore Size, Expressing, Cell Culture, Activity Assay, Lactate Dehydrogenase Assay, Enzyme-linked Immunosorbent Assay, Flow Cytometry, Control, Micro-CT, Immunohistochemistry, Clinical Proteomics, Generated, Sequencing, Immunohistochemical staining, Real-time Polymerase Chain Reaction

Schematic model illustrates how DXM enhances anti-myeloma immunity by restoring the STING/IRF3 signaling. Under basal conditions (without DXM), the GR protein acts as a scaffold, assembling an inhibitory complex with PPP1CB, TBK1, and IRF3. This complex keeps STING-TBK1-IRF3 dephosphorylated and the pathway silenced in MM cells (lower left). Upon DXM stimulation, DXM binds the GR, leading to the dissociation of an inhibitory complex containing GR and the phosphatase PPP1CB. This disinhibition releases the TBK1-IRF3 axis, potentiating IFN production and subsequent ISG expression (lower right). The resulting immunogenic signals reshape the tumor microenvironment, promoting the infiltration and activation of cytotoxic NK cells and driving macrophage polarization toward an M1-like phenotype, and enhancing the anti-tumor effect (upper). In parallel, the PP1 inhibitor Salubrinal activates the cGAS-STING pathway by directly targeting PPP1CB, offering a complementary pharmacological strategy to augment anti-tumor immunity (lower right). cGAS-STING, cyclic GMP-AMP synthase/stimulator of interferon genes; DXM, dexamethasone; GR, glucocorticoid receptor; MM, multiple myeloma; NK, natural killer.

Journal: Journal for Immunotherapy of Cancer

Article Title: Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling

doi: 10.1136/jitc-2026-015256

Figure Lengend Snippet: Schematic model illustrates how DXM enhances anti-myeloma immunity by restoring the STING/IRF3 signaling. Under basal conditions (without DXM), the GR protein acts as a scaffold, assembling an inhibitory complex with PPP1CB, TBK1, and IRF3. This complex keeps STING-TBK1-IRF3 dephosphorylated and the pathway silenced in MM cells (lower left). Upon DXM stimulation, DXM binds the GR, leading to the dissociation of an inhibitory complex containing GR and the phosphatase PPP1CB. This disinhibition releases the TBK1-IRF3 axis, potentiating IFN production and subsequent ISG expression (lower right). The resulting immunogenic signals reshape the tumor microenvironment, promoting the infiltration and activation of cytotoxic NK cells and driving macrophage polarization toward an M1-like phenotype, and enhancing the anti-tumor effect (upper). In parallel, the PP1 inhibitor Salubrinal activates the cGAS-STING pathway by directly targeting PPP1CB, offering a complementary pharmacological strategy to augment anti-tumor immunity (lower right). cGAS-STING, cyclic GMP-AMP synthase/stimulator of interferon genes; DXM, dexamethasone; GR, glucocorticoid receptor; MM, multiple myeloma; NK, natural killer.

Article Snippet: Salubrinal and toyocamycin were obtained from MedChemExpress.

Techniques: Expressing, Activation Assay

OGD/R induces early activation of ER stress sensors followed by apoptosis in cultured cortical neurons, which is ameliorated by ER stress inhibitors. (A) Schematic representation of the timeline of the experimental procedures. Cortical neurons (7 DIV) were cultured in normal conditions (Control group) or exposed to oxygen/glucose deprivation for 4 hours followed by reperfusion (OGD/R group). Cell lysates were collected at various time points for Western blotting, and cell viability was evaluated after 24 hours reperfusion. (B) The cell viability of primary cortical neurons after OGD/R 24 hours was detected by MTT assay. Cortical neurons (7 DIV) under standard culture conditions were used as the control group ( n = 3). ** P < 0.01, vs. control, unpaired t -test. (C) Cell lysates from the OGD/R group were collected at different time points (0–24 hours) after reperfusion. For the control group, cell lysates were collected at the same time corresponding to 0 hours reperfusion of OGD/R group. Levels of ER stress sensors, protein synthesis, and apoptosis-related proteins were examined by western blot analysis. (D–K) Quantifications of the normalized levels of p-PERK/PERK (D, n = 4), p-eIF2α/eIF2α (E, n = 3), p-IRE1/IRE1 (F, n = 3), ATF6 (G, n = 3), puromycin (H, n = 3), ATF4 (I, n = 3), CHOP (J, n = 3), and cleaved-caspase-3 (K, n = 3). GAPDH and α-tubulin served as the loading control. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, vs . control, one-way analysis of variance followed by Dunnett’s multiple comparison test. (L) A schematic illustration of the application of ER stress inhibitors, sodium 4-PBA or Sal, to neurons 1 hour before OGD and during OGD (−5 to 0 hours). (M, N) MTT assay was performed to evaluate cell viability of neurons treated with 4-PBA or Sal ( n = 3). **** P < 0.0001, OGD/R vs. control; # P < 0.05, ## P < 0.01, 4-PBA (50 or 100 µM) or Sal (25 or 100 µM) vs. OGD/R, unpaired t -test. Data are shown as mean ± SEM. 4-PBA: Sodium 4-phenylbutyrate; ATF: activating transcription factor; CHOP: CCAAT/enhancer binding protein homologous protein; C-Casp-3: cleaved-caspase-3; DIV: day in vitro ; eIF2α: eukaryotic translation initiation factor 2α; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IRE1: inositol requiring enzyme 1; MTT: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; OGD: oxygen-glucose deprivation; OGD/R: oxygen-glucose deprivation/reperfusion; p-: phosphorylated-; PERK: double-stranded RNA-activated protein kinase-like ER kinase; Sal: salubrinal.

Journal: Neural Regeneration Research

Article Title: Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress

doi: 10.4103/NRR.NRR-D-24-00044

Figure Lengend Snippet: OGD/R induces early activation of ER stress sensors followed by apoptosis in cultured cortical neurons, which is ameliorated by ER stress inhibitors. (A) Schematic representation of the timeline of the experimental procedures. Cortical neurons (7 DIV) were cultured in normal conditions (Control group) or exposed to oxygen/glucose deprivation for 4 hours followed by reperfusion (OGD/R group). Cell lysates were collected at various time points for Western blotting, and cell viability was evaluated after 24 hours reperfusion. (B) The cell viability of primary cortical neurons after OGD/R 24 hours was detected by MTT assay. Cortical neurons (7 DIV) under standard culture conditions were used as the control group ( n = 3). ** P < 0.01, vs. control, unpaired t -test. (C) Cell lysates from the OGD/R group were collected at different time points (0–24 hours) after reperfusion. For the control group, cell lysates were collected at the same time corresponding to 0 hours reperfusion of OGD/R group. Levels of ER stress sensors, protein synthesis, and apoptosis-related proteins were examined by western blot analysis. (D–K) Quantifications of the normalized levels of p-PERK/PERK (D, n = 4), p-eIF2α/eIF2α (E, n = 3), p-IRE1/IRE1 (F, n = 3), ATF6 (G, n = 3), puromycin (H, n = 3), ATF4 (I, n = 3), CHOP (J, n = 3), and cleaved-caspase-3 (K, n = 3). GAPDH and α-tubulin served as the loading control. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, vs . control, one-way analysis of variance followed by Dunnett’s multiple comparison test. (L) A schematic illustration of the application of ER stress inhibitors, sodium 4-PBA or Sal, to neurons 1 hour before OGD and during OGD (−5 to 0 hours). (M, N) MTT assay was performed to evaluate cell viability of neurons treated with 4-PBA or Sal ( n = 3). **** P < 0.0001, OGD/R vs. control; # P < 0.05, ## P < 0.01, 4-PBA (50 or 100 µM) or Sal (25 or 100 µM) vs. OGD/R, unpaired t -test. Data are shown as mean ± SEM. 4-PBA: Sodium 4-phenylbutyrate; ATF: activating transcription factor; CHOP: CCAAT/enhancer binding protein homologous protein; C-Casp-3: cleaved-caspase-3; DIV: day in vitro ; eIF2α: eukaryotic translation initiation factor 2α; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IRE1: inositol requiring enzyme 1; MTT: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; OGD: oxygen-glucose deprivation; OGD/R: oxygen-glucose deprivation/reperfusion; p-: phosphorylated-; PERK: double-stranded RNA-activated protein kinase-like ER kinase; Sal: salubrinal.

Article Snippet: The ER stress inhibitors sodium 4-phenylbutyrate (4-PBA, 50 and 100 μM, Selleck, Houston, TX, USA) and salubrinal (25 and 100 μM, Selleck) were added for 1 hour before OGD or after reperfusion.

Techniques: Activation Assay, Cell Culture, Control, Western Blot, MTT Assay, Comparison, Binding Assay, In Vitro

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