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Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN . Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients. The molecular mechanisms underlying acquired chemoresistance to proteasome inhibitors (PIs) in multiple myeloma (MM) remain to be explored. Here, the authors highlight the role of heterochromatin protein 1 gamma as a potential target for overcoming resistance to PIs in MM.

Retroviruses, especially the pathogenic human immunodeficiency virus type 1 (HIV-1), have severely threatened human health for decades. Retroviruses can form stable latent reservoirs via retroviral DNA integration into the host genome, and then be temporarily transcriptional silencing in infected cells, which makes retroviral infection incurable. Although many cellular restriction factors interfere with various steps of the life cycle of retroviruses and the formation of viral latency, viruses can utilize viral proteins or hijack cellular factors to evade intracellular immunity. Many post-translational modifications play key roles in the cross-talking between the cellular and viral proteins, which has greatly determined the fate of retroviral infection. Here, we reviewed recent advances in the regulation of ubiquitination and SUMOylation in the infection and latency of retroviruses, focusing on both host defense- and virus counterattack-related ubiquitination and SUMOylation system. We also summarized the development of ubiquitination- and SUMOylation-targeted anti-retroviral drugs and discussed their therapeutic potential. Manipulating ubiquitination or SUMOylation pathways by targeted drugs could be a promising strategy to achieve a “sterilizing cure” or “functional cure” of retroviral infection.

A three-dimensional numerical investigation of turbulent heat transfer and fluid flow characteristics of the new heat exchanger and self-support of a rectangular converging-diverging (SS-RCD) tube bundle heat exchanger with different inserts was performed. The values of the Reynolds number varied from 27,900 to 41,900. The baseline case (without an insert) was compared with two enhanced configurations: one circular hole in the baffle plate (one-circle case) and a rectangular hole in the baffle plate (one-rectangle case). Compared with the baseline case, the airside Nusselt number (Nu) of the enhanced cases improved by 39.6~48.0% and 36.2~40.2% and had an associated friction factor (f) penalty increase of 53.9–66.7% and 60.7–77.8%, respectively. The baseline case was compared with three enhanced configurations: one-circle case, two-circle case, and three-circle case baffle plate. Compared with the baseline case, Nu of the enhanced cases improved by 39.6–48.0%, 36.2–45.4%, and 35.0–44.2%, with f penalty increases of 53.9–66.7%, 44.9–60.0%, and 43.8–60.0%, respectively. The overall performance was conducted by heat transfer enhancement factor (η). It was found that the one circle case obtained the best overall performance. The numerical results were analyzed from the viewpoint of the field synergy principle. It was found that the reduction in the average intersection angle between the velocity vector and the temperature gradient (θ) was one of the essential factors influencing heat transfer performance.

Oxaliplatin (Oxa) has been extensively employed in treatment of colorectal cancer (CRC), yet frequent occurrence of chemoresistance poses a significant obstacle to achieving long-term disease-free survival for CRC patients. In this study, we employed a CRISPR/Cas9 sgRNA library targeting 1,117 human ubiquitination-related genes to screen key regulators of sensitivity to Oxa and identified the Makorin Ring Finger Protein 1 (MKRN1), an E3 ligase, as an Oxa-resistant gene of CRC cells. Clinically, MKRN1 is highly expressed in CRC tissues compared with the adjacent normal tissue, and its upregulation is correlated with poor therapeutic response, disease progression, and worse overall survival of CRC patients treated with Oxa-based regimens. In CRC cells, gain- and loss-of-function studies of MKRN1 respectively altered the sensitivity to Oxa treatment, as evidenced by changes in IC50 values and cell apoptosis. Mechanistic analysis revealed that MKRN1 interacts with Aspartate/Glutamate Carrier 1 (AGC1), facilitating degradation of AGC1 via K11- and K29-linked ubiquitination, thereby affecting mitochondrial function including energy metabolism and antioxidant responses. Through reprogramming of metabolic genes, this process enhances the expression of heat shock protein HSPD1 and HSP90AA1, while reducing oxidative stress, ultimately contributing to the development of Oxa resistance in CRC cells. Moreover, AGC1 knockdown rescued the MKRN1-deficiency induced Oxa-sensitivity of CRC cells and in xenograft mouse model. Translationally, we identified Rabdosiin as a potential inhibitor of MKRN1 through virtual screening, and validated the synergetic effect of Rabdosiin and Oxa in treating Oxa-resistant CRC cells both in vitro and in vivo. Taken together, our findings highlight the pivotal role of MKRN1-AGC1 axis in dictating CRC chemoresistance and offer novel therapeutic strategies for overcoming Oxa-resistance. Graphical Abstract

Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).

Viruses have threatened human lives for decades, causing both chronic and acute infections accompanied by mild to severe symptoms. During the long journey of confrontation, humans have developed intricate immune systems to combat viral infections. In parallel, vaccines are invented and administrated to induce strong protective immunity while generating few adverse effects. With advancements in biochemistry and biophysics, different kinds of vaccines in versatile forms have been utilized to prevent virus infections, although the safety and effectiveness of these vaccines are diverse from each other. In this review, we first listed and described major pathogenic viruses and their pandemics that emerged in the past two centuries. Furthermore, we summarized the distinctive characteristics of different antiviral vaccines and adjuvants. Subsequently, in the main body, we reviewed recent advances of nanoparticles in the development of next-generation vaccines against influenza viruses, coronaviruses, HIV, hepatitis viruses, and many others. Specifically, we described applications of self-assembling protein polymers, virus-like particles, nano-carriers, and nano-adjuvants in antiviral vaccines. We also discussed the therapeutic potential of nanoparticles in developing safe and effective mucosal vaccines. Nanoparticle techniques could be promising platforms for developing broad-spectrum, preventive, or therapeutic antiviral vaccines.

In addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

The outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.

Background Aging‐associated osteoporosis is frequently seen in the elderly in clinic, but efficient managements are limited because of unclear nosogenesis. The current study aims to investigate the role of melatonin on senescent bone marrow stromal cells (BMSCs) and the underlying regulating mechanism. Methods Melatonin levels were tested by ELISA. Gene expression profiles were performed by RNA‐sequencing, enrichment of H3K36me2 on gene promoters was analyzed by Chromatin Immunoprecipitation Sequencing (ChIP‐seq), and chromatin accessibility was determined by Assay for Transposase‐Accessible Chromatin with high‐throughput sequencing (ATAC‐seq). Osteogenesis of BMSCs in vitro was measured by Alizarin Red and Alkaline Phosphatase staining, and in vivo effects of melatonin was assessed by histological staining and micro computed tomography (micro‐CT) scan. Correlation of NSD2 expression and severity of senile osteoporosis patients were analyzed by Pearson correlation. Results Melatonin levels were decreased during aging in human bone marrow, accompanied by downregulation of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) expression in the senescent BMSCs. Melatonin stimulated the expression of NSD2 through MT1/2‐mediated signaling pathways, resulting in the rebalancing of H3K36me2 and H3K27me3 modifications to increase chromatin accessibility of the osteogenic genes, runt‐related transcription factor 2 (RUNX2) and bone gamma‐carboxyglutamate protein (BGLAP). Melatonin promoted osteogenesis of BMSCs in vitro, and alleviates osteoporosis progression in the aging mice. In clinic, severity of senile osteoporosis (SOP) was negatively correlated with melatonin level in bone marrow, as well as NSD2 expression in BMSCs. Similarly, melatonin remarkably enhanced osteogenic differentiation of BMSCs derived from SOP patients in vitro. Conclusions Collectively, our study dissects previously unreported mechanistic insights into the epigenetic regulating machinery of melatonin in meliorating osteogenic differentiation of senescent BMSC, and provides evidence for application of melatonin in preventing aging‐associated bone loss. Melatonin enhances osteoblastogenesis of senescent BMSCs by upregulating the expression of the histone methyltransferase NSD2. NSD2 rebalances the distribution of H3K36me2 and H3K27me3 and faciliates chromatin accessibility on promoters of osteogenic genes RUNX2 and BGLAP. Our study potentiates the application of melatonin as a therapeutic agent for the prevention of aging‐associated osteoporosis in clinic.

BackgroundImmunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored.MethodsThe efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging.ResultsWe report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo.ConclusionThis study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now