Muhammad Zahoor

• Farhan, Hesso; Zahoor, Muhammad; Tauer, Josephine T. & Högler, Wolfgang (2025). The endoplasmic reticulum proteostasis network and bone disease. Trends in Molecular Medicine. ISSN 1471-4914. 2193, s. 1–14. doi: 10.1016/j.molmed.2025.06.005. Fulltekst i vitenarkiv Vis sammendrag

  Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the function of these cells is proteostasis, where the endoplasmic reticulum (ER) oversees protein synthesis, quality control, folding, and the secretion of proteins such as collagen type I. Emerging research links ER proteostasis defects to skeletal disorders caused by impaired bone development and mass. We explore the mechanisms of ER proteostasis, including the unfolded protein response (UPR), and discuss how genetic, metabolic, and environmental factors disrupt these pathways and contribute to bone pathology. We also highlight the need for further mechanistic insights which could pave the way for novel therapies that target ER–Golgi traffic and inhibit ER stress in bone diseases.

• Våtsveen, Thea Kristin; Giliberto, Mariaserena; Björnsdottir, Valgerdur; Centonze, Federica Grazia; Besse, Andrej & Frey, Yannick [Vis alle 19 forfattere av denne artikkelen] (2025). Targeting proteostasis in multiple myeloma through inhibition of LTK. Leukemia. ISSN 0887-6924. 39(9), s. 2237–2245. doi: 10.1038/s41375-025-02682-8. Fulltekst i vitenarkiv Vis sammendrag

  Multiple myeloma (MM) cells secrete high levels of immunoglobulin and are therefore addicted to mechanisms that maintain proteome homeostasis (proteostasis). While proteasome inhibitors that target the degradative aspect of proteostasis have proven effective, only limited attempts have been made to target protein secretion. Here we show that the receptor tyrosine kinase LTK is a regulatory node in the proteostasis network that responds to secretory load and helps cells maintain a high secretory output. LTK is a highly similar paralog to ALK and by repurposing existing ALK inhibitors, we demonstrate that targeting LTK causes immunoglobulin retention, ER stress and subsequent apoptosis of primary MM cells, even in patients refractory to proteasome inhibitors. Thus, LTK is a novel therapeutic target in the biosynthetic pathway of proteostasis, with significant potential for MM treatment.

• Khan, Muhammad Zahoor; Li, Liangliang; Zhan, Yandong; Binjiang, Huang; Liu, Xiaotong & Kou, Xiyan [Vis alle 13 forfattere av denne artikkelen] (2025). Targeting Nrf2/KEAP1 signaling pathway using bioactive compounds to combat mastitis. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1425901. Fulltekst i vitenarkiv Vis sammendrag

  Mastitis is a common inflammation of mammary glands that has a significantly impact on dairy production and animal health, causing considerable economic burdens worldwide. Elevated reactive oxygen species (ROS) followed by oxidative stress, apoptosis, inflammatory changes and suppressed immunity are considered the key biomarkers observed during mastitis. The Nrf2/KEAP1 signaling pathway plays a critical role in regulating antioxidant responses and cellular defense mechanisms. When activated by bioactive compound treatment, Nrf2 translocates to the nucleus and induces the expression of its target genes to exert antioxidant responses. This reduces pathogen-induced oxidative stress and inflammation by inhibiting NF-kB signaling in the mammary glands, one of the prominent pro-inflammatory signaling pathway. Here, we summarize recent studies to highlight the therapeutic potential of Nrf2/KEAP1 pathway in the prevention and treatment of mastitis. Collectively this review article aims to explore the potential of bioactive compounds in mitigating mastitis by targeting the Nrf2/KEAP1 signaling pathway.

• Qadeer, Abdul; Wajid, Abdul; Rafey, Hafiz Abdul; Nawaz, Saqib; Khan, Sawar & Rahman, Sajid Ur [Vis alle 13 forfattere av denne artikkelen] (2024). Exploring extracellular vesicles in zoonotic helminth biology: implications for diagnosis, therapeutic and delivery. Frontiers in Cellular and Infection Microbiology. 14. doi: 10.3389/fcimb.2024.1424838. Fulltekst i vitenarkiv Vis sammendrag

  Extracellular vesicles (EVs) have emerged as key intercellular communication and pathogenesis mediators. Parasitic organisms’ helminths, cause widespread infections with significant health impacts worldwide. Recent research has shed light on the role of EVs in the lifecycle, immune evasion, and disease progression of these parasitic organisms. These tiny membrane-bound organelles including microvesicles and exosomes, facilitate the transfer of proteins, lipids, mRNAs, and microRNAs between cells. EVs have been isolated from various bodily fluids, offering a potential diagnostic and therapeutic avenue for combating infectious agents. According to recent research, EVs from helminths hold great promise in the diagnosis of parasitic infections due to their specificity, early detection capabilities, accessibility, and the potential for staging and monitoring infections, promote intercellular communication, and are a viable therapeutic tool for the treatment of infectious agents. Exploring host-parasite interactions has identified promising new targets for diagnostic, therapy, and vaccine development against helminths. This literature review delves into EVS’s origin, nature, biogenesis, and composition in these parasitic organisms. It also highlights the proteins and miRNAs involved in EV release, providing a comprehensive summary of the latest findings on the significance of EVs in the biology of helminths, promising targets for therapeutic and diagnostic biomarkers.

• Khan, Muhammad Zahoor; Khan, Adnan; Huang, Bingjian; Wei, Ren; Kou, Xiyan & Wang, Xinrui [Vis alle 10 forfattere av denne artikkelen] (2024). Bioactive Compounds Protect Mammalian Reproductive Cells from Xenobiotics and Heat Stress-Induced Oxidative Distress via Nrf2 Signaling Activation: A Narrative Review. Antioxidants. 13(5). doi: 10.3390/antiox13050597. Fulltekst i vitenarkiv Vis sammendrag

  Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses. It poses a significant threat to the physiological function of reproductive cells. Factors such as xenobiotics and heat can worsen this stress, leading to cellular damage and apoptosis, ultimately decreasing reproductive efficiency. The nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway plays a crucial role in defending against oxidative stress and protecting reproductive cells via enhancing antioxidant responses. Dysregulation of Nrf2 signaling has been associated with infertility and suboptimal reproductive performance in mammals. Recent advancements in therapeutic interventions have underscored the critical role of Nrf2 in mitigating oxidative damage and restoring the functional integrity of reproductive cells. In this narrative review, we delineate the harmful effects of heat and xenobiotic-induced oxidative stress on reproductive cells and explain how Nrf2 signaling provides protection against these challenges. Recent studies have shown that activating the Nrf2 signaling pathway using various bioactive compounds can ameliorate heat stress and xenobiotic-induced oxidative distress and apoptosis in mammalian reproductive cells. By comprehensively analyzing the existing literature, we propose Nrf2 as a key therapeutic target for mitigating oxidative damage and apoptosis in reproductive cells caused by exposure to xenobiotic exposure and heat stress. Additionally, based on the synthesis of these findings, we discuss the potential of therapies focused on the Nrf2 signaling pathway to improve mammalian reproductive efficiency.

• Zahoor, Muhammad; Dong, Yanchen; Preussner, Marco; Reiterer, Veronika; Alam, Sabrina Shameen & Haun, Margot [Vis alle 14 forfattere av denne artikkelen] (2024). The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development. EMBO Journal. ISSN 0261-4189. 43(19), s. 4228–4247. doi: 10.1038/s44318-024-00208-z. Fulltekst i vitenarkiv Vis sammendrag

  Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.

• Khan, Muhammad Zahoor; Chen, Wenting; Liu, Xiaotong; Kou, Xiyan; Khan, Adnan & Khan, Rahat Ullah [Vis alle 8 forfattere av denne artikkelen] (2024). An Overview of Bioactive Compounds’ Role in Modulating the Nrf2/Keap1/NF-κB Pathway to Alleviate Lipopolysaccharide-Induced Endometritis. International Journal of Molecular Sciences. ISSN 1661-6596. 25(19). doi: 10.3390/ijms251910319. Fulltekst i vitenarkiv
• Khan, Muhammad Zahoor; Li, Liangliang; Wang, Tongtong; Liu, Xiaotong; Chen, Wenting & Ma, Qingshan [Vis alle 8 forfattere av denne artikkelen] (2024). Bioactive Compounds and Probiotics Mitigate Mastitis by Targeting NF-κB Signaling Pathway. Biomolecules. 14(8). doi: 10.3390/biom14081011. Fulltekst i vitenarkiv Vis sammendrag

  Mastitis is a significant inflammatory condition of the mammary gland in dairy cows. It is caused by bacterial infections and leads to substantial economic losses worldwide. The disease can be either clinical or sub-clinical and presents challenges such as reduced milk yield, increased treatment costs, and the need to cull affected cows. The pathogenic mechanisms of mastitis involve the activation of Toll-like receptors (TLRs), specifically TLR2 and TLR4. These receptors play crucial roles in recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses through the NF-κB signaling pathway. Recent in vitro studies have emphasized the importance of the TLR2/TLR4/NF-κB signaling pathway in the development of mastitis, suggesting its potential as a therapeutic target. This review summarizes recent research on the role of the TLR2/TLR4/NF-κB signaling pathway in mastitis. It focuses on how the activation of TLRs leads to the production of proinflammatory cytokines, which, in turn, exacerbate the inflammatory response by activating the NF-κB signaling pathway in mammary gland tissues. Additionally, the review discusses various bioactive compounds and probiotics that have been identified as potential therapeutic agents for preventing and treating mastitis by targeting TLR2/TLR4/NF-κB signaling pathway. Overall, this review highlights the significance of targeting the TLR2/TLR4/NF-κB signaling pathway to develop effective therapeutic strategies against mastitis, which can enhance dairy cow health and reduce economic losses in the dairy industry.

• Khan, Muhammad Zahoor; Chen, Wenting; Naz, Saima; Liu, Xiaotong; Liang, Huili & Chen, Yinghui [Vis alle 13 forfattere av denne artikkelen] (2024). Determinant genetic markers of semen quality in livestock. Frontiers in Endocrinology. 15. doi: 10.3389/fendo.2024.1456305. Fulltekst i vitenarkiv Vis sammendrag

  The reproductive efficiency of livestock is crucial for agricultural productivity and economic sustainability. One critical factor in successful fertilization and the viability of offspring is the quality of semen. Poor semen quality, especially in frozen-thawed semen used in artificial insemination (AI) have been shown to influence conception outcomes, resulting a negative impact on livestock production. Recent advancements in genetic research have identified specific markers linked to semen quality traits in various livestock species, such as cattle, sheep, goats, pigs, buffalo, and equines. These genetic markers are essential in screening males for breeding suitability, which in turn enhances selective breeding programs. Understanding these markers is crucial for improving reproductive performance and increasing productivity in livestock populations. This review offers a comprehensive overview of the genetic markers associated with semen quality in key livestock. It explores the underlying genetic mechanisms and their practical implications in animal breeding and management. The review underscores the importance of integrating genetic insights into breeding strategies to optimize reproductive efficiency and ensure the sustainable development of livestock industries.

• Kastnes, Martin Haugrud; Aass, Kristin Roseth; Bouma, Siri Anshushaug; Årseth, Charlotte; Zahoor, Muhammad & Yurchenko, Mariya [Vis alle 7 forfattere av denne artikkelen] (2023). The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes. Frontiers in Oncology. 13. doi: 10.3389/fonc.2023.1197542. Fulltekst i vitenarkiv Vis sammendrag

  IL-32 is a pro-inflammatory cytokine expressed by several types of cancer cells and immune cells. Currently, no treatment targeting IL-32 is available, and its intracellular and exosomal localization make IL-32 less accessible to drugs. We previously showed that hypoxia promotes IL-32 expression through HIF1α in multiple myeloma cells. Here, we demonstrate that high-speed translation and ubiquitin-dependent proteasomal degradation lead to a rapid IL-32 protein turnover. We find that IL-32 protein half-life is regulated by the oxygen-sensing cysteine-dioxygenase ADO and that deubiquitinases actively remove ubiquitin from IL-32 and promote protein stability. Deubiquitinase inhibitors promoted the degradation of IL-32 and may represent a strategy for reducing IL-32 levels in multiple myeloma. The fast turnover and enzymatic deubiquitination of IL-32 are conserved in primary human T cells; thus, deubiquitinase inhibitors may also affect T-cell responses in various diseases.

• Li, Bin; Khan, Muhammad Zahoor; Khan, Ibrar Muhammad; Ullah, Qudrat; Cisang, Zhuo-Ma & Zhang, Nan [Vis alle 12 forfattere av denne artikkelen] (2023). Genetics, environmental stress, and amino acid supplementation affect lactational performance via mTOR signaling pathway in bovine mammary epithelial cells. Frontiers in Genetics. 14. doi: 10.3389/fgene.2023.1195774. Fulltekst i vitenarkiv Vis sammendrag

  Mammary glands are known for their ability to convert nutrients present in the blood into milk contents. In cows, milk synthesis and the proliferation of cow mammary epithelial cells (CMECs) are regulated by various factors, including nutrients such as amino acids and glucose, hormones, and environmental stress. Amino acids, in particular, play a crucial role in regulating cell proliferation and casein synthesis in mammalian epithelial cells, apart from being building blocks for protein synthesis. Studies have shown that environmental factors, particularly heat stress, can negatively impact milk production performance in dairy cattle. The mammalian target of rapamycin complex 1 (mTORC1) pathway is considered the primary signaling pathway involved in regulating cell proliferation and milk protein and fat synthesis in cow mammary epithelial cells in response to amino acids and heat stress. Given the significant role played by the mTORC signaling pathway in milk synthesis and cell proliferation, this article briefly discusses the main regulatory genes, the impact of amino acids and heat stress on milk production performance, and the regulation of mTORC signaling pathway in cow mammary epithelial cells.

• Bibi, Shaheen; Abbas, Ghulam; Khan, Muhammad Zahoor; Nawaz, Tanzeela; Ullah, Qudrat & Uddin, Aziz [Vis alle 11 forfattere av denne artikkelen] (2023). The mutational analysis of mitochondrial DNA in maternal inheritance of polycystic ovarian syndrome. Frontiers in Endocrinology. 14. doi: 10.3389/fendo.2023.1093353. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Polycystic Ovarian Syndrome (PCOS) is a globally prevalent condition that leads to infertility in women. While environmental factors contribute to PCOS, maternal genetics also play a significant role. Currently, there is no definitive test for identifying predisposition to PCOS. Hence, our objective is to discover novel maternal genetic risk factors for PCOS by investigating the genomes of patients from Pakistan. Methods We utilized Next-Generation Sequencing (NGS) to sequence the complete mitochondrial DNA of three PCOS patients. Subsequently, we employed MitoTIP (Mitochondrial tRNA Informatics Predictor) and PON-mt-tRNA tools to identify variations in the mitochondrial DNA. Our analysis focused on the genes MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB, which displayed common variations in all three genomes. Additionally, we observed individual variations. The D-loop region exhibited the highest frequency of mutations, followed by the non-coding regions of RNR1 and RNR2 genes. Moreover, we detected frameshift mutations in the mitochondrially encoded NADH Dehydrogenase 2 (MT-ND2) and mitochondrially encoded NADH Dehydrogenase 5 (ND5) genes within individual genomes. Results Our analysis unveiled six regions with common variations in the mitochondrial DNA of all three PCOS patients. Notably, the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes exhibited these variations. Additionally, we identified individual variations in the mitochondrial DNA. The D-loop region displayed the highest mutation frequency, followed by the non-coding regions of RNR1 and RNR2 genes. Furthermore, frameshift mutations were detected in the MT-ND2 and ND5 genes within individual genomes. Conclusion Through our study, we have identified variations in mitochondrial DNA that may be associated with the development of PCOS and have the potential to serve as predisposition tests. Our findings highlight the presence of novel mutations in the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes, as well as frameshift mutations in the MT-ND2 and ND5 genes. Pathogenicity analysis indicated that most variants were likely to result in benign cysts. However, the frameshift mutations in the ND2 gene were associated with a high risk of complications and pathogenicity in PCOS. This is the first report identifying these mutations and their association with PCOS, contributing to our understanding of the genetic factors underlying the condition.

• Ghannoum, Salim; Fantini, Damiano; Zahoor, Muhammad; Reiterer, Veronika; Phuyal, Santosh & Netto, Waldir Leoncio [Vis alle 13 forfattere av denne artikkelen] (2023). A combined experimental-computational approach uncovers a role for the Golgi matrix protein Giantin in breast cancer progression. PLoS Computational Biology. ISSN 1553-734X. 19(4). doi: 10.1371/journal.pcbi.1010995. Fulltekst i vitenarkiv Vis sammendrag

  Our understanding of how speed and persistence of cell migration affects the growth rate and size of tumors remains incomplete. To address this, we developed a mathematical model wherein cells migrate in two-dimensional space, divide, die or intravasate into the vasculature. Exploring a wide range of speed and persistence combinations, we find that tumor growth positively correlates with increasing speed and higher persistence. As a biologically relevant example, we focused on Golgi fragmentation, a phenomenon often linked to alterations of cell migration. Golgi fragmentation was induced by depletion of Giantin, a Golgi matrix protein, the downregulation of which correlates with poor patient survival. Applying the experimentally obtained migration and invasion traits of Giantin depleted breast cancer cells to our mathematical model, we predict that loss of Giantin increases the number of intravasating cells. This prediction was validated, by showing that circulating tumor cells express significantly less Giantin than primary tumor cells. Altogether, our computational model identifies cell migration traits that regulate tumor progression and uncovers a role of Giantin in breast cancer progression.

• Yaqoob, Khurram; Amjad, Izza; Awan, Muhammad Awais Munir; Liaqat, Usman; Zahoor, Muhammad & Kashif, Muhammad (2023). Novel Method for the Production of Titanium Foams to Reduce Stress Shielding in Implants. ACS Omega. 8(2), s. 1876–1884. doi: 10.1021/acsomega.2c02340. Fulltekst i vitenarkiv Vis sammendrag

  Titanium foams have potential applications in orthopedic and dental implants because of their low elastic modulus and good bone in-growth properties. In the present study, a novel method for the preparation of three-dimensional interconnected microporous titanium foams has been developed. This method is based on the insertion of a filler metal into the titanium metal by arc melting, followed by its removal by an electrochemical dealloying process for the development of foams. Complete removal of the filler metal by the electrochemical dealloying process was confirmed by an X-ray diffractometry (XRD) analysis, whereas scanning electron microscopy (SEM) analysis of the developed foams showed the development of interconnected porosity. Ti foams with different levels of porosities were successfully developed by varying the amount of the filler metal. Mechanical and thermal characterizations of the developed foams were carried out using compression testing and laser flash apparatus, respectively. The yield strength and elastic modulus of the developed foams were found to decrease by increasing the volume fraction of pores. The elastic modulus of the developed titanium foams (15.5–36 GPa) was found to be closer to that of human bones, whereas their yield strength (147–170 MPa) remained higher than that of human bones. It is therefore believed that the developed Ti foams can help in reducing the problem of stress shielding observed in orthopedic implants. The thermal diffusivity of the developed foams (4.3–0.69 mm2/s) was found to be very close to that of human dentine.

• Aass, Kristin Roseth; Mjelle, Robin; Kastnes, Martin Haugrud; Tryggestad, Synne Stokke; Brink, Luca Mare van den & Roseth, Ingrid Aass [Vis alle 19 forfattere av denne artikkelen] (2021). Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells. iScience. 25(1). doi: 10.1016/j.isci.2021.103605. Fulltekst i vitenarkiv Vis sammendrag

  Interleukin-32 (IL-32) is a nonclassical cytokine expressed in cancers, inflammatory diseases, and infections. Its expression is regulated by two different oxygen sensing systems; HIF1α and cysteamine dioxygenase (ADO), indicating that IL-32 may be involved in the response to hypoxia. We here demonstrate that endogenously expressed, intracellular IL-32 interacts with components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in three myeloma cell lines reduced cell survival and proliferation in vitro and in vivo. High-throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that cells depleted of IL-32 had perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors, and citrate. IL-32 was expressed in a subgroup of myeloma patients with inferior survival, and primary myeloma cells expressing IL-32 had a gene signature associated with immaturity, proliferation, and oxidative phosphorylation. In conclusion, we demonstrate a previously unrecognized role of IL-32 in the regulation of plasma cell metabolism.

• Westhrin, Marita; Holien, Toril; Zahoor, Muhammad; Moen, Siv Helen; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 16 forfattere av denne artikkelen] (2020). Bone Morphogenetic Protein 4 Gene Therapy in Mice Inhibits Myeloma Tumor Growth, But Has a Negative Impact on Bone. JBMR Plus. 4(1). doi: 10.1002/jbm4.10247. Fulltekst i vitenarkiv Vis sammendrag

  Multiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre‐ and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4‐treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human‐mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2−/− γC−/−mice. Mice were treated with adeno‐associated virus serotype 8 BMP4 vectors (AAV8‐BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8‐BMP4 mice compared with the AAV8‐CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4‐treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non‐myeloma femurs by μCT. Surprisingly, the AAV8‐BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8‐CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

• Khan, Muzamil Ahmad; Hussain, Zakir; Liaqat, Usman; Liaqat, Muhammad Arman & Zahoor, Muhammad (2020). Preparation of pbs/plla/hap composites by the solution casting method: Mechanical properties and biocompatibility. Nanomaterials. 10(9), s. 1–15. doi: 10.3390/nano10091778. Fulltekst i vitenarkiv Vis sammendrag

  The use of biodegradable polymeric scaffolds for tissue regeneration is becoming a common practice in the clinic. Therefore, an inclined trend is developing with regards to improving the mechanical properties of these scaffolds. Here, we aim to improve the mechanical properties of poly (butylene succinate) (PBS)/poly (l-lactic acid) (PLLA) blends by incorporating hydroxyapatite nanoparticles (HAP) in the blends to form composites. PBS/PLLA = 100/0, 95/5, 90/10, 85/15, and 0/100 wt% blends, along-with the loadings of a few mg of HAPs, were prepared using the solution casting method. A scanning electron microscope showed the voids and droplets, indicating the immiscibility of blends. Due to this immiscibility, the tensile strength values of the blends were found to be in between that of pure PBS (42.85 MPa) and pure PLLA (31.39 MPa). HAPs act as a compatibilizer by incorporating themselves in the voids and spaces caused by the immiscibility, thus increasing the overall tensile strength of the resulting composite to a certain extent, e.g., the tensile strength of PBS/PLLA = 95/5 loaded with 50 mg HAPs was found to be 51.16 MPa. The structural analysis employing the X-ray diffraction (XRD) patterns confirmed the formation of polymer blends and composites. The contact angle analysis showed that the addition of HAPs increased the hydrophilicity of the resulting composites. Selective samples were investigated based on mechanical properties to see if the blends and composites are biocompatible. The obtained results showed that all of the samples with better mechanical properties demonstrated good biocompatibility. This indicates the effectiveness of scaffolds for tissue regeneration.

• Gilljam, Karin Margaretha; Holm, Kristine Lillebø; Zahoor, Muhammad; Centonze, Federica Grazia; Farhan, Hesso & Blomhoff, Heidi Kiil (2020). Differential Effects of Reactive Oxygen Species on IgG versus IgM Levels in TLR-Stimulated B Cells. Journal of Immunology. ISSN 0022-1767. 204(8), s. 2133–2142. doi: 10.4049/jimmunol.1901131. Fulltekst i vitenarkiv
• Beig, Bilal; Liaqat, Usman; Niazi, Muhammad Farooq Khan; Douna, Inamullah; Zahoor, Muhammad & Niazi, Muhammad Bilal Khan (2020). Current challenges and innovative developments in hydroxyapatite-based coatings on metallic materials for bone implantation: A review. Coatings. 10(12), s. 1–29. doi: 10.3390/coatings10121249. Fulltekst i vitenarkiv Vis sammendrag

  Biomaterials are in use for the replacement and reconstruction of several tissues and organs as treatment and enhancement. Metallic, organic, and composites are some of the common materials currently in practice. Metallic materials contribute a big share of their mechanical strength and resistance to corrosion properties, while organic polymeric materials stand high due to their biocompatibility, biodegradability, and natural availability. To enhance the biocompatibility of these metals and alloys, coatings are frequently applied. Organic polymeric materials and ceramics are extensively utilized for this purpose due to their outstanding characteristics of biocompatibility and biodegradability. Hydroxyapatite (HAp) is the material from the ceramic class which is an ultimate candidate for coating on these metals for biomedical applications. HAp possesses similar chemical and structural characteristics to normal human bone. Due to the bioactivity and biocompatibility of HAp, it is used for bone implants for regenerating bone tissues. This review covers an extensive study of the development of HAp coatings specifically for the orthopaedic applications that include different coating techniques and the process parameters of these coating techniques. Additionally, the future direction and challenges have been also discussed briefly in this review, including the coating of HAp in combination with other calcium magnesium phosphates that occur naturally in human bone.

• Cui, Yixian; Parashar, Smriti; Zahoor, Muhammad; Needham, Patrick; Mari, Muriel & Zhu, Ming [Vis alle 12 forfattere av denne artikkelen] (2019). A COPII subunit acts with an autophagy receptor to target endoplasmic reticulum for degradation. Science. ISSN 0036-8075. 365(6448), s. 53–60. doi: 10.1126/science.aau9263. Fulltekst i vitenarkiv Vis sammendrag

  The COPII-cargo adaptor complex Lst1-Sec23 selectively sorts proteins into vesicles that bud from the endoplasmic reticulum (ER) and traffic to the Golgi. Improperly folded proteins are prevented from exiting the ER and are degraded. ER-phagy is an autophagic degradation pathway that uses ER-resident receptors. Working in yeast, we found an unexpected role for Lst1-Sec23 in ER-phagy that was independent from its function in secretion. Up-regulation of the stress-inducible ER-phagy receptor Atg40 induced the association of Lst1-Sec23 with Atg40 at distinct ER domains to package ER into autophagosomes. Lst1-mediated ER-phagy played a vital role in maintaining cellular homeostasis by preventing the accumulation of an aggregation-prone protein in the ER. Lst1 function appears to be conserved because its mammalian homolog, SEC24C, was also required for ER-phagy.

• Farhan, Hesso & Zahoor, Muhammad (2018). Crosstalk of Autophagy and the Secretory Pathway and Its Role in Diseases. International Review of Cell and Molecular Biology. ISSN 1937-6448. 337, s. 153–184. doi: 10.1016/bs.ircmb.2017.12.004. Fulltekst i vitenarkiv Vis sammendrag

  The secretory and autophagic pathways are two fundamental, evolutionary highly conserved endomembrane processes. Typically, secretion is associated with biosynthesis and delivery of proteins. In contrast, autophagy is usually considered as a degradative pathway. Thus, an analogy to metabolic pathways is evident. Anabolic (biosynthetic) and catabolic (degradative) pathways are usually intimately linked and intertwined, and likewise, the secretory and autophagy pathways are intertwined. Investigation of this link is an emerging area of research, and we will provide an overview of some of the major advances that have been made to contribute to understanding of how secretion regulates autophagy and vice versa. Finally, we will highlight evidence that supports a potential involvement of the autophagy-secretion crosstalk in human diseases.

• Khan, Muhammad Zahoor & Zahoor, Muhammad (2018). An overview of brucellosis in cattle and humans, and its serological and molecular diagnosis in control strategies. Tropical Medicine and Infectious Disease. 3:65(2), s. 1–14. doi: 10.3390/tropicalmed3020065. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Westhrin, Marita; Aass, Kristin Roseth; Moen, Siv Helen; Misund, Kristine & Psonka-Antonczyk, Katarzyna Maria [Vis alle 12 forfattere av denne artikkelen] (2017). Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss. Blood Advances. ISSN 2473-9529. 27(1), s. 2656–2666. doi: 10.1182/bloodadvances.2017010801. Fulltekst i vitenarkiv Vis sammendrag

  Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α–dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients.

• Moen, Siv Helen; Westhrin, Marita; Zahoor, Muhammad; Nørgaard, Nikolai Nordberg; Hella, Hanne & Størdal, Berit Fladvad [Vis alle 10 forfattere av denne artikkelen] (2016). Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells. Immunity,Inflammation and Disease. 4(3), s. 327–337. doi: 10.1002/iid3.117. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs). Methods: Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase-8 were silenced using siRNA. Caspase-8 was also inhibited using a caspase-8 inhibitor, z-IEDT. Results: We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro-inflammatory cytokines in a TLR-dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti-inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1β, IL-6, CXCL10, and in the inhibition of HGF and TGFβ. Conclusion: Caspase-8 appears to modulate hBMSCs into gaining a pro-inflammatory phenotype. Therefore, inhibiting caspase-8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.

• Zahoor, Muhammad; Cha, Pu-Hyeon; Min, Do Sik & Choi, Kang-Yell (2014). Indirubin‐3′‐Oxime Reverses Bone Loss in Ovariectomized and Hindlimb‐Unloaded Mice Via Activation of the Wnt/β‐Catenin Signaling. Journal of Bone and Mineral Research. ISSN 0884-0431. 29(5), s. 1196–1205. doi: 10.1002/jbmr.2147. Fulltekst i vitenarkiv
• Cha, Pu-Hyeon; Shin, Wookjin; Zahoor, Muhammad; Kim, Hyun-Yi; Min, Do Sik & Choi, Kang Yell (2014). Hovenia dulcis Thunb Extract and Its Ingredient Methyl Vanillate Activate Wnt/β-Catenin Pathway and Increase Bone Mass in Growing or Ovariectomized Mice. PLOS ONE. 9(1), s. e85546–e85546. doi: 10.1371/journal.pone.0085546. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Cha, Pu-Hyeon; Min, Do Sik & Choi, Kang-Yell (2014). Indirubin‐3′‐Oxime Reverses Bone Loss in Ovariectomized and Hindlimb‐Unloaded Mice Via Activation of the Wnt/β‐Catenin Signaling. Journal of Bone and Mineral Research. ISSN 0884-0431. 29(5), s. 1196–1205. doi: 10.1002/jbmr.2147. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Cha, Pu-Hyeon & Choi, Kang Yell (2014). Indirubin-3’-oxime, an activator of Wnt/β-catenin signaling, enhances osteogenic commitment of ST2 cells and restores bone loss in high fat diet-induced obese male mice. Bone. ISSN 8756-3282. 65, s. 60–68. doi: 10.1016/j.bone.2014.05.003. Fulltekst i vitenarkiv

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• Holien, Toril; Westhrin, Marita; Zahoor, Muhammad; Moen, Siv Helen; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 16 forfattere av denne artikkelen] (2019). BMP4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone. Fulltekst i vitenarkiv
• Aass, Kristin Roseth; Mjelle, Robin; Westhrin, Marita; Zahoor, Muhammad; Yurchenko, Mariya & Buene, Glenn [Vis alle 10 forfattere av denne artikkelen] (2019). IL-32 is a novel growth factor and metabolic regulator in multiple myeloma cells. Fulltekst i vitenarkiv
• Aass, Kristin Roseth; Mjelle, Robin; Zahoor, Muhammad; Yurchenko, Mariya; Westhrin, Marita & Buene, Glenn [Vis alle 10 forfattere av denne artikkelen] (2019). IL-32 is a novel growth factor and metabolic regulator for multiple myeloma cells. Fulltekst i vitenarkiv
• Holien, Toril; Westhrin, Marita; Zahoor, Muhammad; Moen, Siv Helen; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 16 forfattere av denne artikkelen] (2019). BMP4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone. Fulltekst i vitenarkiv
• Holien, Toril; Westhrin, Marita; Moen, Siv Helen; Zahoor, Muhammad; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 9 forfattere av denne artikkelen] (2018). BMP4 gene therapy inhibits myeloma tumor growth, but has a negative impact on bone. Fulltekst i vitenarkiv
• Holien, Toril; Westhrin, Marita; Moen, Siv Helen; Zahoor, Muhammad; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 15 forfattere av denne artikkelen] (2018). BMP4 Gene Therapy Inhibits Myeloma Tumor Growth, but Has a Negative Impact on Bone. Blood. ISSN 0006-4971. 132, s. 1928–1928. doi: 10.1182/blood-2018-99-112429. Fulltekst i vitenarkiv
• Zahoor, Muhammad (2018). Imaged-based RNAi Screen Identifies Autophagy and Secretion Intersecting Nodes. Fulltekst i vitenarkiv
• Holien, Toril; Westhrin, Marita; Moen, Siv Helen; Zahoor, Muhammad; Buene, Glenn & Størdal, Berit Fladvad [Vis alle 15 forfattere av denne artikkelen] (2018). BMP4 Gene Therapy Inhibits Myeloma Tumor Growth, but Has a Negative Impact on Bone. Fulltekst i vitenarkiv
• Standal, Therese; Westhrin, Marita; Zahoor, Muhammad; Aass, Kristin Roseth & Moen, Siv Helen (2017). IL-32 in multiple myeloma. Fulltekst i vitenarkiv
• Standal, Therese; Zahoor, Muhammad; Westhrin, Marita & Moen, Siv Helen (2016). IL-32 is produced by myeloma cells in response to hypoxia: potential role for exosomal IL-32 in multiple myeloma bone disease. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Westhrin, Marita; Moen, Siv Helen & Standal, Therese (2016). IL-32 is produced by myeloma cells in response to hypoxia: potential role for exosomal IL-32in multiple myeloma bone disease. Fulltekst i vitenarkiv
• Moen, Siv Helen; Westhrin, Marita; Zahoor, Muhammad & Standal, Therese (2016). Caspase-8 regulates the expresion of pro- and anti-inflammatory cytokines in human bone marrow-dervied mesenchymal stromal cells. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Westhrin, Marita; Moen, Siv Helen & Standal, Therese (2016). Myeloma cells secrete IL-32 in response to hypoxia: a potential role for exosomal IL-32in multiple myeloma bone disease. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Westhrin, Marita; Moen, Siv Helen & Standal, Therese (2016). IL-32 is produced by myeloma cells in response to hypoxia: potential role for exosomal IL-32in multiple myeloma bone disease. Fulltekst i vitenarkiv
• Zahoor, Muhammad; Westhrin, Marita; Moen, Siv Helen & Standal, Therese (2016). IL-32 is produced by myeloma cells in response to hypoxia: potential role for exosomal IL-32in multiple myeloma bone disease (Oral presentation). Fulltekst i vitenarkiv

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