IUBMB Life最新文献

Heavy metals, a major source of pollution in the environment, pose a substantial threat due to their non-biodegradability and ability to accumulate in living organisms, causing health problems. Recently, researchers have been searching for cost-effective and safe ways to remove heavy metals from polluted waterways using agricultural waste substitutes. The present study focused on the low-cost treatments for the reduction of chromium Cr⁺⁶ metal from the effluent, wherein it has been found that chemically and bacterially treated agro-waste had increased heavy metal ion adsorption capabilities. A sequential optimization of the process parameters was attempted using Plackett–Burman design (PBD) and central composite design of response surface methodology (CCD-RSM) for the maximum reduction of the chromium metal from the effluent. A total of eight parameters were screened out using a 12-run PBD experiment. Out of the eight parameters, time, HCl, NaOH, and bacterial treatments were found to be significantly affecting the maximum reduction of Cr⁺⁶ from the effluent. To investigate the interactions' effects of the chosen parameters, they were evaluated using CCD-RSM. Maximum 74% Cr⁺⁶ reduction was achieved under the optimum treatment to rice husk of HCl 4.52 N, NaOH 3.53 N, bacterial suspension 7.41%, and with an interaction time 14.32 min using 30 run CCD-RSM experiment. A scanning electron microscope was used to confirm the effects of selected variables on the agro-waste for the Cr⁺⁶ reductions, as well as a Fourier transform infrared spectrometer.

In 2020, the number of deaths caused by lung cancer worldwide reached 1,796,144, making it the leading cause of cancer-related deaths. Cyclooxygenase-2/prostaglandin endoperoxide synthase 2 (COX-2/PTGS2) is overexpressed in lung cancer, which promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that the oligonucleotide drug HQi-sRNA-2 from Traditional Chinese Medicine Huangqin targeting COX-2/PTGS2 significantly inhibited proliferation, migration, and invasion and induced apoptosis in the human lung cancer cell line NCI-H460. Oral delivery of HQi-sRNA-2 bencaosomes prolonged survival, reduced tumor burden, and maintained weight in a spontaneous mouse lung cancer model. Compared with paclitaxel, HQi-sRNA-2 may be less toxic and have approximately equal efficacy in reducing tumor burden. Our previous studies reported that herbal small RNAs (sRNAs) are functional medical components. Our data suggest that sphingosine (d18:1)-HQi-sRNA-2 bencaosomes, targeting COX-2/PTGS2 and downregulating the PI3K and AKT signaling pathways, may provide novel therapeutics for lung cancer.

The utilization of anti-CD3/CD28 magnetic beads for T cell expansion in vitro has been investigated for adoptive cell transfer therapy. However, the impact of the CD3/CD28 antibody ratio on T cell differentiation and function remains incompletely elucidated. This study seeks to address this knowledge gap. To begin with, CD3 antibodies with a relatively low avidity for Jurkat cells (Kd = 13.55 nM) and CD28 antibodies with a relatively high avidity (Kd = 5.79 nM) were prepared. Afterwards, anti-CD3/CD28 antibodies with different mass ratios were attached to magnetic beads to examine the impacts of different antibody ratios on T cell capture, and proliferation. The research demonstrated that the most significant expansion of T cells was stimulated by the anti-CD3/CD28 magnetic beads with a mass ratio of 2:1 for CD3 antibodies and CD28 antibodies. Moreover, CD25 and PD1 expression of expanded T cells increased and then decreased, with lower CD25 and PD1 expression in the later stages of expansion indicating that T cells were not depleted. These T cells, which are massively expanded in vitro and have excellent expansion potential, can be infused back into the patient to treat tumor patients. This study shows that altering the ratio of anti-CD3/CD28 antibodies can control the strength of T cell stimulation, thereby leading to the improvement of T cell activation. This discovery can be utilized as a guide for the creation of other T cell stimulation approaches, which is beneficial for the further development of tumor immunotherapy technology.

Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.

Cryomyces antarcticus, a melanized cryptoendolithic fungus endemic to Antarctica, can tolerate environmental conditions as severe as those in space. Particularly, its ability to withstand ionizing radiation has been attributed to the presence of thick and highly melanized cell walls, which—according to a previous investigation—may contain both 1,8-dihydroxynaphthalene (DHN) and L-3,4 dihydroxyphenylalanine (L-DOPA) melanin. The genes putatively involved in the synthesis of DHN melanin were identified in the genome of C. antarcticus. Most important is capks1 encoding a non-reducing polyketide synthase (PKS) and being the ortholog of the functionally characterized kppks1 from the rock-inhabiting fungus Knufia petricola. The co-expression of CaPKS1 or KpPKS1 with a 4′-phosphopantetheinyl transferase in Saccharomyces cerevisiae resulted in the formation of a yellowish pigment, suggesting that CaPKS1 is the enzyme providing the precursor for DHN melanin. To dissect the composition and function of the melanin layer in the outer cell wall of C. antarcticus, non-melanized mutants were generated by CRISPR/Cas9-mediated genome editing. Notwithstanding its slow growth (up to months), three independent non-melanized Δcapks1 mutants were obtained. The mutants exhibited growth similar to the wild type and a light pinkish pigmentation, which is presumably due to carotenoids. Interestingly, visible light had an adverse effect on growth of both melanized wild-type and non-melanized Δcapks1 strains. Further evidence that light can pass the melanized cell walls derives from a mutant expressing a H2B-GFP fusion protein, which can be detected by fluorescence microscopy. In conclusion, the study reports on the first genetic manipulation of C. antarcticus, resulting in non-melanized mutants and demonstrating that the melanin is rather of the DHN type. These mutants will allow to elucidate the relevance of melanization for surviving extreme conditions found in the natural habitat as well as in space.

Osteoporosis (OP) is a systemic metabolic bone disease resulting in reduced bone strength and increased susceptibility to fractures, making it a significant public health and economic problem worldwide. The clinical use of anti-osteoporosis agents is limited because of their serious side effects or the high cost of long-term use. The Xianlinggubao (XLGB) formula is an effective traditional Chinese herbal medicine commonly used in orthopedics to treat osteoporosis; however, its mechanism of action remains unclear. In this study, we screened 40 small RNAs derived from XLGB capsules and found that XLGB28-sRNA targeting TNFSF11 exerted a significant anti-osteoporosis effect in vitro and in vivo by simultaneously promoting osteogenesis and inhibiting osteoclastogenesis. Oral administration of bencaosome [16:0 Lyso PA+XLGB28-sRNA] effectively improved bone mineral density and reduced the damage to the bone microstructure in mice. These results suggest that XLGB28-sRNA may be a novel oligonucleotide drug that promotes osteogenesis and inhibits osteoclastogenesis in mice.

Clinical data from over two decades, involving more than 3000 treated patients, demonstrate that adeno-associated virus (AAV) gene therapy is a safe, effective, and well-tolerated therapeutic method. Clinical trials using AAV-mediated gene delivery to accessible tissues have led to successful treatments for numerous monogenic disorders and advancements in tissue engineering. Although the US Food and Drug Administration (FDA) has approved AAV for clinical use, systemic administration remains a significant challenge. In this review, we delve into AAV biology, focusing on current manufacturing technologies and transgene engineering strategies. We examine the use of AAVs in ongoing clinical trials for ocular, neurological, and hematological disorders, as well as cancers. By discussing recent advancements and current challenges in the field, we aim to provide valuable insights for researchers and clinicians navigating the evolving landscape of AAV-based gene therapy.

Aegerolysin proteins are involved in various interactions by recognising a molecular receptor in the target organism. The formation of pores in combination with larger, non-aegerolysin-like protein partners (such as membrane attack complex/perforin proteins [MACPFs]) is one of the possible responses in the presumed competitive exclusion of other organisms from the ecological niche. Bicomponent pairs are already observed at the gene level. Fungi growing under extreme conditions can be divided into ubiquitous and extremotolerant generalists which can compete with mesophilic species and rare, isolated extremophilic and extremotolerant specialists with narrow ecological amplitude that cannot compete. Under extreme conditions, there are fewer competitors, so fungal specialists generally produce less diverse and complicated profiles of specialised molecules. Since extremotolerant and extremophilic fungi have evolved in numerous branches of the fungal tree of life and aegerolysins are unevenly distributed across fungal genomes, we investigated whether aegerolysins, together with their partner proteins, contribute to the extreme survival ecology of generalists and specialists. We compiled a list of 109 thermo-, psihro-, acido-, alkali-, halo-, metallo- and polyextremo-tolerant/-philic fungal species. Several challenges were identified that affected the outcome: renaming fungal species, defining extremotolerant/extremophilic traits, identifying extremotolerant/extremophilic traits as metadata in databases and linking fungal isolates to fungal genomes. The yield of genomes coding aegerolysins or MACPFs appears to be lower in extremotolerant/extremophilic fungi compared to all fungal genomes. No candidates for pore-forming gene pairs were identified in the genomes of extremophilic fungi. Aegerolysin and MACPFs partner pairs were identified in only two of 69 species with sequenced genomes, namely in the ubiquitous metallotolerant generalists Aspergillus niger and A. foetidus. These results support the hypothesised role of these pore-forming proteins in competitive exclusion.

DNA–protein crosslinks (DPC) are common DNA lesions induced by various external and endogenous agents. One of the sources of DPC is the apurinic/apyrimidinic site (AP site) and proteins interacting with it. Some proteins possessing AP lyase activity form covalent complexes with AP site-containing DNA without borohydride reduction (suicidal crosslinks). We have shown earlier that tyrosyl-DNA phosphodiesterase 1 (TDP1) but not AP endonuclease 1 (APE1) is able to remove intact OGG1 from protein–DNA adducts, whereas APE1 is able to prevent the formation of DPC by hydrolyzing the AP site. Here we demonstrate that TDP1 can remove intact PARP2 but not XRCC1 from covalent enzyme–DNA adducts with AP-DNA formed in the absence of APE1. We also analyzed an impact of APE1 and TDP1 on the efficiency of DPC formation in APE1^−/− or TDP1^−/− cell extracts. Our data revealed that APE1 depletion leads to increased levels of PARP1–DNA crosslinks, whereas TDP1 deficiency has little effect on DPC formation.

tRNAs are not only essential for decoding the genetic code, but their abundance also has a strong impact on the rate of protein production, folding, and on the stability of the translated messenger RNAs. Plasmodium expresses a unique surface protein called tRip, involved in the import of exogenous tRNAs into the parasite. Comparative proteomic analysis of the blood stage of wild-type and tRip-KO variant of P. berghei parasites revealed that downregulated proteins in the mutant parasite are distinguished by a bias in their asparagine content. Furthermore, the demonstration of the possibility of charging host tRNAs with Plasmodium aminoacyl-tRNA synthetases led us to propose that imported host tRNAs participate in parasite protein synthesis. These results also suggest a novel mechanism of translational control in which import of host tRNAs emerge as regulators of gene expression in the Plasmodium developmental cycle and pathogenesis, by enabling the synthesis of asparagine-rich regulatory proteins that efficiently and selectively control the parasite infectivity.